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Analysis of D/D translocations in man by differential staining Wilson, Robert Douglas 1974

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ANALYSIS OF D/D TRANSLOCATIONS IN MAN BY DIFFERENTIAL STAINING  by  ROBERT DOUGLAS WILSON B.Sc,  University  of B r i t i s h Columbia, 1971  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE  i n the Department of Medical  We accept t h i s required  Genetics  t h e s i s as conforming  to the  standard  THE UNIVERSITY OF BRITISH COLUMBIA DECEMBER,  19 74  In p r e s e n t i n g t h i s  thesis  an advanced degree at  further  for  freely  of  the  requirements  B r i t i s h Columbia, I agree  available  for  t h a t p e r m i s s i o n f o r e x t e n s i v e copying o f  this  representatives. thesis for  It  financial  that  this  thesis or  i s understood that copying or p u b l i c a t i o n gain s h a l l not be allowed without my  written permission.  Department  for  reference and study.  s c h o l a r l y purposes may be granted by the Head of my Department  by h i s of  agree  fulfilment  the U n i v e r s i t y of  the L i b r a r y s h a l l make it I  in p a r t i a l  of  The U n i v e r s i t y o f B r i t i s h Columbia Vancouver 8, Canada  ABSTRACT With the advent of new c y t o g e n e t i c t e c h n i q u e s , more quest i o n s can be answered concerning chromosomal rearrangements. questions  The  c o n s i d e r e d i n t h i s study ask which chromosomes are i n -  v o l v e d i n the t(Dq Dq) t r a n s l o c a t i o n , where are l o c a t e d , and what are l o c a t i o n formation.  the p o s s i b l e  the break  points  mechanisms of t(Dq Dq)  trans-  The s e g r e g a t i o n p a t t e r n of the D/D t r a n s l o -  c a t i o n was c o n s i d e r e d when the chromosome t r a n s l o c a t i o n was shown to be f a m i l i a l . Chromosomes were obtained from leukocyte b l o o d c u l t u r e s and  three d i f f e r e n t i a l  fluorescent-banding,  s t a i n i n g techniques  C-banding) were used to i d e n t i f y the chromo-  somes i n v o l v e d i n the D/D t r a n s l o c a t i o n . allowed the break p o i n t s families  and a s i n g l e  (Giemsa-banding,  These techniques  also  i n each chromosome to be e s t i m a t e d .  spontaneous  case were examined.  The seg-  r e g a t i o n p a t t e r n of the t(Dq Dq) t r a n s l o c a t i o n was d i s c u s s e d the f a m i l i a l t r a n s l o c a t i o n s .  The p o s s i b l e  t i o n of these D/D t r a n s l o c a t i o n s  was a l s o  Four  for  mechanisms of formadiscussed.  The c y t o g e n e t i c i n v e s t i g a t i o n r e v e a l e d these general r e sults . 1.  A homologous t(14q;14q)  chromosome, which appeared  be monocentric, was found i n a male i n f a n t who was  ascertained  to  through an i n v e s t i g a t i o n 2.  A homologous  of h i s  short  t(13q;13q)  stature.  chromosome, which appeared  be d i c e n t r i c , was found i n a family who was a s c e r t a i n e d the b i r t h of a male with numerous c o n g e n i t a l 3.  A t(13q;14q)  translocation  through  malformations.  chromosome, which  appeared  to be d i c e n t r i c , was found i n a family who was a s c e r t a i n e d the b i r t h of a mentally r e t a r d e d 4.  A t(13q;14q)  t r a n s l o c a t i o n chromosome, which  through the b i r t h of a mentally r e t a r d e d A t(13q;14q)  translocation  through  male.  to be monocentric, was found i n a family who was  5.  to  translocation  appeared  ascertained  male.  chromosome and a t(13p;14p)  chromosome was found i n a family who was  through the b i r t h of a mentally r e t a r d e d  male.  ascertained  TABLE OF CONTENTS  ABSTRACT TABLE OF CONTENTS LIST OF TABLES LIST OF FIGURES LIST OF APPENDICES ACKNOWLEDGEMENTS Chapter I.  INTRODUCTION A.  Chromosomal rearrangement which r e s u l t s in the formation of a t(Dq Dq) t r a n s l o cation  B.  Incidence of the t(Dq Dq) i n the p o p u l a t i o n  C.  Chromosomal c o n s t i t u t i o n translocation  translocation of the t(Dq Dq)  D. Segregation p a t t e r n s o f t(Dq Dq) t r a n s locations  II.  E.  F e r t i l i t y i n balanced zygotes  t(Dq Dq)  F.  Other aspects of the t(Dq Dq) cation  heterotranslo-  MATERIALS AND METHODS A. Experimental  procedures  1.  Fluorescent  2.  Trypsin-Giemsa banding and analys iv  banding and a n a l y s i s  3. B. III.  IV.  C-banding and a n a l y s i s  C r i t e r i a for e s t a b l i s h i n g the p a t i e n t ' s karyotype  RESULTS  17 17 19  Case 1  19  Case 2  26  Case 3  37  Case 4  48  Case 5  62  DISCUSSION  75  A . Segregation of the t(Dq Dq) t r a n s l o c a t i o n s  B.  75  1. Homologous t(Dq Dq) t r a n s l o c a t i o n s  75  2. Non-homologous t(Dq Dq) t r a n s l o c a tions  79  P o s s i b l e mechanisms of formation of the t(Dq  Dq) t r a n s l o c a t i o n  C. C l i n i c a l  and chromosome a s s o c i a t i o n s  LITERATURE. CITED  81 86 98  APPENDIX  108  v  LIST OF TABLES Table  Page  1.  Analysis  of c e l l  chromosome number f o r pedigree 1  22  2.  Analysis  of c e l l  chromosome number for pedigree 2  30  3.  Analysis of c e l l  chromosome n umb e r for pedigree 3  41  4.  Analysis  of c e l l  chromosome number f o r pedigree 4  53  5.  Analysis  of c e l l  chromosome number f o r pedigree 5  67  6.  Comparison of c l i n i c a l  signs; f o r  vi  trisomy-13  93  LIST OF FIGURES Figure  Page  1.  Pedigree  - case 1  22  2.  Giemsa-banded karyotype - proband case 1  23  3.  P a r t i a l Giemsa-banded karyotype - proband case 1  23  4.  F l u o r e s c e n t karyotype - proband case 1  24  5.  C-banded karyotype - proband'case 1  24  6.  Schematic diagram of D/D t r a n s l o c a t i o n  7.  Pedigree  8.  Unhanded karyotype - proband case 2  31  9.  A n t e r i o r and f u l l  31  - case 1  - case 2  25 30  l e n g t h view - proband case 2  10.  Hand and foot of proband case 2 with e x t r a  11.  L a t e r a l view of head - proband case 2  12.  Giemsa-banded karyotype - i n d i v i d u a l 2 - 1 - 4  13.  P a r t i a l Giemsa-banded karyotype - i n d i v i d u a l pedigree 2 - 1 - 4  33  14.  P a r t i a l Giemsa-banded karyotype - i n d i v i d u a l pedigree 2 - 1 - 4  34  15.  P a r t i a l f l u o r e s c e n t karyotype 13/13 t r a n s l o c a t i o n chromosome, chromosome 14 p a i r , chromosome 15 p a i r , s i n g l e chromosome 3 - i n d i v i d u a l pedigree 2 - 1 - 4  34  16.  C-banded karyotype - i n d i v i d u a l pedigree 2 - 1 - 4  " 35  17.  Schematic diagram of D/D t r a n s l o c a t i o n  36  vii  digit  32 32  pedigree  - case 2  33  18.  Pedigree  - case 3  41  19.  Giemsa-banded karyotype - i n d i v i d u a l 3 - 1 - 1  20.  F l u o r e s c e n t Karyotype - i n d i v i d u a l 3 - 1 - 1  21.  Giemsa-banded karyotype - proband case 3  22.  Giemsa-banded karyotype - i n d i v i d u a l  pedigree  pedigree  42 42 43  pedigree  3 - 1 - 4  43  23.  P a r t i a l Giemsa-banded karyotype - proband case 3  44  24.  F l u o r e s c e n t karyotype - proband case 3  44  25.  F l u o r e s c e n t karyotype - i n d i v i d u a l pedigree 3- 1 - 4 P a r t i a l f l u o r e s c e n t karyotype - s i n g l e chromosome 13, 13./14 t r a n s l o c a t i o n chromosome, s i n g l e chromosome 14, chromosome 15 p a i r - proband case 3  45  27.  C-banded karyotype - proband case 3  46  28.  Schematic diagram of D/D t r a n s l o c a t i o n  29.  Pedigree  30.  Giemsa-banded karyotype - i n d i v i d u a l 4 - 1 - 15  26.  - case 3  - case 4  45  47 52  pedigree 54,  31.  F l u o r e s c e n t karyotype - i n d i v i d u a l 4- 1-15  32.  Giemsa-banded karyotype - proband case 4  55  33.  Giemsa-banded karyotype - i n d i v i d u a l 4 - 1 - 2  pedigree  55  34.  Giemsa-banded karyotype - i n d i v i d u a l 4 - 0 - 1 1  pedigree  35.  Giemsa-banded karyotype - i n d i v i d u a l 4 - 0 - 1 2  pedigree  36.  F l u o r e s c e n t karyotype - proband case 4  57  37.  F l u o r e s c e n t karyotype - i n d i v i d u a l 4 - 1 - 2  57  viii  pedigree  pedigree  54  56 56  38.  F l u o r e s c e n t karyotype - i n d i v i d u a l 4 - 0 - 1 1  pedigree  39.  F l u o r e s c e n t karyotype - i n d i v i d u a l 4 - 0 - 1 2  pedigree  40.  P a r t i a l f l u o r e s c e n t karyotype s i n g l e chromosome 13, 1 3 / 1 4 t r a n s l o c a t i o n chromosome, s i n g l e chromosome 14, chromosome 15 p a i r - proband case 4  41.  C-banded karyotype - i n d i v i d u a l 4-  58 58  59  pedigree  1-2  59  42.  P a r t i a l C-banded karyotype - proband case 4  60  43. 44.  Schematic diagram of D/D t r a n s l o c a t i o n Pedigree - case 5  61 67  45.  Giemsa-banded karyotype - i n d i v i d u a l 5- 1-1  46.  F l u o r e s c e n t karyotype - i n d i v i d u a l 5 - 1 - 1  47.  Giemsa-banded karyotype - proband case 5  69  48.  Giemsa-banded karyotype - i n d i v i d u a l 5 - 1 - 2  pedigree  69  49.  Giemsa-banded karyotype - i n d i v i d u a l 5 - 0 - 1  pedigree  50.  Giemsa-banded karyotype - i n d i v i d u a l 5 - 0 - 4  pedigree  51.  P a r t i a l Giemsa-banded karyotype - proband case 5  71  52.  F l u o r e s c e n t karyotype - proband case 5  71  53.  F l u o r e s c e n t karyotype - i n d i v i d u a l 5 - 1 - 2  pedigree  54.  F l u o r e s c e n t karyotype - i n d i v i d u a l 5 - 0 - 1  pedigree  55.  F l u o r e s c e n t karyotype - i n d i v i d u a l 5 - 0 - 4  pedigree  56.  Schematic diagram of D/D t r a n s l o c a t i o n ix  - case 4  pedigree "  pedigree  68 68  70 70  72  - case 5  72 73 74  LIST OF APPENDICES Appendix  Page  A  Leucocyte  Culture Method  B  Fluorescent  C  Trypsin-Giemsa Banding Technique  D  C-Banding Technique  E  Staining  1  0  8  Banding Technique  Technology  x  m  ACKNOWLEDGEMENTS I wish t o e x p r e s s my thanks t o t h e members o f my t h e s i s committee a t t h e U n i v e r s i t y o f B r i t i s h Columbia f o r t h e i r s u p p o r t and g u i d a n c e d u r i n g t h e c o u r s e o f t h i s p r o j e c t : Dr. J.R. M i l l e r , Department o f M e d i c a l G e n e t i c s ( C h a i r m a n ) ; Dr. F . J . D i l l , Department o f M e d i c a l G e n e t i c s ( S u p e r v i s o r ) ; Dr. P . J . MacLeod, Department o f M e d i c a l G e n e t i c s ; Dr. D.G. Holm, Department o f Z o o l o g y ; and Dr. C.O. P e r s o n , Department o f Botany. S i n c e r e a p p r e c i a t i o n i s e x p r e s s e d t o Dr. F . J . D i l l and Ms. S. Masui-Smith  f o r t h e i r t e a c h i n g and t e c h n i c a l a s s i s t a n c e  throughout the course o f t h i s study. I thank t h e f o l l o w i n g p e o p l e and p l a c e s f o r t h e i r c o - o p e r a t i o n and a s s i s t a n c e i n c e r t a i n a s p e c t s o f t h i s s t u d y : (1)  Ms. D. Gibson and Ms. J . Sandercock f o r t h e i r a s s i s t a n c e i n o b t a i n i n g b l o o d samples n e c e s s a r y f o r t h i s s t u d y .  (2)  The Woodlands S c h o o l , New W e s t m i n s t e r , B.C. f o r t h e p e r m i s s i o n t o use s e v e r a l p a t i e n t s s t a y i n g a t t h e s c h o o l .  (3)  The G e n e t i c s L a b o r a t o r y , V.G.H. and Dr. T z e , C h i l d r e n ' s H o s p i t a l , f o r the assistance i n obtaining the information and r e s u l t s f o r c a s e 1.  (4)  Ms. S. Manning f o r h e r p e d i g r e e i l l u s t r a t i o n s . My s i n c e r e a p p r e c i a t i o n and thanks i s g i v e n t o my w i f e , Wendy,  whose s u p p o r t and u n d e r s t a n d i n g was a m a j o r f o r c e i n a l l o w i n g me t o complete t h i s t h e s i s .  xi  I acknowledge  the support  of the U n i v e r s i t y of B r i t i s h  Columbia Summer Research Grants d u r i n g May - August 1973 and 1974.  xii  CHAPTER I INTRODUCTION Over the past f i f t e e n associate s p e c i f i c  years  alterations  number with s p e c i f i c  clinical  i t has become p o s s i b l e  to  i n the human d i p l o i d chromosome signs.  In many syndromes,  for  example P a t a u ' s syndrome (trisomy Dj_) the chromosomal abnormality can be p r e d i c t e d by phenotypic s i g n s . was based on s i z e  changes  c o u l d be d e t e c t e d .  i n d i v i d u a l human chromosomes was p o s s i b l e  but i t was a time consuming procedure. tions  such as  with  autoradiography  Furthermore, small  (Caspersson  19 71, 19 73; A r r i g h i  and Hsu, 19 71)  i d e n t i f i e d by i t s  the p o s s i b l e  translocations  et a l . ,1969a, 1969b,  c h a r a c t e r i s t i c banding p a t t e r n .  of chromosome a b e r r a t i o n s .  of these techniques which enable  the chromosome was r e v i s e d The present  translocations  changes  increased  (Paris  i n chromo-  Also  as  the  classification  Conference.; 1971).  study was c a r r i e d out to i n v e s t i g a t e  i n man, s p e c i f i c a l l y D/D f u s i o n s , 1  of  understanding  the morphology of  human complement to be examined, the system f o r the of  Seabright,  As a r e s u l t  more d i s c r e e t  can be i d e n t i f i e d and t h i s has consequences  1970 ;  each human chromosome can be  these new s t a i n i n g methods, s m a l l e r , some s t r u c t u r e  aberra-  With the advent of new d i f f e r e n t i a l  s t a i n i n g techniques  a result  Identification  i n v e r s i o n s , small equal r e c i p r o c a l  c o u l d not be i d e n t i f i e d .  of  recently karyotyping  and centromere p o s i t i o n and hence only n u m e r i c a l  and obvious s t r u c t u r a l of  Until  D group  utilizing  the new  2 s t a i n i n g techniques.  S p e c i f i c questions  these D/D t r a n s l o c a t i o n s are  such as:  i n v o l v e d i n the t r a n s l o c a t i o n ;  were asked when c o n s i d e r i n g  1) which chromosome p a i r or 2) where are  the p o s s i b l e  p o i n t s on the long or s h o r t arms of the chromosomes 3) what i s and  the s e g r e g a t i o n p a t t e r n  4) what i s  the p o s s i b l e  the t(Dq Dq) t r a n s l o c a t i o n s ?  pairs break  involved;  of f a m i l i a l t(Dq Dq)  translocations;  mechanism or mechanisms of formation of The reason  these t(Dq Dq)  were s t u d i e d was due to the a v a i l a b i l i t y of f a m i l i e s v i o u s l y been shown to have t h i s  translocations  which had pre-  type of t r a n s l o c a t i o n .  This  of t r a n s l o c a t i o n was a l s o chosen because of the i n t e r e s t i n g  type pattern  of s e g r e g a t i o n shown by the t r a n s l o c a t i o n and the r i s k of producing translocation carriers.  trisomy D o f f s p r i n g by male or female D/D t r a n s l o c a t i o n  This present  there by l i m i t i n g  group were A.  to only the P a t a u ' s  This would not have been p o s s i b l e  if  trans-  i n v o l v i n g the D group chromosomes and another chromosome studied.  Chromosomal rearrangement which r e s u l t s t(Dq Dq)  i n the formation of a  translocation  This general Robertson  to D/D t r a n s l o c a t i o n s  the t r i s o m i c s t a t e d i s c u s s i o n  syndrome ( t r i s o m y - D i ) . locations  study was r e s t r i c t e d  type of t r a n s l o c a t i o n was f i r s t  d e s c r i b e d by  (1916) i n c e r t a i n orthopteran p o p u l a t i o n s .  I t has been  termed " R o b e r t s o n i a n t r a n s l o c a t i o n " or more l o o s e l y " c e n t r i c In the human complement the D group of chromosomes are in structure  and are  organized i n t o 3 p a i r s ,  fusion".  acrocentric  numbered 13, 14,  and 15.  3  The mechanism of formation of the " c e n t r i c f u s i o n " t r a n s l o c a t i o n has  type  g e n e r a l l y been regarded as an unequal r e c i p r o c a l  t r a n s l o c a t i o n between two a c r o c e n t r i c chromosomes with breaks on opposite  s i d e s of the centromeres  long arms. fragment,  This u s u a l l y r e s u l t s  and subsequent r e j o i n i n g of  i n the l o s s of a minute c e n t r i c  the formation of a new m e t a c e n t r i c chromosome and reduc-  t i o n i n the chromosome number i n the balanced heterozygote ton,  1972).  there are fragment is  The minute c e n t r i c fragment  reports loss  frequently  1969;  the  i s not always  of complete r e c i p r o c a l t r a n s l o c a t i o n s  (Emerit e t a l . , l o s t but i s  de Grouchy et a l . ,  1972)  present  and reports  i n some c e l l s  (Hamer-  lost  as  without  where the  fragment  (Palmer et  al.,  1970).  A l t e r n a t i v e mechanisms have been suggested f o r the " c e n t r i c fusion"  type t r a n s l o c a t i o n .  centromeres  It has been suggested e i t h e r  simply fuse or that n e i t h e r of the centromeres  but one of them i s not v i s i b l e under l i g h t microscopy 1969; N i e b u h r , 1972a). Niebuhr  that  (1972b).  Another p o s s i b i l i t y  are  the lost,  (Hsu and Mead,  has been proposed by  He suggests formation may be due to breaks i n the  short arms o f both a c r o c e n t r i c s l o c a t i o n chromosomes.  with formation of d i c e n t r i c  He proposes centromeric suppression  transby yet  an unexplained mechanism might e x p l a i n the monocentric appearance generally noticed in centric  fusions.  4 B.  I n c i d e n c e o f the t ( D q Dq) t r a n s l o c a t i o n i n t h e p o p u l a t i o n S e r g o v i c h e t a l . (1969) s u g g e s t t h a t D/D t r a n s l o c a t i o n  h e t e r o z y g o s i s p r o b a b l y r e p r e s e n t s the most f r e q u e n t t y p e o f chromosomal r e a r r a n g e m e n t .  From t h e work o f Court-Brown  (1967)  and newborn s t u d i e s by W a l z e r e t a l . ( 1 9 6 9 ) , S e r g o v i c h e t a l . (1969) , Lubs and Ruddle ( 1 9 7 0 ) , Hamerton e t a l . ( 1 9 7 2 ) , F r i e d r i c h and N e i l s e n (1973), and J a c o b s e t a l . ( 1 9 7 4 ) , i t has been e s t i m a t e d t h a t t r a n s l o c a t i o n s o f t h e " c e n t r i c f u s i o n " t y p e between two members o f the D group chromosomes o c c u r i n a p p r o x i m a t e l y 1 p e r 1000 t o 2000 i n d i v i d u a l s examined.  While t h e t ( D q Dq) t r a n s l o c a t i o n  c a n n o t be c o n s i d e r e d common, i t i s not r a r e .  For comparison,  the  frequency o f c e n t r i c f u s i o n type t r a n s l o c a t i o n s i n v o l v i n g acroc e n t r i c chromosomes from the D group and t h e G group (2 p a i r s , numbered 21,,22) has been e s t i m a t e d a t 1 p e r 3000 ( G e r a l d and W a l z e r , (1970) . In o t h e r s u r v e y s , where newborn i n f a n t s were n o t u s e d , i n c i d e n c e v a l u e s were s i m i l a r .  S a s k i e t a l . (1971), d o i n g chromosome  s t u d i e s i n e a r l y embryogenesis,  found 1 t ( D q Dq) specimen i n 898  i n d u c e d a b o r t u s e s randomly c o l l e c t e d i n Sapporo.  In s t u d i e s done  i n p s y c h i a t r i c h o s p i t a l s , t h e f r e q u e n c y o f b a l a n c e d t ( D q Dq) r e a r r a n g e m e n t s was n o t s i g n i f i c a n t l y h i g h e r than t h a t found i n t h e newborn o r t h e g e n e r a l a d u l t p o p u l a t i o n (Newton e t a l . , 1972; N i e l s e n e t a l . , 1973).  In a s u r v e y o f males examined f o r m i l i t a r y  s e r v i c e , Zeuthen and N i e l s e n (1973) found t h e p r e v a l e n c e o f t ( D q Dq) t r a n s l o c a t i o n among the males s e l e c t e d f o r chromosome i n v e s t i g a t i o n  5 was 2.69 p e r 1000 and the p r e v a l e n c e among t h e t o t a l p o p u l a t i o n sample was 0.78 p e r 1000.  The d i f f e r e n c e between t h e s e two v a l u e s i n non-  significant.  C.  Chromosomal c o n s t i t u t i o n o f the t ( D q Dq) t r a n s l o c a t i o n s From an i n v e s t i g a t i o n on c h i l d r e n w i t h D t r i s o m y p l u s a  t r a n s l o c a t i o n , Hecht e t a l . (1966) c o n c l u d e d t h a t t h e t r a n s l o c a t i o n s tended t o be o f t h e t ( D q Dq) t y p e r a t h e r than t ( D q Gq) t y p e .  They  s u g g e s t e d t h a t a l l a c r o c e n t r i c s d i d n o t have an equal chance o f b e i n g found i n the t r a n s l o c a t i o n w i t h a g i v e n a c r o c e n t r i c chromosome. By the use o f  - t h y m i d i n e a u t o r a d i o g r a p h y , the chromosome  c o n s t i t u t i o n o f t ( D q Dq) t r a n s l o c a t i o n s c o u l d be i d e n t i f i e d 1963; G i a n n e l l i and H o w l e t t , 1966).  (Schmid,  Bloom and G e r a l d (1967, c i t e d i n  Hecht and K i m b e r l i n g , 1071) p r e s e n t e d a u t o r a d i o g r a p h i c d a t a s u g g e s t i n g the t(Dq Dq) t r a n s l o c a t i o n might be non-random i n c o m p o s i t i o n . non-randomness has been c o n f i r m e d by numerous a u t h o r s (Rowley  This and  Pergament, 1969; de Grouchy e t a l . , 1970, K r m p o t i c e t a l . , 1970; Hecht and K i m b e r l i n g , 1971; Cohen, 1971).  Cohen (1971) r e v i e w e d 64  t ( D q Dq) (58 p r e v i o u s l y r e p o r t e d and 6 new c a s e s ) which had had a u t o r a d i o g r a p h i c i d e n t i f i c a t i o n , and he showed t h e d i s t r i b u t i o n o f chromosomal c o m b i n a t i o n s was 5 ( 1 3 / 1 3 ) , 49 ( 1 3 / 1 4 ) , 6 ( 1 3 / 1 5 ) , 3 (14/15) and 1 (15/15). The homologous 14/14 t r a n s l o c a t i o n was n o t o b s e r v e d .  To t h e a u t h o r ' s  knowledge, the t ( 1 4 q 14q) t r a n s l o c a t i o n has o n l y been r e p o r t e d once ( H u l t e n and L i n d s t e n , 1970; C a s p e r s s o n e t a l . , 1971).  6 Rowley and Pergament suggested four p o s s i b l e bution:  1)  (1969) and Hecht and K i m b e r l i n g  explanations  f o r the non-random d i s t r i -  that the breaks near the centromere occur at  ent frequencies  f o r each: chromosome; 2)  s e l e c t i o n and s u r v i v a l of t r a n s l o c a t i o n s of d e f i c i e n c e s ;  3)  (1971)  that there i s  differ-  differential  due to c e r t a i n combinations  that m e i o t i c p a i r i n g and c r o s s i n g  over of  homologous segments of DNA i n non-homologous a c r o c e n t r i c chromosomes may d i c t a t e pairs  m e i o t i c p a i r i n g and c r o s s i n g over between c e r t a i n  more f r e q u e n t l y than o t h e r s .  The r e c i p r o c a l product of  this  type of c r o s s i n g over would be a small m e t a c e n t r i c chromosome t(Dp Dp).  These have been r e p o r t e d by Palmer et a l . ( 1 9 6 9 ) , de  Grouchy et a l . ( 1 9 7 0 ) , and Emerit et a l . ( 1 9 7 2 ) ;  4)  s p e c i f i c chromo-  some breakage p o i n t s which vary from the long to short arms depending on the chromosome. C e r t a i n authors propose  that  the non-randomness  to d i f f e r e n t i a l breakage f r e q u e n c i e s , break w i t h equal frequency and i t  is  but that a l l the s t r i c t  i s not due  acrocentrics  d i s p o s i t i o n of the  D group chromosomes around the n u c l e o l u s which leads to p r e f e r e n t i a l associations  (de Grouchy et a l . , 1 9 7 0 ;  Rowley and Pergament,  1969).  Hamerton (1968) proposed that p r e z y g o t i c s e l e c t i o n or meiot i c d r i v e might e x p l a i n the s i g n i f i c a n t excess of balanced heterozygote  translocation carriers  among the o f f s p r i n g these t r a n s l o c a t i o n s  over chromosomally normal progeny  of male t(Dq Dq) c a r r i e r s .  He suggested  that  occur randomly among the D and G chromosomes  7 and that a s e l e c t i o n different possible  e x i s t s a c c o r d i n g to the v i a b i l i t y of  combinations.  Hamerton (1972) suggested another  mechanism due to the intermediate  of chromosome 14. the proximal p a r t may be more l i a b l e  replicating position  The heterochromatic b l o c k i n the short of the long arm are  arm and  l a t e r e p l i c a t i n g and e i t h e r  to breakage or once broken take longer to h e a l .  Krmpotic et a l . ( 1 9 7 0 ) proposed that the non-randomness the D group chromosomes  i n v o l v e d i n the t(Dq Dq) chromosomes may  be due to the time at which c e r t a i n chromosomal p o r t i o n s It i s  for f e t a l  tions  replicate.  b e l i e v e d that e a r l y r e p l i c a t i n g chromosomes or p o r t i o n s  e a r l y r e p l i c a t i n g chromosomes are sary  development.  genetically active,  with l i f e  inactive;  thus  Late r e p l i c a t i n g chromosomes  of l a t e r e p l i c a t i n g chromosomes are g e n e r a l l y  genetically  of  t h e i r l o s s or d u p l i c a t i o n i s  of  necesor por-  considered compatible  i f the d e l e t i o n or d u p l i c a t i o n i s not e x c e s s i v e .  Chromo-  some 14 has a l a t e r e p l i c a t i n g p o r t i o n around the centromeric r e g i o n so i t s  l o s s may be compatible with l i f e while that  of  chromosome 13 and 15 l o s s would n o t . D.  Segregation  p a t t e r n s of t(Dq Dq)  Hamerton (1968) r e p o r t e d that excess of heterozygotes t(Dq Dq) f a m i l i e s .  there was a  significant  by comparison with normal o f f s p r i n g  The excess of heterozygotes  by progeny of heterozygous but not by the heterozygous that  translocations  class.  It was a l s o  the sex r a t i o d i d not s i g n i f i c a n t l y depart  Hamerton found no i n c r e a s e  was accounted  males and unknown heterozygous female  in for  parents,  reported  from e q u a l i t y .  i n the frequency of a b o r t i o n and there  8 was no s i g n i f i c a n t  difference  i n the frequency of a b o r t i o n  the male or female h e t e r o z y g o t e . ports  This data c o n f l i c t e d w i t h r e -  of Court-Brown (1967) which i n d i c a t e d that  zygotes,  spontaneous  abortions  i n 43.1% of c o n c e p t i o n s .  spontaneous  These d i f f e r e n c e s  a r i s e from Court-Brown's smaller histories  abortions  carriers  thought  to  conceptual  histories.  the i n c r e a s e  zygous progeny from male t r a n s l o c a t i o n s  occurred  were l a t e r  and Hamerton's incomplete c o n c e p t u a l  translocation  conceptions,  sample but complete  Hamerton (1968) e x p l a i n e d that  parental  for male hetero-  o c c u r r e d i n 35.3% of  while for female h e t e r o z y g o t e s ,  for  carriers  i n hetero-  and unknown  was due to the sperm c a r r y i n g  chromosomally balanced t r a n s l o c a t i o n s  having a s e l e c t i v e  advan-  tage over chromosomally normal sperm. Jacobs et a l . ( 1 9 7 4 )  found no excess of heterozygotes  the progeny of e i t h e r male or female location.  Independent  of the sex  carriers  of a t(Dq Dq)  of the c a r r i e r p a r e n t ,  from the expected  no evidence of unbalanced t r a n s l o c a t i o n c h i l d r e n of the balanced c a r r i e r was no excess of p r e n a t a l  balanced t(Dq Dq) heterozygotes 1%). of having a f f e c t e d and female  carriers.  ratio.  to  They found  trisomy among the l i v e b o r n  families.  deaths.  1:1  In a d d i t i o n ,  there  Hamerton (1968) s t a t e d  have a very low r i s k  translocation  trans-  the  s e g r e g a t i o n r a t i o o f balanced t r a n s l o c a t i o n heterozygotes normals d i d not deviate  among  (less  that than  trisomy progeny f o r both male  9 D u t r i l l a u x and Lejeune of male t(Dq Dq) t r a n s l o c a t i o n population values, (151  - 20%);  nificant births  2)  (1970) concluded from the progeny carriers  there was no i n c r e a s e  increase  all  r a t e of spontaneous  births,  there was an equal  live  ratio  t(Dq Dq) t r a n s l o c a t i o n  translocation  abortion frequency  (25%); 2); among the (1%)  to n o n - c a r r i e r ) .  (1:1  For the female  they suggested an "interchromosomal e f f e c t "  car-  was l i k e l y  tri-  there ratio  carrier the cause  the 2% frequency of trisomy 13 or trisomy 21, with an o v e r a l l  risk  of anomalies  i n the order of 5%.  This i n f o r m a t i o n suggests that have a g r e a t l y  increased  having t r a n s l o c a t i o n  t(Dq Dq) female  carriers  though s t i l l low r i s k of 1 - 2% of  trisomy D c h i l d r e n .  P o p u l a t i o n estimates  primary trisomy 13 range from 1 per 7602 - 14,500 ( T a y l o r , 19 71; E.  They  live  of trisomy 13 and  s e g r e g a t i o n of the t r a n s l o c a t i o n  carrier  trans-  there was an i n -  and 3) among the p h e n o t y p i c a l l y normal c h i l d r e n ,  was no p r e f e r e n t i a l  for  (1:1  sig-  were p h e n o t y p i c a l l y normal.  compared to p o p u l a t i o n v a l u e s ,  creased  somy 21;  among the  c h i l d r e n i n the progeny  concluded from the progeny of female 1)  abortions  there was no  i n the frequency o f anomalies  and 3) almost  that:  1) compared to  i n spontaneous  compared to p o p u l a t i o n v a l u e s ,  l o c a t i o n c a r r i e r to n o n - c a r r i e r )  riers  that:  of  1968,  Conen and Erkman, 1966).  F e r t i l i t y i n balanced t(Dq Dq) Infertility  heterozygotes  has been mentioned i n a s s o c i a t i o n  t(Dq Dq) heterozygotes  (Walker and H a r r i s , 1962;  with balanced  Yunis et  al.,1964j  10 Kjessler,  1966; W i l s o n ,  1971).  Chandley et a l . ( 1 9 7 2 )  that i n f e r t i l i t y or s u b f e r t i l i t y  in translocation  can be brought about i n two ways: a consequence  suggest  heterozygotes  f e r t i l i t y may be reduced  of the p r o d u c t i o n of gametes c a r r y i n g a  as  genetically  imbalanced genome, and s i n c e a n e u p l o i d gametes appear to f u n c t i o n at  f e r t i l i z a t i o n i n man, f e r t i l i t y may be reduced through preim-  plantation^zygotic fetuses.  and (or)  A l t e r n a t i v e l y , f e r t i l i t y may be reduced through gameto-  genic disturbance  which appears c o n f i n e d mainly to male hetero-  zygotes and r e s u l t s Slightly heterozygotes (1972).  a b o r t i o n of chromosomally unbalanced  i n o l i g o or  azospermia.  lower mean chiasma counts  was observed i n two p a t i e n t s  t(13q;14q)  by Chandley et  al.  These r e s u l t s were s i m i l a r to a report by K j e s s l e r  who found s l i g h t l y  lower mean chiasma counts  t(Dq Dq) male h e t e r o z y g o t e .  e l i m i n a t e d during spermiogenesis. c a r r i e r showed a homogeneous number of spermatogonia lack of spermatids  subfertile  a n e u p l o i d gametes  but may be  A t(Dq Dq)  selectively  translocation  and spermatocytes  (Skakkebach e t a l . ,  but an almost  1973).  However, one  translocation  (Hulten and L i n d s t e n , 1970).  total  showed normal  Chandley et  al.  suggested that a h i g h p r o p o r t i o n of chromosomally un-  balanced  zygotes may be l o s t before  escape d e t e c t i o n as  (1966)  h i s t o l o g i c a l p i c t u r e with a normal  p a t i e n t with a balanced t ( 1 4 q ; l 4 q ) spermatogenesis  for a  He suggested that  may be formed i n Dq Dq h e t e r o z y g o t e s ,  (19 72)  for male  abortions.  i m p l a n t a t i o n and thereby  11 Fraccaro e t a l . ( 1 9 7 3 )  r e p o r t e d 4 cases of t(13q;14q)  92 men a t t e n d i n g a f e r t i l i t y c l i n i c and a f t e r other r e p o r t s  in  r e v i e w i n g three  of men a t t e n d i n g s i m i l a r c l i n i c s found 8 t(Dq.Dq)  male heterozygotes  i n a sample  of 333 men.  They concluded that  among men a t t e n d i n g f e r t i l i t y c l i n i c s , the i n c i d e n c e of D/D translocations  is  s i g n i f i c a n t l y higher than 1 per 1000  i n the general a d u l t p o p u l a t i o n .  A n a l y s i s of sperm from t h e i r  four p a t i e n t s  revealed q u a l i t a t i v e  abnormalities  i n a l l of them.  ity patients,  K o u l i s c h e r and Schoysman (1974)  (0.05%) c a r r i e d a t(Dq Dq) Palmer et a l . ( 1 9 7 3 ) effects  and/or q u a n t i t a t i v e  are v a r i a b l e ,  as  semen  In another study of male  found 1 i n 202  comments on the heterogeneous  some f a m i l i e s  produce.  are i n f e r t i l e  clinical  The e f f e c t s  on  show l i t t l e evidence of  r e p r o d u c t i v e impairment (Hamerton, 1972 ; Palmer et a l . , while other f a m i l i e s  infertil-  translocation.  that the t(Dq Dq) t r a n s l o c a t i o n s  fertility  estimated  (Wilson,  1971).  1973)  Palmer et  (1973) mention that e a r l y s t u d i e s which d i d not i d e n t i f y  al.  the  chromosomes i n v o l v e d when i n f e r t i l i t y was a s s o c i a t e d , may have been homologous t(Dq Dq) chromosomes.  These homologous t(Dq Dq)  chromosomes may c o n t r i b u t e to the i n f e r t i l i t y by the formation of t r i s o m i c or monosomic zygotes. variability points fusions  Palmer (1969) suggested that  the  of f e r t i l i t y may be due to the l o c a t i o n of the break  i n the t ( 1 3 q ; 1 4 q ) , with some r e p r e s e n t i n g true and others  reciprocal  translocations.  Cohen (1971) s t a t e d that among the t(Dq Dq) cases he c o n s i d e r e d ,  centric  translocation  the f a m i l i a l t r a n s l o c a t i o n was present  four  12 times as  often as  s p o r a d i c or n o n - f a m i l i a l  (1973) suggested t h i s as p o s s i b l e effect  translocations.  evidence f o r some  selective  which would cause c e r t a i n s p o r a d i c t(Dq Dq) to become  familial  t r a n s l o c a t i o n s while others are  Cacheiro et a l .  l o s t due to  (19 74) made observations  infertility.  i n the mouse  which may suggest some reasons f o r t(Dq Dq) t r a n s l o c a t i o n ity.  Palmer  infertil-  They found that t r a n s l o c a t i o n s which caused s t e r i l i t y ,  rather  than p a r t i a l s t e r i l i t y , i n males appeared to be those i n which at l e a s t one of the breaks some.  occurs c l o s e  to one end of a chromo-  They proposed that many cases of induced F-^ male s t e r i l i t y  may be the r e s u l t  of p o s i t i o n e f f e c t s  produced when p a r a c e n t r o -  meric regions are t r a n s l o c a t e d to euchromatic regions of c e r t a i n other chromosomes. Where a b o r t i o n s have already been c o n s i d e r e d i n the s e c t i o n on s e g r e g a t i n g p a t t e r n s briefly  be c o n s i d e r e d as  of the t(Dq Dq) t r a n s l o c a t i o n s , c o n t r i b u t i n g to i n f e r t i l i t y .  family examined by Chandley et a l .  In s t u d i e s Bhasin e t a l . ,  a specific  on r e c u r r e n t a b o r t i o n couples  1968)  1973; Bhasin e t a l . ,  feature  (Kaosaar,  1969; Stenchever e t a l . ,  identify  the chromosomes  1973;  1968;  only the more recent references  1973)  of  translocations.  1973; W i l s o n ,  Pergament et a l . ,  50% o f conceptions  had no evidence of m i s c a r r i a g e .  They concluded that a high a b o r t i o n rate i s only a m i n o r i t y o f t(Dq Dq)  In the  (1972) , some male heterozygotes  in the family had a b o r t i o n r a t e s as high as while other male heterozygotes  they w i l l  (Kaosaar,  involved.  13 Since t r a n s l o c a t i o n s  between homologous p a i r s  unbalanced zygotes and of t h i s translocations  could possibly  a translocation  trisomy -13.  t(Dq Dq) h e t e r o z y g o t e s ,  can only produce  type of t r a n s l o c a t i o n  only  13/13  come to term, i t would always be Hagen et a l .  (1971) mention:- that  with involvement of chromosome 13,  have  a chance of a h e a l t h y c h i l d w i t h normal or balanced k a r y o t y p e , but i n a d d i t i o n there non-viable  fetuses  formations.  is  the chance of repeated  abortions  of  or c h i l d r e n with trisomy 13 and severe mal-  Heterozygote  with unbalanced karyotypes  combinations of chromosome 14 and 15 (trisomy  14 or 15) would not  survive  to term. F.  Other aspects o f the t(Dq Dq)  translocation  Conen and Erkman (1966) found no s i g n i f i c a n t difference  between primary trisomy 13 and t r a n s l o c a t i o n  13, apart from the g r e a t e r s e v e r i t y i n the primary trisomy 13 Magenis et a l . and p a r e n t a l  age  They found that survival  clinical  of c a r d i o - v a s c u l a r  patient.  (1968) c o n s i d e r e d the s u r v i v a l , sex  translocation  There was an  excess of females w i t h primary trisomy 13 and no ratio  with age-dependent  significant The bimodal  for primary trisomy 13 was  and age-independent  of t r a n s l o c a t i o n  patients.  insignificant  through three months o f age.  d i s t r i b u t i o n of maternal age  ratio  and mosaic trisomy 13 had a longer  than primary trisomy 13.  maternal age  lesions  of 221 chromosomally proven trisomy 13  change i n the sex  trisomy  subgroups,  trisomy 13 i n f a n t s  consistent  while the corresponded  to  14 a younger peak.  T h i s younger peak i s  that t r a n s l o c a t i o n s all  consistent  with the  idea  occur independently of maternal age.  Not  the cases of trisomy 13 syndrome c o n s i d e r e d by Magenis et  (1968) were of the t(Dq Dq) Taylor clinical  al.  type.  (1971) r e p o r t e d that approximately  trisomy -13 cases are  17% of  t(Dq Dq) t r a n s l o c a t i o n  the  carriers.  T h i s f i n d i n g supports  the e a r l i e r presented evidence which showed  the low r i s k  of t r a n s l o c a t i o n heterozygotes  (1 - 2%)  a translocation  trisomy D c h i l d .  (1971) d i f f e r e d  from those of Magenis e t a l .  producing  Other r e s u l t s r e p o r t e d by T a y l o r (1968).  She  reported  a h i g h e r mean maternal age and a bimodal d i s t r i b u t i o n of  the  maternal ages f o r the t r a n s l o c a t i o n  support  of Magenis et a l .  c a r r i e r mothers.  (1968), she r e p o r t e d a s l i g h t  In  excess o f  females  (55%) . Taylor et a l .  (1970) reached the f o l l o w i n g c o n c l u s i o n s :  1) the frequency of t r a n s l o c a t i o n s times h i g h e r than i n trisomy 21; chromosomes  similar results  trisomy  13.  2)  translocations  from 3 to 9  between two D  r e s u l t i n g i n trisomy 13 was more common than  c a t i o n between two G chromosomes  maternal age  i n trisomy 13 was  to Magenis e t a l .  for translocation  causing trisomy 21.  translo-  They  reported  (1968) concerning the lower  trisomy 13 than f o r primary  CHAPTER II MATERIALS AND METHODS A.  Experimental  Procedures  Chromosome analyses were c a r r i e d out on t h e . c u l t u r e d human l e u k o c y t e s ,  using a m o d i f i c a t i o n of the technique by  Moorhead et a l . ( 1 9 6 0 ) ,  adapted f o r micro-amounts  blood (Arakaki and Sparkes, A leukocyte mately 0.25 For  1963).  c u l t u r e was i n i t i a t e d by adding  approxi-?  cc of whole b l o o d to 5 ml of chromosome medium.  each p a t i e n t  blished.  of whole  studied,  two to three  cultures  Each c u l t u r e was incubated f o r  One hour before  the c e l l s  were h a r v e s t e d ,  at a f i n a l c o n c e n t r a t i o n of 0.02  were e s t a -  72 hours at  Colcemid was  ug/ml of c u l t u r e .  end of the 72 hour i n c u b a t i o n p e r i o d ,  37°C.  the c e l l s  were  At the treated  with a hypotonic s o l u t i o n  (0.075 KC1) and were f i x e d i n  absolute methyl a l c o h o l :  glacial  s l i d e s were then prepared  from each of the c u l t u r e s  acetic  acid.  added  3:1  Flame d r i e d (complete  technique i n Appendix A ) . 1.  F l u o r e s c e n t Banding and A n a l y s i s The  fluorescent  Caspersson's  (1969  a,b).  technique used was a m o d i f i c a t i o n of The flame 15  and a i r d r i e d s l i d e s  from  16 each p a t i e n t were immersed i n a s o l u t i o n of q u i n a c r i n e d i h y d r o chloride  ( A t r e b i n - G . T . Gurr) for a minimum of 20 minutes.  The s l i d e s were then r i n s e d and mounted i n d i s t i l l e d The c o v e r s l i p s  were s e a l e d with p a r a f f i n  water.  wax (complete  tech-  nique i n Appendix B ) . All  observations  scope using as  were made with a Zeiss Photomicro-  a source of u l t r a - v i o l e t  with a BG 12 e x c i t e r  filter  The photographs  light,  a mercury lamp  and a 500 um b a r r i e r  filter.  were taken using Kodak T r i - X Pan  film  under o i l immersion (X100) w i t h an exposure time of 4 minutes. 2.  Trypsin-Giemsa Banding and A n a l y s i s The t r y p s i n technique used was a m o d i f i c a t i o n of  b r i g h t ' s (1971). room temperature fore  The flame for 5 - 7  trypsinization  trypsin digestion modifications  and a i r d r i e d s l i d e s were l e f t days, which i s  (Seabright,  i n a s e r i e s of s o l u t i o n s  1973).  The s l i d e s were immersed  solution.  made during the study were f o r the steps  tions  from 5 - 2 0  for  seconds and were then dipped i n v a r i o u s the t r y p s i n .  i n Giemsa s o l u t i o n f o r  solution,  between  stain.  to remove or i n a c t i v a t e  stained  the  Technique  The s l i d e s were p l a c e d i n the t r y p s i n s o l u t i o n iods  at  the optimum time be-  w i t h the two major steps being  and the Giemsa s t a i n  the t r y p s i n and Giemsa  Sea-  1-5  The s l i d e s  minutes.  solu-  were  A f t e r the Giemsa  the s l i d e s were b r i e f l y r i n s e d i n d i s t i l l e d  b l o t t e d dry and then a i r d r i e d .  per-  water,  The s l i d e s were then dipped i n  17 xylol  and mounted i n a s u i t a b l e  mounting medium (complete  tech-  nique i n Appendix C ) . All  observations  under phase c o n t r a s t . and 10 - 15 c e l l s  were made with a Zeiss Photomicroscope A minimum of t h i r t y c e l l s were  were photographed under o i l immersion (X100)  u s i n g Kodak high c o n t r a s t 3.  observed  copy f i l m  5069.  C-Banding and A n a l y s i s The C-banding technique used was a combination of the  techniques used by F o r e j t  (1973) and A r r i g h i and Hsu (1971).  The flame and a i r d r i e d s l i d e s solution  f o r 90 seconds,  were immersed i n a NaOH-NaCl  were r i n s e d i n d i s t i l l e d water,  ped i n 70 and 90% methanol and were a i r d r i e d . were then t r e a t e d hour. tion  slides  1973)  were s t a i n e d i n b u f f e r e d Giemsa s o l u -  f o r 15 minutes,  water, b l o t t e d dry and a i r d r i e d . xylol  The d r i e d  i n Sorensen b u f f e r pH 6.8 at 6 8 ° C f o r one  The heated s l i d e s (Forejt,  dip-  and mounted i n a s u i t a b l e  then r i n s e d i n d i s t i l l e d S l i d e s were then dipped i n  mounting medium (complete  tech-  nique i n Appendix D) . Observations and photography were s i m i l a r to the t r y p s i n Giemsa technique. B.  C r i t e r i a for e s t a b l i s h i n g For each p a t i e n t ,  the p a t i e n t ' s  karyotype  30 - 50 t r y p s i n banded c e l l s  analysed f o r chromosome number to r u l e out p o s s i b l e  were  mosaicism.  18 From the banded c e l l s  examined, only 10 - 15 having the best  r e s o l u t i o n were photographed.  Chromosome counts were done  under X40 m a g n i f i c a t i o n to ensure one c e l l were b e i n g counted. only when c e l l s  that chromosomes from only  O i l immersion (X100) was used  had morphological c r o s s - o v e r s not separable  at X40 m a g n i f i c a t i o n . After  the p r i n t e d photographs were o b t a i n e d , the karyo-  type was completed by f o l l o w i n g the s t a n d a r d i z a t i o n Conference  (1971).  Paris  K a r y o t y p e s , e i t h e r complete or p a r t i a l ,  were made to e s t a b l i s h  the chromosomes i n v o l v e d i n the t(Dq Dq)  t r a n s l o c a t i o n or to determine normal v a r i a n t s chromosomes.  of the  i n the  patient's  CHAPTER  III  RESULTS Case 1 This male i n f a n t was born to young unmarried parents on November 25,  19 71.  No f u r t h e r  i n f o r m a t i o n on the parents or  the pregnancy was a v a i l a b l e as of e i g h t months. Canadian Indian  However, i t (figure  the c h i l d was adopted is  1) .  The a v a i l a b l e growth date i s  summarized as  (yrs.)  Height (cm)  retardation.  follows: Weight  birth  47  2.38  4/12  -  2.06  6/12  62.8  6.70  1.11/12  71.1  8.60  2.1/12  74.3  8.80  No other p a s t p h y s i c a l measurements are examination  at  two years of age  revealed  available.  (kg)  Physical  a miniature, well-  p r o p o r t i o n e d male.  He appeared q u i t e  His l e n g t h was  cm which i s below the t h i r d p e r c e n t i l e  chronological  74.3 age.  age  known that the mother was a  Development was normal except f o r p h y s i c a l  C h r o n o l o g i c a l age  at the  hyperactive  and  co-operative, for  The head appeared normal and the sutures 19  20 were a l l c l o s e d .  There was marked crowding of the t e e t h and  the jaw appeared s m a l l .  The abdomen and the  cardio-vascular  system were shown to be i n f a n t i l e by p h y s i c a l examination. The scrotum was underdeveloped. was normal except  The n e u r o l o g i c a l examination  for a m i l d h y p o t o n i a .  An endocrine i n v e s t i -  gation was c a r r i e d out due to a suspected growth hormone deficiency. its  Tests showed that h i s growth hormone was normal i n  response to  insulin.  A c y t o g e n e t i c i n v e s t i g a t i o n y i e l d e d the f o l l o w i n g observations : a)  the proband i s  b)  the t(Dq Dq) i s chromosomes  c a r r y i n g a t(Dq Dq)  a homologous t r a n s l o c a t i o n between two 14  (figures  2 and 4 ) .  c) based on the G-banding ( f i g u r e s (figure  5)  translocation.  2-3)  and the C-banding  the t r a n s l o c a t i o n appears to be monocentric.  d) based on the G-banding ( f i g u r e s  2 - 3) , the break  points  were i d e n t i f i e d as being i n the short arm of one chromosome 14 at pl2 and i n the long arm of the other chromosome 14 at q l l . Analysis (Table 1). figure  4.  Conference cation  and chromosome counts were done i n t h i s  Fluorescent analysis The schematic f i g u r e (1971)  (figure  6).  male  and karyotype are shown i n is  d e r i v e d from the P a r i s  to show the i d e a l i z e d form of the  translo-  21 Summary:  Pedigree  No.  Karyotype  0-1  45, XY,  0-1  Clinical  t ( 1 4 ; 14) signs:  (pl2 ; q l l )  small stature, mild hypotonia, s m a l l jaw, underdeveloped scrotum  pedigree - case 1  a  i  22  2  / M = D/D translocation carrier • O = not tested Figure 1.  Pedigree - case 1  TABLE 1  Number on pedigree  Number o f chromosomes <44  0 - 1  2  44  45  46  47  1  30  -  -  . >47  total 33  23  • I •: ;  •  •»  .* •  5  K3  1  -> **  >X  y  tr  « a  *~  19  Figure 2.  i it  .fit. 15 *  16  J  20  a-  6 i2  V  13  « 3  4  3  2  5  1  4  •  .3.;.  17  18  •  21  Giemsa-banded karyotype  • t 22  - proband case 1  4r fc M  1  Figure 3.  2  P a r t i a l Giemsa-banded karyotype - proband case 1  24  n o » w \) )) if U I I  Figure 4.  !  M  (I it  F l u o r e s c e n t karyotype  K  j; >|  i ,  it  - proband case 1  il \i It 14  19  Figure 5.  in U  6- 12  15  16  20  C-banded karyotype  - proband case 1  17  18  21  22  Figure  6.  Schematic  d i a g r a m o f D/D  translocation  - case  1  26 Case 2 The proband, a male born on November 10, 1962, was result  of the second pregnancy of an u n r e l a t e d c o u p l e .  The  pregnancy was uneventful and the proband was f u l l - t e r m . maternal age was 32 years After  four years  and the p a t e r n a l age was 34  of marriage,  this couple's  nancy r e s u l t e d i n a f u l l - t e r m female 6,  1959.  This female  heart defect disease.  analysis  The parents first  preg-  birth.  She had a  c o u l d not be performed at  had been i n v e s t i g a t e d p r i o r to the de-  c h i l d because they had d i f f i c u l t y i n con-  had r e v e a l e d a low count.  anomalies.  the proband was noted to have m u l t i p l e congenThe c h i l d d i e d at  time weighed 2400 grams. with s i x  first  This i n v e s t i g a t i o n was c a r r i e d out i n 1958 and sperm  At b i r t h , ital  years.  and death was s a i d to be due to h y a l i n e membrane  l i v e r y of t h i s ceiving.  The  i n f a n t , born on December  died s h o r t l y after  Chromosome i n v e s t i g a t i o n s  that time.  the  fingers  two months of age  At autopsy,  on both hands and s i x  and at  that  the i n f a n t had P o l y d a c t y l y toes on the l e f t  foot.  The ears were markedly h y p o p l a s t i c and a c l e f t p a l a t e was present.  The omphalocele which had been present  at b i r t h had been  r e p a i r e d and a M e c k e l ' s d i v e r t i c u l u m was observed.  The v i s c e r a  were noted to be hypermobile.  retrocaval  and b i f i d  The r i g h t u r e t e r was  and there were two r e n a l pelves present  The t e s t e s were undescended, psoas muscle.  A patent  on the r i g h t .  l y i n g on e i t h e r side of the  ductus a r t e r i o s u s  was present  ilio-  and there  27 was b i l a t e r a l colobomata and microphthalmos. was noted throughout both l u n g s .  Spotty  congestion  M i c r o s c o p i c a l l y , the  lungs  were congested and c o n t a i n e d a bronchopneumonia p r o c e s s . d i c a t i o n of u n i l a t e r a l p y e l o n e p h r i t i s was present kidney,  An i n -  i n the r i g h t  the other organs were normal. Chromosome s t u d i e s r e v e a l e d a member missing from the 13 -  15 group and an e x t r a body present b a s i s of the c l i n i c a l p a t t e r n  i n the 1 - 3  of anomalies  group.  On the  i t was assumed  that  the c h i l d was a trisomy D syndrome and the e x t r a body i n the group 1 - 3 15 group.  was a t(Dq Dq) between two chromosomes of the 13 The parents  were i n v e s t i g a t e d  the mother was 46,XX and that location  a s c h o o l p r i n c i p a l , was p h e n o t y p i c a l l y normal.  mother, s i s t e r ,  and b r o t h e r had normal k a r y o t y p e s .  p a t e r n a l grandfather was dead ( f i g u r e somal a n a l y s i s (figures  8 -  and c l i n i c a l  a)  trans-  pictures  7).  The The  The o r i g i n a l chromo-  of the proband are i n c l u d e d  11).  A re-investigation present  carried a similar  to that observed i n the proband but trt was b a l a n c e d .  The f a t h e r , father's  the f a t h e r  and i t was found that  of t h i s  family i n i t i a t e d during this  study r e v e a l e d the f o l l o w i n g :  the t r a n s l o c a t i o n was a homologous t r a n s l o c a t i o n between two 13 chromosomes  (figures  12 -  15).  b) on the b a s i s of the symmetrical appearance  and the  that both the 13 chromosomes centromeres are present  suggestion as shown  28 by the G-banding ( f i g u r e s  12 - 14)  and the C-banding  (figure  16) , the t r a n s l o c a t i o n i s p o s s i b l y d i c e n t r i c , c) based on G-banding ( f i g u r e s  12 - 14),  the break p o i n t s  ed to be i n the s h o r t arms of both chromosome 13's  appear-  i n the re-  gion o f p l l - 1 2 . A n a l y s i s and chromosome counts were done only on the  father  of the proband s i n c e he was the only l i v i n g member o f the family with the t r a n s l o c a t i o n location  (i.e.  assumed that as w e l l .  (Table 2 ) .  Due to the nature  i n v o l v i n g both number 13 chromosomes),  the f i r s t  The f a i l u r e  to t h r i v e and the heart defect  trans-  i t can be  born female was a t r a n s l o c a t i o n O  to t h i s  of the  trisomy D  add s t r e n g t h  O  assumption.  Fluorescent results The schematic f i g u r e  is  and karyotype are shown i n f i g u r e  d e r i v e d from the P a r i s  to show the i d e a l i z e d form of the t r a n s l o c a t i o n  IS.  Conference (1971) (figure  17).  Summary: Pedigree No.  Karyotype  1-1  46, XX  1-4  45 , XY, t d i c (13;13)  0-1  (translocation t(13q;13q))  0-2  46, XY, t d i c  (pl2;pl2)  trisomy D 46, XX,  (13;13)  (pl2;pl2)  29  Clinical  signs:  h e a r t d e f e c t , h y a l i n e membrane d i s e a s e , f a i l u r e to t h r i v e  Clinical  signs:  Polydactyly, hypoplastic ears, c l e f t p a l a t e , Meckel's d i v e r t i c u l u m , omphalocele, hypermobile abdominal v i s c e r a , b i f i d retrocaval right ureter, undescended t e s t e s , colobomata, m i c r o p h t h a l m o s , p a t e n t ductus a r t e r i o s u s , apneic s p e l l s , f a i l u r e to thrive  I  pedigree - case 2  30  a  o  2  a  o  cT3 iTSTi 6 3  ^2  4  5  7  • # = trisomy-D with D/D translocation •  = D/D translocation carrier  0 ® = normal  chromosomes  4  miscarriage  f  dead  Figure 7.  Pedigree - case 2 TABLE 2 Number of chromosomes  Number on pedigree  <44 .  44,-  45  '46  47  1 - 4  2  2  29  1  -  ' >4'7  total34  •  31  ^  U  K  K  U  1 - 3  +  T  6 -12  am  4-5  +X  A A AAA 13-15 - D  16-18  A A A 4 19 -  21-2  20  Figure 8.  Unbanded karyotype  Figure 9.  A n t e r i o r and f u l l  - proband  ft  2  +Y  case 2  length view - proband  case 2  Figure  11.  Lateral  v i e w o f head  - proband  case 2  33  B  a  8 « 2  S  1v  P I 13  IS  i  M  14  3  4  X 12 ! | 6  M  12  1/  IK 19  Figure 12.  •  20  18  4 2  1  2  2  Giemsa-banded karyotype - i n d i v i d u a l pedigree  f  \  *_ _l_ 1  2  _i  3  X  6 - 12  13  Figure 13.  * *•  IS  16  15  « »  4 6 Sfe 14  15  P a r t i a l Giemsa-banded karyotype pedigree 2-1-4  individual  Y 2-1-4  34  I  IV  Mi t l 14  6 - 12  15  Figure 14.  P a r t i a l Giemsa-banded karyotype pedigree 2-1-4  individual  Figure 15.  P a r t i a l f l u o r e s c e n t karyotype 13/13 t r a n s l o c a t i o n chromosome, chromosome 14 p a i r , chromosome 15 p a i r , s i n g l e chromosome 3 - i n d i v i d u a l pedigree 2-1-4  35  j] 1  4*  111)  *  U  I ftl II II E <  6  19  ,3  I.  *  X 19  Figure 16.  14  12  S*  11 II ftl 16  1/  IH  21  2?  15  I K 20  C-banded. karyotype  - i n d i v i d u a l pedigree  Y  2-1-4  Figure  17.  Schematic diagram  o f D/D  translocation  - case  37 Case 3 This proband, a male born on January sult  7,  1969, was the re-  of the second pregnancy of Jthis unrelated, c o u p l e .  t e r n a l age was 23 years  and the p a t e r n a l age was 24 y e a r s .  couple was married i n 1965 and t h e i r f i r s t spontaneous  a b o r t i o n at  3 - 4 months g e s t a t i o n  The mother was a p p a r e n t l y  (figure  At the f i f t h  For t h i s  f o r 12 years  band and d u r i n g the l a s t 2 - 3 unable to c o n t r o l her d i a b e t e s .  month of g e s t a t i o n ,  she de-  The mother  p r i o r to the b i r t h  of the pro-  months of the pregnancy she was As a r e s u l t  she was h o s p i t a l i -  weeks p r i o r to the proband's b i r t h and the d e l i v e r y  was by Caesarian s e c t i o n , she was s t e r i l i z e d .  30 days p r i o r to term.  At t h i s  On two o c c a s i o n s ,  at  grams.  3 and 5 weeks,  the proband had an  episode  of breath h o l d i n g d u r i n g which he became s t i f f  tense.  During these episodes there were no c l o n i c  and no l o s s of c o n s c i o u s n e s s . h o s p i t a l i z e d and the parents developmentally slow.  time  The proband was d e s c r i b e d as a c t i v e and  the b i r t h weight was approximately 2500  infancy.  throughout.  she was g i -  veloped f l u - l i k e symptoms and a kidney i n f e c t i o n .  zed 7 - 8  18).  i n contact with r u b e l l a near the be-  ginning of the t h i r d month of g e s t a t i o n .  had been a d i a b e t i c  The  pregnancy eried i n  The second pregnancy had numerous c o m p l i c a t i o n s  ven Gamma G l o b u l i n .  The ma-  At 4 1/2  appeared  were delayed from e a r l y  He was r e p o r t e d to smile at age  bubbles at around 7 months, and at  activities  months the proband was  were informed that he  H i s milestones  and  4 months, to blow  1 year l e a r n e d to r o l l  over  38 from prone to supine p o s i t i o n .  He was unable to s i t ,  c r a w l , or  stand. On p h y s i c a l examination at 4 1/2 significantly -2 standard  small f o r h i s c h r o n o l o g i c a l age.  deviations  ence was -2.5  months, the proband was  for his height-age.  standard  deviations  H i s weight was  His head c i r c u m f e r -  for h i s c h r o n o l o g i c a l age,  but t h i s was not c o n s i d e r e d m i c r o c e p h a l i c .  The head was of  normal c o n f i g u r a t i o n and the a n t e r i o r f o n t a n e l l e was s t i l l  open.  He had s p a s t i c q u a d r i p l e g i a of severe degree and f r e q u e n t l y  as-  sumed a hyperextended p o s i t i o n of h i s back and head, p a r t i c u l a r l y when handled.  There was obvious b i l a t e r a l  with p u p i l s equal i n s i z e changes.  internal  and no evidence of macular or r e t i n a l  On examination the p a l a t e appeared  Examination of h e a r t ,  lungs,  s l i g h t l y arched.  abdomen, and g e n i t a l i a were normal,  although the t e s t e s were undescended. absent or exaggerated.  Severe  intellectual  development.  and s o c i a l  strabismus,  His r e f l e x e s  were e i t h e r  r e t a r d a t i o n was evident i n both  Chromosome i n v e s t i g a t i o n s  on the proband r e v e a l e d that two  chromosomes from the 13 - 15 group were missing and an e x t r a body was present  i n the 1 - 3  group.  It was presumed that a  t r a n s l o c a t i o n had occurred between two chromosomes i n the 13 15 group.  The parents  were examined and i t was found that  f a t h e r was 46, XY ( f i g u r e s  the  19 - 20) but the mother was a c a r r i e r  of a t r a n s l o c a t i o n s i m i l a r to that observed i n the proband.  39 A re-investigation present a)  of t h i s  family i n i t i a t e d d u r i n g t h i s  study r e v e a l e d the f o l l o w i n g :  the t r a n s l o c a t i o n was between a chromosome 13 and 14 21 -  26).  b) based on the G-banding ( f i g u r e s (figure  21 - 23)  27), both the centromeres  f l u o r e s c e n t banding ( f i g u r e region of chromosome 13 i s c)  (figures  26)  appear  27),  to be p r e s e n t .  The  shows the b r i g h t centromeric  present.  on the b a s i s of the G-banding ( f i g u r e s (figure  and the C-banding  21 - 23)  and C-banding  the break p o i n t s were determined to be i n the  short arms of both chromosome 13 and 14 i n the r e g i o n p l l - 1 2 . The immediate f a m i l y o f the mother refused  to  so the t r a n s l o c a t i o n c o u l d not be f o l l o w e d i n t h i s  co-operate, pedigree.  A n a l y s i s and chromosome counts were done f o r each f a m i l y member s t u d i e d (Table  3).  The schematic f i g u r e  is  d e r i v e d from  the P a r i s Conference (1971) to show the i d e a l i z e d form of the translocation  (figure  28).  Summary: Pedigree No.  Karyotype  1-1  46, XY  1-4  45, XX t d i c  Spontaneous 0-1  abortion  possible  (13;14)  (p!2;pl2)  trisomy D  45, XY, t d i c (13;14)  (pl2;pl2)  40  Clinical  signs:  S i g n i f i c a n t l y small head, s p a s t i c i t y , strabismus, mental r e t a r d a t i o n (social, intellectual), significantly small s t a t u r e , undescended testes  41  pedigree? - case 3  O  O  4  2 A"  0  D/D translocation carrier o ® = normal chromosomes • o = untested 9 miscarriage Figure 18.  Pedigree  - case 3 TABLE 3  Number on Pedigree  Number, of, .Chromosomes , ^144  44  45  46  47  1 - 1  1  2  1  30  -  34  1 - 4  3  2  33  -  38  0 - 1  1  5  30  -  36  >47  TOTAL  42  a  s  3  6  A 13  1!)  Figure 19.  i-l  12  4  a v  15  16  Giemsa-banded karyotype  II  .M.  17  18  22  21  II  F l u o r e s c e n t karyotype  Y  - i n d i v i d u a l pedigree  3-1-1  II H  v« H M  |I i f (I  Figure 20.  .  20  \\ J l II II  7  "  - individual  »  I  4 1  pedigree  3-1-1  43  5 g a  it  A  ?  s  4 15  ' V *  *  *  t i  Aft  8  l/  16  18  J 20  19  Figure 21.  Giemsa-banded karyotype  ) If If  P 8.4 13  19  Figure 22.  - proband  118 gill in11 1  •1 •  21  8  M  i.e. 20  IM IS  22  case 3  Ml)  8 III Mi  <  17  18  21  Giemsa-banded karyotype - i n d i v i d u a l pedigree  3-1-4  Figure 23.  P a r t i a l Giemsa-banded karyotype  )• iv ir i f  Figure 24.  K  . i  II  : ;•  F l u o r e s c e n t karyotype  - proband case 3  i »  n « •  - proband case 3  • '  45  11 11 i f -.; « t ) i  it  >•  n 1  II  i l.i  Figure 25.  F l u o r e s c e n t karyotype  - i n d i v i d u a l pedigree  3-1-4  Figure 26.  P a r t i a l f l u o r e s c e n t karyotype s i n g l e chromosome 13, 13/14 t r a n s l o c a t i o n chromosome, s i n g l e chromosome 14, chromosome 15 p a i r - proband case 3  46  A II  li  i H  13, i II  IB  17  a,  u I/  111  in  Figure  27.  .'i  C-banded k a r y o t y p e  - proband  case  3  ft<t in  13  Figure  28.  Schematic  d i a g r a m o f D/D  translocation  - case  48 Case 4 The proband, a male born on January  1957, was  the  t h i r d pregnancy of u n r e l a t e d parents who had been married  for  eight years.  24,  The maternal age was 31 years and the p a t e r n a l  age was 29 y e a r s .  P r i o r to the proband's  two m i s c a r r i a g e s .  The times  birth,  there had been  of these m i s c a r r i a g e s  are not knoxvn.  The t h i r d pregnancy of t h i s mother was abnormal. complicated with eclampsia As a r e s u l t , full  term.  a Caesarian  and severe toxemia with c o n v u l s i o n s .  s e c t i o n was performed four weeks  band began walking and had spoken h i s At 18 months, p a r e n t a l  concern about  first  year.  the proband's  i n v e s t i g a t i o n was c a r r i e d out and the. r e s u l t s  h e a r i n g and E . E . G . from the b i l a t e r a l  No p h y s i c a l a b n o r m a l i t i e s epicanthic folds  ened hands and f e e t .  On t e s t i n g  at  cal  speech  examination.  showed normal  were apparent  and the appearance of three years of age,  tures d i d not suggest mental d u l l n e s s .  time.  lack of  he was f u n c t i o n i n g at a l e v e l of two years o l d .  were w i t h i n  The pro-  words by that  and h i s h y p e r a c t i v e behaviour l e a d to a more d e t a i l e d  felt  before  The b i r t h weight was 2670 grams.  Development appeared normal f o r the f i r s t  Full  I t was  it  His  apart shortwas fea-  His h e i g h t and weight  the normal range for h i s age.  His head was symmetri-  and of normal shape, although the s k u l l circumference was  about one standard systolic markable.  d e v i a t i o n below the mean for h i s age.  murmur was n o t e d .  The lungs  The t e s t e s were  descended.  and abdomen were not  A soft re-  49 He showed r a p i d changes  i n mood and i n t e r e s t .  was i n d i s t i n c t and p o o r l y a r t i c u l a t e d . tendon r e f l e x e s  proband s u f f e r e d  may have l e f t  presence  were d o u b t f u l .  From these examinations,  of h i s mother's  Limb tone, power, and  were w i t h i n normal l i m i t s , though the  of abdominal r e f l e x e s  His speech  the d i a g n o s i s  made was that  from c e r e b r a l anoxia i n utero during the p e r i o d toxemia and c o n v u l s i o n .  It was thought that  autism w i t h p o s s i b l e  mental  It was l a t e r  called  infantile  retardation.  The mother's f o u r t h pregnancy r e s u l t e d i n a male born October 27,  nancy.  this  him with patchy b r a i n damage c h a r a c t e r i z e d by the  " o r g a n i c behaviour syndrome".  a horseshoe  the  1959, who i s normal except  kidney.  natal achalasia  pregnancy r e s u l t e d i n a female  1961, who i s normal. in this  nervous with f i t s  f o r the presence  The mother had no toxemia d u r i n g t h i s  The mother's f i f t h  born October 20,  infant,  female.  of temper.  of  preginfant,  There was a r e p o r t of neo-  The mother has been r e p o r t e d  Her E . E . G . ,  she s a y s , i s  as  "slightly  abnormal". Chromosome s t u d i e s on the proband r e v e a l e d two chromosomes from the 13 - 15 group were m i s s i n g and an e x t r a body was in  the 1 - 3  group.  It was presumed that a t r a n s l o c a t i o n had oc-  c u r r e d between two chromosomes i n the 13 - 15 group. were i n v e s t i g a t e d (figure  30 - 31)  present  The parents  and i t was found that the f a t h e r was 46, XY and that  the mother was a c a r r i e r of a t r a n s l o c a t i o n  50 similar  to that observed i n the proband.  siblings  The male and female  were examined and i t was shown that  they both c a r r i e d  the t r a n s l o c a t i o n chromosome. F u r t h e r i n v e s t i g a t i o n of the maternal family i n I r e l a n d t r a c e d the t r a n s l o c a t i o n back to the maternal grandmother of the proband.  Because of d e a t h s ,  not be t r a c e d any f u r t h e r .  the t r a n s l o c a t i o n chromosome c o u l d The pedigree  The maternal grandmother (II-2)  had f i v e  females) with no r e p o r t e d spontaneous five  offspring  abortions.  the proband's p a r e n t s .  carriers  trans-  those of  A re-investigation  The  transloca-  offspring.  of the proband's  i n i t i a t e d during t h i s present  two o f f s p r i n g .  t r a n s m i t t e d the  t i o n chromosome to at l e a s t one of t h e i r  immediate f a m i l y  study r e v e a l e d the f o l l o w i n g :  the t r a n s l o c a t i o n was between a chromosome 13 and 14 32 -  four  One t r a n s l o c a t i o n c a r r i e r f a i l e d to pass  three remaining t r a n s l o c a t i o n  b)  These  r e p o r t e d are  the t r a n s l o c a t i o n chromosome to e i t h e r of h i s  a)  Four o f these  5 of whom had the  abortions  29.  (3 males, 2  chromosome.  had 10 o f f s p r i n g ,  The only spontaneous  shown i n f i g u r e  children  c a r r i e d the t r a n s l o c a t i o n  translocation carriers location.  is  (figures  40).  on the b a s i s o f the G-banding ( f i g u r e s ; 32 - 35) , Q-banding (figures  37 - 39),  and C-banding ( f i g u r e s  l o c a t i o n appears to be monocentric. of chromosome 13 as  the f l u o r e s c e n t  41 - 42),  the  The centromere i s results  transthat  show the b r i g h t  51 centromeric r e g i o n i s present  and the Giemsa s t a i n i n g adds  f u r t h e r evidence f o r t h i s c o n c l u s i o n , c) on the b a s i s of the G-banding ( f i g u r e s  32 - 35),  the break  p o i n t s were determined to be i n the s h o r t arms of chromosome 13 at pl2 and i n the long arms of chromosome 14 at q l l . A n a l y s i s and chromosome counts were done f o r each family member (Table Conference tion  4).  The schematic f i g u r e  is  d e r i v e d from the P a r i s  (1971) to show the i d e a l i z e d form of the  (figure  transloca-  43) .  Summary: Pedigree No.  Karyotype  1-15  46, XY  1-2  45, XX, t(13;14)  (pl2;qll)  0-10  45, XY, t(13;14)  (pl2;qll)  0-11  45, XY, t(13;14)  (pl2;qll)  0-12  45, XX, t(13;14)  (pl2;qll)  0-10  Clinical  signs:  " i n f a n t i l e autism", mental r e t a r d a t i o n , b i l a t e r a l epicanthic f o l d s , shortened hands and f e e t .  0-11  Clinical  signs:  horseshoe kidney  0-12  Clinical  signs:  neonatal  achalasia  reaigree - case  ^ O 2  n  4-n 2  5"  2  l6  ^5  4  5  4  3  In] 6  ID] (•) 7  8  6  ID] (0) IDI 4> 9  10  II  II  12  12-14  Hd  15  7  (!) 16  r1\  0  n(Q)  (r3KQ) 1 2  3  4  J o 5  6  © ^ i 7  8  9  H © = D / D translocation carrier 0(5)= normal chromosomes • O = not tested + - dead Figure  29.  P e d i g r e e - case 4  10  13 14  15 16  17  TABLE 4  Number on Pedigree  Number of -<44  chromosomes  44  45  46  47  >47  TOTAL  1 - 2  4  2  36  1  43  1 - 15  3  2  1  24  30  0 - 10  1  2  35  1  39  0 - 11  2  2  27  -  0 - 12  5  -  24  1  -  -  31 30  54  I f 1)1  •<  8  14 3  3  J  R[( A,IU :A> JIMJI  p.  6  ^ 0  PM  13  l'4  19  20  Figure 30.  12  M l  H A la  16  i.i. 17  i/a 18  21  Giemsa-banded karyotype  - individual  22  pedigree  M I i II  l» »»  II  •  Figure 31.  •  •• 1  F l u o r e s c e n t karyotype  4-1-15  ••  - i n d i v i d u a l pedigree 4-1-15  55  ^  »  6  i  *  ft-'  *  ^  m  ?  I 1 in i  (i  M  1  ft  13  12  14  it,  16  1!>  ! 17  HI  4  ft!  19 Figure 32.  »  i\  Giemsa-banded karyotype  - proband  :'  i  case 4  lilt  l i l y ? i  r  m  A  i  Ir * ) l > r i n i i c i f  f r* u l.l  Figure 33.  14  T I!)  19 20 Giemsa-banded karyotype  w tt It.  1/  ?1  u Ii!  <j  - i n d i v i d u a l pedigree 4-1  56  Suisse X  A 13  19  Figure  I  a A «* 6-12  ft i4  M 15  20  . M . 16  17  18  21  22  Y  34.  Giemsa-banded karyotype  - i n d i v i d u a l pedigree  4-0-11  Figure 35.  Giemsa-banded karyotype  - i n d i v i d u a l pedigree  4-0-12  57  Figure  37.  Fluorescent  karyotype  - i n d i v i d u a l pedigree  4-1-2  58  0  i t II  iii) * »  H i t  : «  5  $i i  i i  1 • •• I . Figure  38.  M It  Figure 39.  F l u o r e s c e n t karyotype - i n d i v i d u a l pedigree  4-0-11  If i t  i  •  .  i I  F l u o r e s c e n t karyotype - i n d i v i d u a l  9 ft  pedigree  4-0-12  59  Figure  40.  P a r t i a l f l u o r e s c e n t karyotype s i n g l e chromosome 13, 13/14 t r a n s l o c a t i o n chromosome, s i n g l e chromosome 14, chromosome 15 p a i r - proband case 4  iii »  •  s  X  4 13  •i 19  Figure 41.  l  6 12  A A 15  14  i 0  S;  U  »  •  M i. A 16  ' ! *  U  §_  •  |  17  18  21  22  i i  • 20  C-banded karyotype  - i n d i v i d u a l pedigree  4-1-2  Figure  42.  Partial  C-banded k a r y o t y p e  - proband  case  4  13  Figure 43.  Schematic diagram of D/D t r a n s l o c a t i o n  - case  62 Case 5 The proband, a male born on A p r i l pregnancy of t h i s u n r e l a t e d c o u p l e . til  14,  1969, was the  The pregnancy continued un-  38 weeks and was complicated by excessive weight g a i n ,  eclampsia without any s p e c i a l  medications  and a h i s t o r y  i b l e with a generalized convulsion during d e l i v e r y . at  pre-  compat-  Maternal age  the b i r t h of the proband was 28 years and the p a t e r n a l  30 y e a r s .  third  age  was  The b i r t h weight was 1960 grams and i n the i n i t i a l new-  born p e r i o d , the proband appeared normal. The c o u p l e ' s J u l y 25,  first  pregnancy r e s u l t e d  i n a female,  born  1966, who i s normal i n development and i n t e l l i g e n c e .  The second pregnancy ended i n the b i r t h o f a 7 1/2'month male, who died at  2 days of age with m u l t i p l e anomalies  c l e f t p a l a t e and P o l y d a c t y l y . born June 23,  premature including  The f o u r t h pregnancy was a  female,  1972, whose b i r t h weight was 3494 grams ( f i g u r e  The proband was delayed i n development through the twenty months, he s m i l e d at three months, r o l l e d over at months, and c o u l d h o l d h i m s e l f up at examination was performed before developed but had a p e c u l i a r ging forehead.  fourteen months.  one year of age.  first  seven  A physical  He was w e l l  f a c i e s , with a r a t h e r high and b u l -  His head circumference was at  h e i g h t was one standard  44).  the mean and h i s  d e v i a t i o n below the mean f o r h i s  age.  His eyes were normal and although h i s p a l a t e was h i g h l y arched, he had a normal o r a l c a v i t y otherwise.  His chest was  somewhat  f l a t t e n e d b u t t h e r e were no a b n o r m a l i t i e s i n t h e c a r d i o v a s c u l a r , pulmonary, o r a l i m e n t a r y sent at  over  the p a r i e t o - a c c i p i t a l  the t i p o f the r i g h t  bilaterally. borders left and  ring  Developmentally, s i t with  this  although  t o those  female  difficulty  one  year  third percentile  A l l of h i s primitive  was  present  head.  mannerisms  i n the proband.  a l w a y s slow  and a t n i n e  but r e q u i r e d s u p p o r t .  sounds.  Her eyes  months  She d i d n o t  P h y s i c a l examination  appeared  and s o f t  n a s o p h a r y n x was  skin  noted  at less  was  than  above the  f o r h e r age w h i l e h e i g h t and w e i g h t were w i t h i n  of the hard  atory,  and t h e  generally hypotonic  normal w i t h  a l l o w e d h e r t o f o l l o w moving o b j e c t s .  cleft  fingers  o f age r e v e a l e d t h a t h e a d c i r c u m f e r e n c e  ranges.  on t h e u l n a r  she h a d some w e i g h t b e a r i n g movements and she  o n l y a few c o o i n g  The  He was  of h i s j o i n t s .  similar  had  that  o f the s m a l l  the newborn p e r i o d t h e p a r e n t s  the f o u r t h c h i l d  normal  digits  absent.  During  crawl,  a r e a , and  He h a d u n d e s c e n d e d t e s t e s  supernumerary  crease.  had h y p e r e x t e n s i b i l i t y  could  r e g i o n , lumbar s a c r a l  phalanges  hand showed a s i m i a n  were  T h e r e were haemangiomata p r e -  finger.  T h e r e were t i n y  o f the p r o x i m a l  reflexes  in  systems.  The g e n i t a l i a were  through  a complete t o the u v u l a .  The c a r d i o v a s c u l a r , r e s p i r -  and a b d o m i n a l s y s t e m s were n o r m a l .  showed no a b n o r m a l i t i e s o t h e r  strabismus  T h e r e was  p a l a t e , extending  q u i t e hyperemic.  mild  than  g r o s s l y normal  Examination  of the  a haemangioma on t h e f o r e f o r a female  o f h e r age.  64 The n e u r o l o g i c a l examination showed she had moderate h y p o t o n i a with normal r e f l e x e s of her l e f t  throughout.  She had a p e c u l i a r  hand with the thumb and f i f t h  finger  posturing  crossing  over  the dorsum of the hand to meet i n the m i d l i n e . C y t o g e n e t i c examination of the proband r e v e a l e d a chromosome m i s s i n g from the 13 - 15 group and an e x t r a body i n the 1 3 group.  I t was presumed due to the c l i n i c a l p a t t e r n  lies  the c h i l d was a trisomy -D syndrome and the e x t r a body  that  i n the 1 - 3  group was a t(Dq Dq) between two chromosomes o f  13 - 15 group. that  The parents were i n v e s t i g a t e d  the father was 46, XY ( f i g u r e s  a c a r r i e r of a t r a n s l o c a t i o n band.  45 - 46)  and i t was  She a l s o had a s m a l l t(Dp Dp) fragment.  to her mother as  the f i r s t  sib  found  i n the pro-  The two s i b s were  (0-1)  was  similar  she c a r r i e d both the t(Dq Dq) t r a n s l o c a t i o n  the t(Dp Dp) fragment.  The other s i b  (0-4)  the  and the mother was  s i m i l a r to that observed  examined and i t was found that  large  of anoma-  d i d not c a r r y  t(Dq Dq) t r a n s l o c a t i o n but d i d c a r r y the small  and  the  t(Dp Dp)  fragment. A re-investigation i n i t i a t e d during t h i s a)  present  study r e v e a l e d  immediate  family  the f o l l o w i n g :  the r e c i p r o c a l t r a n s l o c a t i o n was between a chromosome 13 and 14 ( f i g u r e s  b)  of the proband's  47 -  55).  on the b a s i s o f the G-banding ( f i g u r e s (figures  52 - 55),  47 - 51)  the t(Dp Dp) t r a n s l o c a t i o n  and Q-banding  involves  the  65 centromere and s h o r t arms of chromosome 13 and the s h o r t of chromosome 14.  The b r i g h t centromeric r e g i o n of chromosome  13 was found i n the t(Dp Dp) fragment. evidence that  the t(Dp Dp) fragment  chromosome 13.  arms  There i s  also  clinical  i s mainly composed of  The t(Dq Dq) t r a n s l o c a t i o n i n v o l v e s the centro-  mere and long arms of chromosome 14 and the long arms of chromosome 13. c)  on the b a s i s of the G-banding, the break p o i n t s were determined as  i n the short arms of chromosome 14 at p l l and i n the long  arms of chromosome 13 at  ql2.  A n a l y s i s and chromosome counts were done for each family member (Table 5). Conference (figure  The schematic f i g u r e  is  d e r i v e d from the  (1971) to show the i d e a l i z e d form of the  translocation  56) .  Summary: Pedigree No.  Karyotype  1-1  46, XY  1-2  46, XX, t(13q;14q)  (ql2;pll)  t(13p;14p)  (ql2;pll)  46, XX, t(13q;14q)  (ql2;pll)  t(13p;14p)  (ql2;pll)  0-1  Paris  0-2  female, probable trisomy 13  translocation  0-3  46, XY, t(13q;14q)  (ql2;pll)  0-4  47, XX, t(13p;14p)  (ql2;pll)  66 0-2  Clinical  signs:  m u l t i p l e anomalies i n c l u d i n g c l e f t p a l a t e and P o l y d a c t y l y , f a i l u r e to t h r i v e  0-3  Clinical  signs:  psychomotor r e t a r d a t i o n , mixed c o n v u l s i v e d i s o r d e r , arched p a l a t e , P o l y d a c t y l y , simian crease, hypotonia, multiple haemangioma, undescended t e s t i c l e s , profound i n t e l l e c t u a l and s o c i a l r e t a r d a t i o n , hyperextensible joints  0-4  Clinical  signs:  psychomotor r e t a r d a t i o n , cleft p a l a t e , s t r a b i s m u s , haemangioma, hypotonia, finger posturing, moderate i n t e l l e c t u a l and severe s o c i a l r e t a r d a t i o n , s m a l l head  pedigree - case 5  • # B<3 M% 0© • O +  = = = =  67  trisomy-D due to Dq Dq translocation trisomy-D due to Dp Dp translocation D/D translocation carrier normal chromosomes not tested dead  Figure 44.  Pedigree - case 5  TABLE 5  Number on pedigree  Number of  chromosomes  < 44  44  XS  46  47  i : - -. i  1  3  1  27  I . -~i  1  5  3  32  (K - ~M OL - 3 0 - 4  2 1 1  -  2 2 1  31 25 6  -  1  -  1 23  >47  TOTAL 32  1  41 35 30 32  68  .Hi 3  A* U S ! 1  ^  HI 3 ;  X  U .3  14  l l *  ll  4  a | 6  .2  1.1 JLIM  HI  16  15  20  18  21  22  C  ir  5-1-1  it  II I I II 1C I f 1 1  ii  % A 1 # 1 ft  Figure 46.  17  Giemsa-banded karyotype - i n d i v i d u a l pedigree  U If n  f •  !.  \ * _  1!)  Figure 45.  3  9  t  i t  i  t *#  * •  F l u o r e s c e n t karyotype - i n d i v i d u a l pedigree  5-1-1  69  »—  M  *>  *•  *  i ...  M  N  sr H  *  •1  *A  A  * *  *  *>  h  if. 14  13  II  i t  * * Hi  if)  * % 1!) Figure  47.  Giemsa-banded  » #1  A)  1  *  2  ft  karyotype  in  ?1  2?  case  M 13 I  Y  5  I*  3  -I  gift j i g  ft • •  *  6 12  x  it*  A  Figure  - proband  I/  48.  13  M  19  ,'(1  ** 16  -  in  ii;  1  Giemsa-banded  a&  t  •  21  karyotype  - individual  pedigree  5-1-2  70  ss ** x  14  13  - . 19  Figure 49.  i»'  * a 4 t t z: n 6 1?  15  |6  1/  V* ;o  16  •• •  21  22  Giemsa-banded karyotype - i n d i v i d u a l pedigree  Ul*!) 1  2  5-0-1  i t If 4  3  5  11 V I M ! ! Ir If 1.1. I * 6  •_t_ 13  U 14  JtiJi 19  Figure 50.  20  12  11  MM. ML 15  16  17  Mil  18  , M _  21  Giemsa-banded karyotype - i n d i v i d u a l pedigree  22  5-0-4  71  I  0  X  '. l j _ * 13 Figure 51.  14  P a r t i a l Giemsa-banded karyotype  ii ii  ir i i ii II II • « •  i  S  Figure 52.  II 1  i « •  1. *  - proband case 5  •  F l u o r e s c e n t karyotype  1  i: •  . - proband case 5  A  II »  •  4  Figure 53.  F l u o r e s c e n t karyotype - i n d i v i d u a l pedigree  ft  5-1-2  U l) a i.i.ti a i * t  Figure 54.  ft  «  #  F l u o r e s c e n t karyotype - i n d i v i d u a l pedigree  5-0-1  73  Figure  55.  Fluorescent  karyotype  - individual  pedigree  5-0-4  Figure  56.  Schematic diagram  o f D/D  translocation  - case  CHAPTER IV DISCUSSION In the i n t r o d u c t i o n , c e r t a i n questions  were asked  con-  c e r n i n g the t(Dq Dq) t r a n s l o c a t i o n chromosome i n man.  These  questions  involved  were:  1) which chromosome p a i r or p a i r s  i n the t r a n s l o c a t i o n ; involved;  3) what i s  2) where are  the p o s s i b l e  the segregation  t(Dq Dq) t r a n s l o c a t i o n ;  and  Segregation  4) what i s  of the t(Dq Dq)  1) Homologous t(Dq Dq) The s e g r e g a t i o n  the p o s s i b l e  from the present  translocations  this  translocation?  translocations  of the t(Dq Dq) t r a n s l o c a t i o n  differs  i n v o l v e d i n the t r a n s l o c a t i o n .  Re-  study have shown homologous t(Dq Dq)  i n two of the cases c y t o g e n e t i c a l l y examined.  The proband i n pedigree t(14q;14q)  mechanism  translocations  depending on the chromosomes sults  break p o i n t s  p a t t e r n of a f a m i l i a l  or mechanisms of formation of the t(Dq Dq) A.  are  1 is  translocation.  an i n f a n t with a homologous  This  is  only the second r e p o r t of  type of homologous t(Dq Dq) chromosome, the f i r s t  p o r t e d by Hulten and L i n d s t e n (19 70)  and Caspersson e t  (1971).  The f a t h e r  of the proband i n pedigree  o l d male  (1974) with a homologous t(13q;13q)  75  2 is  was  re-  al.  a 45 year  translocation.  76 This form of homologue has been the most commonly r e p o r t e d the t(Dq Dq) type  (de Grouchy et a l . ,  1970;  amongst  Cohen, 1971; Niebuhr,  19 72a; Emberger et a l . , 19 72 ; Hsu et a l . , .19 73;  Gardner et a l . ,  1974). Lucas all  (1969) examined a female who had had 13  of which terminated before  the 15th week of g e s t a t i o n .  was shown to be a c a r r i e r of a homologous Caspersson  et a l .  (1971) a s c e r t a i n e d  15/15  miscarriages  a homologous 14/14  translo-  miscarriages.  (1973) examined a female who had experienced  all  mal p r e g n a n c i e s . gous 13/13  She  translocation.  c a t i o n i n the husband of a female who had r e c u r r e n t Parslow et a l .  pregnancies,  t e r m i n a t i n g before  three  the 12th week and had no nor-  They found that she was a c a r r i e r of a homolo-  translocation.  The r e p r o d u c t i v e h i s t o r i e s translocation  carriers  o f the homologous  t(Dq Dq)  show a high r a t e of a b o r t i o n presumably  due to the formation of trisomy -D embryos.  The trisomy -D  c o n s i t t u t i o n would vary depending on the chromosome p a i r i n v o l v e d in  the t r a n s l o c a t i o n .  K a j i i et a l .  seven of D - t r i s o m i c a b o r t i o n s were e i t h e r  trisomy 14 or 15.  in liveborn infants,  (1975) r e p o r t e d that  s t u d i e d by banding This i s  There has been no i n s t a n c e s  techniques  c o n t r a r y to the  whose e x t r a D chromosome i s  all  findings  chromosome  13.  of trisomy 14 or 15 found i n l i v e -  born i n d i v i d u a l s although a case of trisomy 14 mosaicism i s known (Gendel e t  al.,  1970).  There a l s o have been r e p o r t s  of  partial  77 trisomy -D syndromes and 15. et a l . ,  i n l i v e b o r n i n d i v i d u a l s f o r chromosome 14  Cases of p a r t i a l 1973)  and A l f i ,  and p a r t i a l  trisomy 14 (Short et a l . , 1972; trisomy 15 (Webb et a l . , 1971;  1972 ; Bucher e t a l . , 1973;  not separable by c l i n i c a l  (Sinet  et a l . ,  2 is  t(13q;13q)  transloca-  with that shown i n p r e v i o u s  The proband i n pedigree  band's  to the t(13q;13q)  father.  The f i r s t  translocation  born female  observed  of pedigree  s u r v i v e and was  found to have a heart defect  brane d i s e a s e .  With the c y t o g e n e t i c  translocation  in this  female's  she was a l s o a t r a n s l o c a t i o n studied cytogenetically  at  that  time of  abortions  t(13q;13q) that  She c o u l d not be  death.  Although the l i v e b o r n t r a n s l o c a t i o n spontaneous  to  and h y a l i n e mem-  i t might be presumed  trisomy -13.  to  i n the pro-  2 failed  f i n d i n g of the  father,  cases  2 was shown to be  a c a r r i e r of a t(Dq Dq) t r a n s l o c a t i o n which can be presumed be s i m i l a r  are  phenotype.  consistent  1973).  Parker  C r a n d a l l et a l . , 1973)  The s e g r e g a t i o n of the homologous t i o n i n pedigree  Muldal  trisomy -13 and the  give evidence of the c o n s i s t e n t  presence  of the homologous t(Dq Dq) chromosome, the n u l l i s o m i c p o r t i o n of segregation must be c o n s i d e r e d . somy embryo dies before are not found.  is  thought t h a t  the mono-  i m p l a n t a t i o n since monosomy D abortuses  There has been one r e p o r t of a D group monosomy  in a liveborn i n d i v i d u a l (Pelz, karyotype was a c o n s i s t e n t pheral blood.  It  1971).  observation  The 45 XY, -D monosomy i n a l l s t u d i e s of the p e r i -  There was no evidence of mosaicism or  translocation  78 i n 120 c e l l s .  The proband, a male, had s e v e r a l phenotypic an-  omalies and d i e d at s i x months of age. been more valuable  if  skin biopsies  This r e p o r t would have  had been used to v e r i f y the  monosomy karyotype and i f the monosomy D chromosome had been identi f ied. A syndrome for p a r t i a l monosomy 13 (Grosse and Schwanitz, 1973;  Ikeuchi et a l . ,  1974)  is  found e i t h e r as  or r i n g formation (Zink et a l . , Niebuhr and O t t o s e n , 1973).  a simple d e l e t i o n  1973; N i e b u h r , 1973a, 1973b;  Another r e p o r t shows syndrome  s o c i a t i o n due to the D - group d e l e t i o n s of p a r t i c u l a r D chromosomes which r e s u l t s  (Lehrke et a l . ,  as-  1971)  i n p a r t i a l D - group  monosomy k a r y o t y p e s . The low sperm count r e p o r t e d i n pedigree be due to n u l l i s o m i c sperm not maturing.  If  this  2 (1-4) is  may  true then  the only sperm type i n t h i s male would c a r r y the homologous t(13q;13q)  translocation.  Of i n t e r e s t (1973).  is  the case r e p o r t e d by Parslow et  They r e p o r t e d a female homologous 13/13  al.  translocation  c a r r i e r who never had a pregnancy proceed beyond the 12th week. While i n pedigree t(13q;13q)  2 of the present  the male homologous  t r a n s l o c a t i o n c a r r i e r had both h i s conceptions pro-  ceed to f u l l  term.  The other r e p o r t s were i n new-born p a t i e n t s available  study,  of homologous t(Dq Dq)  translocation  and no r e p r o d u c t i v e h i s t o r i e s  (Rowley and Pergament,  1969;  are  de-Grouchy et a l . , 1970 ;  79 Cohen, 1971;  Miller  al.,  It  1,  1972).  t(14q;14q)  N i e b u h r , 1972a; Yoshida e t the proband of  translocation  live-born individuals.  e i t h e r trisomy 14 and w i l l for  1971;  may be p r e d i c t e d that  a homologous  able to f a t h e r  et a l . ,  chromosome 14 w i l l  carrier,  will  be un-  A l l conceptions w i l l  spontaneously  probably be l o s t  2) Non-homologous t(Dq Dq)  pedigree  abort  be  or i f monosomy  p r i o r to i m p l a n t a t i o n .  translocations  The s e g r e g a t i o n p a t t e r n s of non-homologous t(Dq Dq) translocations locations.  differ  from those of homologous t(Dq Dq)  The major d i f f e r e n c e  is  that non-homologous  may produce normal or balanced c a r r i e r karyotypes homologous  types  can only produce  translocation  transtypes  while the  t r i s o m i c karyo-  types . The most commonly r e p o r t e d t(Dq Dq) t r a n s l o c a t i o n the l i t e r a t u r e chromosomes ilies  i n v o l v e s chromosomes  of  r e p o r t e d i n pedigrees  t(13q;14q)  3 and 4.  There i s  of the fam-  3, there  translocation  one r e p o r t of a  is  carrier.  of the t(13q;14q) family i s  spontaneous  i n f o r m a t i o n on i t .  no c o n c l u s i o n s  A much l a r g e r  the  chromosome was found i n the mother  a b o r t i o n but there i s no f u r t h e r the small p e d i g r e e ,  In pedigree  a t(13q;14q)  translocation  the proband as w e l l .  tion pattern  These are  i n v o l v e d i n the t(Dq Dq) t r a n s l o c a t i o n s  only one l i v e b i r t h which i s This  13 and 14.  in  Owing to  can be made on the segrega-  translocation available  in this  i n pedigree  the e x c l u s i o n of the proband and the abortuses  family. 4.  from the  With analysis,  80 the t r a n s l o c a t i o n i s shown t o have been t r a n s m i t t e d t o e i g h t o f f o u r t e e n progeny.  T h i s i s a n o n - s i g n i f i c a n t d e v i a t i o n from a 1:1  r a t i o f o r t h e t r a n s l o c a t i o n c a r r i e r t o n o n - c a r r i e r . These r e s u l t s d i f f e r from t h o s e o f Hamerton (1972) and i t c o r r e s p o n d s w i t h t h o s e o f Jacobs e t a l . (1974).  T h e r e i s no d e v i a t i o n i n t h e sex r a t i o  from 1:1 w i t h i n the t r a n s l o c a t i o n h e t e r o z y g o t e s which c o r r e s p o n d s w i t h the r e s u l t s o f Hamerton (1972) and J a c o b s e t a l . ( 1 9 7 4 ) .  No  chromosomal o r . g e s t a t i o n a l i n f o r m a t i o n i s known a b o u t t h e o n l y two spontaneous a b o r t i o n s i n t h e f a m i l y so no comment can be made about t h e i r s i g n i f i c a n c e t o the s e g r e g a t i o n a n a l y s i s . From the f a m i l y p e d i g r e e s 3 and 4, t h e r e i s no e v i d e n c e o f a d j a c e n t s e g r e g a t i o n i n the male o r f e m a l e t(13q;14q) t r a n s l o c a t i o n carriers.  A d j a c e n t s e g r e g a t i o n i n the s p e r m a t o c y t e o r o o c y t e o f  t h e s e c a r r i e r s would p r o d u c e a d i s o m i c gamete which on f e r t i l i z a t i o n would be t r i s o m i c f o r chromosomes 13 o r 24.  Published results  how  a d j a c e n t s e g r e g a t i o n t o be o f t h e v e r y low l e v e l o f a p p r o x i m a t e l y 1-2%  ( D u t r i l l a u x and L e j e u n e , 1970; Hamerton, 1972; S i n e t e t a l . ,  1973; J a c o b s ' e t a l . , 1974).  S e g r e g a t i o n i n p e d i g r e e s 3 and 4, as  d e t e r m i n e d from the l i v e - b o r n i n d i v i d u a l s , i s a l t e r n a t e , t h e r e b y p r o d u c i n g i n d i v i d u a l s who a r e t(13q;14q) t r a n s l o c a t i o n c a r r i e r s o r have normal k a r y o t y p e s . The chromosomes i n v o l v e d i n the t r a n s l o c a t i o n i n p e d i g r e e 5 a r e chromosomes 13 and 14.  The major d i f f e r e n c e between t h i s  c a s e and t h o s e i n p e d i g r e e s 3 and 4 i s the p r e s e n c e o f a  81 smaller  t(13p;14p)  translocation. gregation  t r a n s l o c a t i o n as w e l l as  The r e s u l t  are present  location in this pole at meiosis  of both a l t e r n a t e  in this pedigree.  t(13q;14q)  and adjacent  The t(13p;14p)  setrans-  family appears to move randomly to e i t h e r I . The p o s s i b i l i t y o f d i s t r i b u t i v e p a i r i n g  ( G r e l l and V a l e n c i a , 1964; since  the l a r g e r  Grell,  1967)  was c o n s i d e r e d but  there i s no evidence of n o n - d i s j u n c t i o n i n chromosomes  similar in size  to the t(13p;14p)  t r a n s l o c a t i o n , no comment  can be made. The a l t e r n a t e is  segregation  of the t r a n s l o c a t i o n complex  shown by i n d i v i d u a l s i n . pedigree  sib  (0-1)  is  5 (0-1  a c a r r i e r of the t(13q;14q)  and 0-4).  The  and t(13p;14p)  trans-  locations  and four normal U chromosomes, while the fourth  (0-4)  the t(13p;14p)  has  The adjacent is  of the t r a n s l o c a t i o n  shown by i n d i v i d u a l s i n pedigree is  t(13p;14p)  translocation.  sib  and s i x normal D chromosomes.  segregation  band (0-3)  first  a translocation  5 (0-2  and 0-3).  complex The p r o -  trisomy 13 and does not c a r r y the  Although no autopsy or  cytogenetic  r e p o r t was done on the s t i l l b o r n ( 0 - 2 ) , m u l t i p l e anomalies i n c l u d i n g c l e f t p a l a t e and P o l y d a c t y l y were noted at b i r t h . clinical  signs  suggest that the i n f a n t had the trisomy  These  -13  syndrome. B.  Possible  mechanism of formation of the t(Dq Dq)  The formation of the homologous t(Dq Dq) on t h e o r e t i c a l grounds must have o c c u r r e d at  translocation  translocations  the f i r s t  division  82 of the f e r t i l i z e d ovum, i f no mosaicism is p r e s e n t . origin  is  u n l i k e l y because the e f f e c t i v e  A prezygotic  disomic gamete,  ferti-  l i z e d by a normal gamete would produce a t r i s o m i c zygote. i t was of p r e z y g o t i c o r i g i n , additional abnormalities  i t would be necessary  to  If  postulate  of chromosome d i s t r i b u t i o n i n the other  gamete to produce the e f f e c t i v e l y balanced chromosome s t a t e shown i n pedigrees  1 and 2.  on c u l t u r e d leukocytes 45 i n pedigrees  logous 2.  These r e s u l t s  in either  I t appears that  suggest there i s no  case.  the mechanism of formation f o r the homo-  t(Dq Dq) t r a n s l o c a t i o n was d i f f e r e n t  Its  cation.  analysis  showed the modal chromosome number was  1 and 2.  mosaicism present  Chromosome counts and c e l l  as  formation i n pedigree  1 is  The chromosome i n pedigree  i n pedigrees  due to a r e c i p r o c a l 1 (0-1)  l;:and translo-  appears to have one  centromere and i s non-symmetrical on e i t h e r side of the c e n t r o mere, as  shown by G and C-banding.  location is  This type of r e c i p r o c a l  trans-  the mechanism o r i g i n a l l y proposed for the formation  of the t(Dq Dq) t r a n s l o c a t i o n s  (Hamerton, 1972).  By t h i s mech-  anism the break p o i n t s would be i n the p r e g i o n of one chromosome 14 and the q- centromere region of the other chromosome 14. This  type of r e c i p r o c a l t r a n s l o c a t i o n may be c o n s i d e r e d "incom-  p l e t e " because there i s no evidence centromere - s h o r t arm fragment  for the presence  of the  due to the break i n the long arm-  centromere region of one chromosome 14.  83 In pedigree  2,  the morphological evidence suggest  the formation of the t r a n s l o c a t i o n was of the c e n t r i c type.  The t r a n s l o c a t i o n  chromosome i n t h i s p a t i e n t  pears to have two centromeres  and i s  Hsu et a l .  (1973) d i s c u s s e d  anism of t r a n s l o c a t i o n  Niebuhr (19 72a)  i n the s h o r t arms of both a c r o c e n t r i c s or t(Gq Gq) t r a n s l o c a t i o n s v i o u s l y been r e c o g n i z e d .  region.  that c r i s s - c r o s s  shown by G and C-  the break  points  assumed that  breaks  i n v o l v e d i n the t(Dq Dq)  Niebuhr r e p o r t e d that i n one c a s e , he chromosomes  This was i n t e r p r e t e d as  centromere  ap-  i n man are more common than had p r e -  found only 6% of t r a n s l o c a t i o n meres.  (1-4)  the c e n t r i c f u s i o n mech-  formation which has  through each centromere.  fusion  completely symmetrical on  e i t h e r side of the centromeric r e g i o n , as banding.  that  showed two c e n t r o -  i n s t a b i l i t y of the  He e x p l a i n e d t h i s  dicentric  i n s t a b i l i t y by suggesting  s e p a r a t i o n s with a breakage - fusion  - bridge  c y c l e , which tended to d i m i n i s h the i n t e r c e n t r o m e r i c segment could occur, r e s u l t i n g i n fusion et a l .  (1973) s t a t e  that  of the two centromeres.  the breaks i n the s h o r t  by reunion between the chromosomes, less l i k e l y  i n view of the s t a b i l i t y  arms  Hsu  followed  cannot be e x c l u d e d , but  is  of the t r a n s l o c a t i o n chromo-  some . The p o s s i b l e familial  instability  of a centromere  region i n a  t(Dq Dq) t r a n s l o c a t i o n was shown i n a female who was  mosaic f o r two major c e l l  lines  (Sinha et a l . ,  l i n e had the t(Dq Dq) t r a n s l o c a t i o n  1972). One c e l l  and the other c e l l  line  84 had 46 chromosomes.  In the 46 chromosome c e l l  l i n e , however,  a normal D-chromosome was r e p l a c e d by a t e l o c e n t r i c marker chromosome comparable and h i s  i n s i z e to the long arm of a D chromosome.  colleagues  suggested that d u r i n g embryonic l i f e ,  c e l l with the t r a n s l o c a t i o n  one  underwent c e n t r i c m i s d i v i s i o n and  t h i s was f o l l o w e d by a p e r i c e n t r i c i n v e r s i o n i n one of the centrics.  This p e r i c e n t r i c i n v e r s i o n mechanism r e s u l t e d  formation of the marker D chromosome with large short The authors  suggested that h e a l i n g occurred at  meric regions  so that f u l l  to each r e s u l t i n g  the presence  (for  example  formation.  - Emberger et a l . ,  Hsu et a l .  formation.  be the c o n c l u s i o n for the t(13q;13q) a,b)  are  i n the homologous t(Dq  l o c a t i o n was due to isochromosome  (1972  1972)  (1973) suggested  l o c a t i o n i n t h e i r case excluded the p o s s i b i l i t y  cations  arms.  restored  t(Dq Dq) t r a n s l o c a t i o n s  of two centromeres  Niebuhr  that  one of the centromeres.  He suggested that  was a determining f a c t o r .  that  their  trans-  i n pedigree  i n t(Dq Dq)  there has been some mechanism of suppressing  due  This would a l s o  translocation  suggested that  have  Dq)trans-  2.  translo-  which appear to be monocentric chromosomes are  the centromeres  i n the  the broken c e n t r o -  centromeric a c t i v i t y was  the homologous  to isochromosome  telo-  chromosome.  Some authors proposed that  Sinha  dicentric;  the a c t i v i t y of  the d i s t a n c e  between  The breaks would have  to occur i n the short arms of the i n v o l v e d chromosomes. suggestions have been that the dominant centromere  Other  suppresses  85  the weaker centromere l e a v i n g i t  to act  only as a connection  between the break p o i n t and the long arm of the chromosome (Niebuhr, pothesis  1972c).  It  seems more reasonable  to favour the hy-  that the breaks may occur i n the short arms of both  the i n v o l v e d chromosomes.  These breaks may occur c l o s e  to the centromere that no or a minute segment material is present.  enough  of short arm  This would allow c e n t r i c f u s i o n to occur  during the formation of the t(Dq Dq) t r a n s l o c a t i o n and may a l low the d i c e n t r i c s t r u c t u r e Theipe i s regions  to be i d e n t i f i e d i n c e r t a i n  good evidence of breaks  o c c u r r i n g i n the short arm  of the a c r o c e n t r i c chromosomes with r e p o r t s  arm d e l e t i o n chromosomes  (Emerit et a l . ,  and complete r e c i p r o c a l t r a n s l o c a t i o n s somes (Palmer et a l , , 1969;  cases.  1972;  of  short  Hoo et a l . ,  1974)  of a c r o c e n t r i c chromo-  de Grouchy et a l . , 1970 ; Emerit e_t  a l . , 19 72). The mechanism of formation for the t(Dq Dq) t i o n s are  transloca-  thought to be s i m i l a r r e g a r d l e s s of whether homologous  or non-homologous chromosome p a i r s to the G and C-banding r e s u l t s , chromosome i n pedigree d i c e n t r i c appearance  are  involved.  the t(13q;14q)  3 appears p o s s i b l y  With  translocation  to be d i c e n t r i c .  was not v i s u a l i z e d i n every c e l l  but was observed i n c e l l s  respect  This  analyzed  from both the proband and h i s mother.  There was no evidence of i n s t a b i l i t y f o r t h i s d i c e n t r i c chromosome.  The mechanism of formation may be s i m i l a r to that In pedigree  4,  the t(13q;14q)  translocated  i n case 2.  chromosome  86 appeared monocentric and the mechanism of formation was b l y an incomplete r e c i p r o c a l t r a n s l o c a t i o n . mechanism was d i s c u s s e d In pedigree  5,  This  classical  previously. the mechanism of formation can be con-  cluded to be a complete r e c i p r o c a l t r a n s l o c a t i o n presence  possi-  of the t(13p;14p)  translocation.  due to  the  This chromosome  is  made up of the short arms and the centromere of chromosome 13 and p a r t  of the short arms of chromosome 14.  t(Dp Dp) or t(Dp Gp) t r a n s l o c a t i o n s ported (Palmer et a l . , et a l . , 19 72).  1969;  The presence  have been p r e v i o u s l y  of  re-  de Grouchy et a l . , 1970; Emerit  The t(13q;14q)  translocation  chromosome i s  made  up of the long arms and centromere of chromosome 14 and the m a j o r i t y of the long arms of chromosome 13. C.  Clinical  and chromosome a s s o c i a t i o n s  The c l i n i c a l phenotype shown by the proband i n p e d i gree 1 may be c o i n c i d e n t a l to the presence t(14q;14q)  translocation.  because of short in a majority  of the homologous  This proband (0-1)  s t a t u r e which i s  was  ascertained  a common abnormality found  of i n d i v i d u a l s with autosomal  aberrations.  other features r e p o r t e d werejfmild h y p o t o n i a , small jaw, underdeveloped scrotum.  These c l i n i c a l  i n many other chromosomal a b n o r m a l i t i e s disorders.  They may, t h e r e f o r e ,  In pedigree  observations  are  The and seen  and a l s o i n non-chromosomal  be c o i n c i d e n t a l .  2, aside from the report  of a low sperm  87  count,  there are no phenotypic a b n o r m a l i t i e s  t(13q;13q)  translocation carrier  (1-4).  i n the homologous  The proband (0-2)  was  shown c y t o g e n e t i c a l l y to be a t r a n s l o c a t i o n trisomy -D and based on the phenotypic c l i n i c a l In view of f a i l u r e disease,  signs was diagnosed t r i s o m y - 1 3 .  to t h r i v e , heart d e f e c t ,  I suggest that  the f i r s t  and h y a l i n e membrane  born female  (0-1)  was  also  a trisomy-13. In pedigrees is  3 and 4, i t  the c a r r i e r of the t(13q;14q)  previously,  some authors  spontaneous  a b o r t i o n for female  contrary, taneous  the proband's mother who  translocation.  r e p o r t an increase  a b o r t i o n for female carriers  As mentioned  i n the r i s k of  t(Dq Dq) c a r r i e r s .  other authors r e p o r t no i n c r e a s e  male t(13q;14q)  (one from pedigree  On the  i n the r i s k of spon-  t(Dq Dq) c a r r i e r s .  gree 4) had three spontaneous All  is  3;  The three  fe-  two from p e d i -  a b o r t i o n s i n nine p r e g n a n c i e s .  the r e p o r t e d a b o r t i o n s were from the mothers of the two  probands i n pedigrees had one spontaneous mother (1-2)  3 and 4.  i n pedigree 3  a b o r t i o n i n two pregnancies while  i n pedigree  five pregnancies.  The mother (1-4)  4 had two spontaneous  There i s  abortions in  a r e p o r t of a female  c a r r i e r who had had three spontaneous mother who had a (or the same),  the  t(13q;14q)  a b o r t i o n s whereas her  s i m i l a r t r a n s l o c a t i o n , had  no a b o r t i o n s i n eleven pregnancies  (Kohno and Makino,  1969).  T h e i r r e p o r t was not mentioned with the assumption that chromosome i s  causal  of the spontaneous  abortions,  as  it  the is  b i a s e d due t o the f a c t t h a t the f e m a l e was a s c e r t a i n e d due t o three spontaneous abortions.  As m e n t i o n e d p r e v i o u s l y ,  these  t(Dq Dq) t r a n s l o c a t i o n chromosomes may have h e t e r o g e n e o u s e f fects within a family.  I t must a l s o be c o n s i d e r e d t h a t t h e s e  e f f e c t s m i g h t be independeny o f the t(Dq Dq) t r a n s l o c a t i o n and due t o o t h e r  causes.  The f a m i l i e s i n cases 3 and 4 were both a s c e r t a i n e d through mentally retarded probands.  The probands were shown  t o be c a r r i e r s o f t ( 1 3 q ; 1 4 q ) t r a n s l o c a t i o n s as were o t h e r members o f e a c h f a m i l y who were p h e n o t y p i c a l l y n o r m a l .  Modal  chromosome numbers o f 45 were f o u n d i n the probands and was no i n d i c a t i o n o f m o s a i c i s m i n the l e u k o c y t e c u l t u r e s . a r e s i m i l a r r e p o r t s ( P i t t e t a l . , 1964; C r a n d a l l e t a l . , 1972;  there There  Glogowska e t a l . , 1971;  R a a i j m a k e r s - E n g e l s e n , 1973) o f m e n t a l l y  r e t a r d e d t(Dq Dq) t r a n s l o c a t i o n c a r r i e r s whose chromosome number and k a r y o t y p e were s i m i l a r t o o t h e r p h e n o t y p i c a l l y normal i n d i v i d u a l s i n t h e same f a m i l y .  V a r i o u s r e a s o n s have been sug-  g e s t e d by t h e s e a u t h o r s f o r the p o s s i b l e c a u s e o f the mental retardation.  Most a u t h o r s s u g g e s t t h a t the c l i n i c a l f i n d i n g s  i n the proband may not be c a u s a l l y r e l a t e d t o the chromosome abnormality,  i . e . the a s s o c i a t i o n i s m e r e l y f o r t u i t o u s .  In the  r e p o r t by Glogowska e t a l . ( 1 9 7 1 ) , t h i s i s p r o b a b l y the c a s e as the probands were a s c e r t a i n e d i n a m e n t a l l y r e t a r d e d tion.  popula-  A s e c o n d common s u g g e s t i o n , which would be hard to a c c o u n t  89 for,  is  that an a d d i t i o n a l small chromosomal anomaly i s  present  i n the proband and not i n the remaining family members. t h i r d suggestion was given by C r a n d a l l et a l .  (1972), who re-  ported two s i s t e r s with t(Dq Dq) t r a n s l o c a t i o n Both s i s t e r s  seemed to have s i m i l a r c l i n i c a l  A  chromosomes.  syndromes while  other f a m i l y members i n c l u d i n g those with the t(Dq Dq) l o c a t i o n were p h e n o t y p i c a l l y normal.  The authors  the two s i s t e r s maykhave been hemizygous  trans-  suggested  that  for a r e c e s s i v e mutant  gene i n h e r i t e d from t h e i r f a t h e r because of the l o s s of the homologous  allele  on the t r a n s l o c a t i o n  Raaijmakers-Engelsen mental r e t a r d a t i o n translocations. a t(13q;14q)  i n h e r i t e d from t h e i r mother.  (1973) made a s i m i l a r p r o p o s a l  for  the  shown i n two probands w i t h d i f f e r e n t  Chromosome 14 was i n v o l v e d i n each as  and the other a t ( 1 4 q ; 1 5 q ) .  He f e l t  the  t i o n may be due to hemizygosity for a c e r t a i n part  t(Dq Dq) one was retarda-  of chromo-  some 14. Jacobs  (1974) presented  data which suggested that  p o s s e s s i o n of a de novo e u p l o i d s t r u c t u r a l autosomes i s ,  i n some c a s e s ,  causal  to,  anisms  for such an e f f e c t :  logical sults c)  detectability;  of  the  a s s o c i a t e d with and presumably  severe mental r e t a r d a t i o n .  unbalanced and c a r r i e s  rearrangement  the  a)  She suggested three mech-  the rearrangement  is  in r e a l i t y  a small d e l e t i o n below the l e v e l of c y t o b)  chromosome breakage and exchange  i n a gene mutation at  c e r t a i n rearrangements  one or both the break p o i n t s ;  are  associated with a p o s i t i o n  re-  and effect  90 d e t r i m e n t a l to t h e i r c a r r i e r s . translocations,  Although her data i s  her suggestions are presented  In pedigree  4,  to be due to c e r e b r a l  the proband's  for  f o r de novo  completeness.  r e t a r d a t i o n was  thought  anoxia i n utero during h i s mother's  emia and c o n v u l s i v e p e r i o d .  Other s u p p o r t i v e  evidence  tox-  for  this  suggestion i s  the l a r g e number of p h e n o t y p i c a l l y normal t(13q;14q)  translocation  carriers  rearrangement  c o u l d be detected  In pedigree  3,  it  is  in his  family.  No a d d i t i o n a l  from the proband's  interesting  that  structural  karyotype.  the proband's  mother had  an abnormal pregnancy owing to her d i a b e t e s , exposure to r u b e l l a , flu-like  symptoms and a kidney i n f e c t i o n .  Although these c o m p l i -  c a t i o n s were not s i m i l a r to those d e s c r i b e d i n the pregnancy of the proband's  mother i n pedigree  ing on the r e s u l t i n g r e t a r d a t i o n .  4,  they may have had some bearNo a d d i t i o n a l s t r u c t u r a l  arrangement  c o u l d be detected  karyotype.  I t must a l s o be considered that  the probands typic  of pedigrees  (pedigree 3 -  the r e t a r d a t i o n  0-1) in  3 and 4 may be u n r e l a t e d to the karyo-  aberration. The c l i n i c a l  tion,  i n the proband's  re-  phenotype, aside from the mental  shown by the proband i n pedigree  to the presence previously, aberrations. retardation  of the t(13q;14q)  short  stature is  3 may be c o i n c i d e n t a l  translocation.  As mentioned  commonly a s s o c i a t e d w i t h  Small head, s p a s t i c i t y ,  retarda-  autosomal  s t r a b i s m u s , and mental  are seen i n many other chromosomal  aberrations.  91 The strabismus  and s p a s t i c i t y  may be secondary owing to another  f a c t o r which has caused r e t a r d e d b r a i n development as the small head. pedigree  The a p n e i c - l i k e s p e l l s  In pedigree except  i n e a r l y infancy i n the  3 proband may be c o i n c i d e n t a l or r e l a t e d  development of the c e n t r a l nervous 4,  all  to the  translocation  the proband (0-10) have normal development.  the presence  of a horseshoe  is  a t(13q;14q)  carrier.  retarded  system.  the t(13q;14q)  is  shown by  kidney i n the 0-11  Renal anomalies  are  carriers  Of i n t e r e s t i n d i v i d u a l who  found i n l e s s than  50% of the observed cases of trisomy 13 syndrome b u t , when present,  a horseshoe  kidney i s  coincidental in this  o c c a s i o n a l l y found.  individual  In c o n s i d e r i n g pedigree  This  is  possibly  (0-11). 5, a s c e r t a i n e d because of the  chromosome i n v e s t i g a t i o n of the mentally r e t a r d e d proband, much of  the d i s c u s s i o n w i l l be concerned with the d i f f e r e n t  of the two types  of t r a n s l o c a t i o n s ,  the small t ( 1 3 p ; 1 4 p ) .  It  makes the proband (0-3) chromosome 13. individual  (0-4)  It i s  is  the large  the t(13q;14q)  expression  t(13q;14q)  and  t r a n s l o c a t i o n which  t r i s o m i c f o r most of the long arm of  the t(13p;14p)  t r a n s l o c a t i o n vrhich makes  t r i s o m i c for a small p o r t i o n of the long arm  proximal to the centromere, the centromere, and short arms of chromosome 13 and a p o r t i o n of the s h o r t arm of chromosome 14. Thus these two i n d i v i d u a l s i n pedigree f e r e n t parts  5 are  t r i s o m i c for  dif-  of chromosomes owing to the formation of the two  92 t r a n s l o c a t i o n chromosomes by complete r e c i p r o c a l exchange. other two i n d i v i d u a l s i n pedigree  5,  1-2  and 0-1, who are pheno-  t y p i c a l l y normal, are completely balanced for these t i o n s as  they have the t(13p;14p)  The  transloca-  and the t(13q;14q)  t i o n s with the remaining four normal D chromosomes  transloca-  (one 13,  one  14, and two 1 5 ' s ) . A summary of the a s s o c i a t e d c l i n i c a l i n trisomy -13,  as  adapted  signs u s u a l l y found  from Smith (1970), i s  shown by Table 6.  Trisomy-13 syndrome summaries  a l s o c o n s i d e r e d were T a y l o r  and Thomas and S c o t t  As shown by Table 6,  (1973).  the  (1968)  clinical  signs which are common to both 0-3 and 0-4 i n d i v i d u a l s are velopmental/mental r e t a r d a t i o n , gioma.  de-  hypotonia and c a p i l l a r y haeman-  The proband ( 0 - 3 ) , who i s  t r i s o m i c for the m a j o r i t y of  the long arm of chromosome 13, has i n a d d i t i o n a mixed c o n v u l s i v e d i s o r d e r , P o l y d a c t y l y , a simian c r e a s e , hyperextensible  joints,  with trisomy-13.  cardiovascular, individual  (0-4)  facies  This  There were no a b n o r m a l i t i e s  in the  The female  trisomy for the proximal p a r t  long arm of chromosome 13,  indivi-  of the m a j o r i t y of  pulmonary, or alimentary systems. who i s  testicles,  and a h i g h l y arched p a l a t e .  dual does not have the c h a r a c t e r i s t i c patients  undescended  of the  the centromere and short arms of  chromosome 13 and a p o r t i o n of the short arm of chromosome 14, has,  in a d d i t i o n , a c l e f t  palate,  strabismus,  finger  and o v e r l a p p i n g and a small head (3rd p e r c e n t i l e ) . clinical  s i g n s are s i m i l a r to some of the c l i n i c a l  flexion These  signs  present  93  TABLE 6  COMPARISON OF CLINICAL SIGNS FOR TRISOMY 13 P5-0-3  >8CH  >50l  C50%  +  c o n g e n i t a l heart developmental/mental r e t a r d a t i o n s e i z u r e s , j i t t e r i n e s s , apnea moderate microcephaly with s l o p i n g forehead microphthalmia i r i s colobomata c l e f t palate cleft lip malformed ears g l a b e l l e r c a p i l l a r y haemangiomata c u t i s a p l a s i a ( s c a l p , neck) f i n g e r n a i l s , l o n g , hyperconvex f i n g e r s , flexed, overlapping simian creases Polydactyly distal triradii t a l i p e s equinovarus g e n i t a l anomalies u m b i l i c a l / i n g u i n a l hernias hypo or h y p e r t e l o r i s m thumbs r e t r o f l e x i b l e f i b u l a r S-shaped h a l l a c a l p a t t e r n hypo or hyper t o n i a strabismus abdominal anomalies r e n a l malformation  Smith (1970)  + +  P5-0-4 +  +  +  +  +  + + +  +  +  + +  94 in a p a r t i a l  trisomy 13,  r e s u l t i n g from a minute e x t r a chromo-  some shown to be the centromere and short arms of chromosome 13 (Krmpotic et a l . ,  1971).  female  i n t o the c l a s s i c trisomy -13 syndrome  sib  (0-4)  fit  shown by Table 6.  N e i t h e r the proband (0-3)  N e i t h e r p a t i e n t has  nor the  the d i s t i n c t i v e  facies  of trisomy 13 but they both look s i m i l a r to each o t h e r . are no eye defects patient.  The l a t t e r  l i v e d to 5 years  very l i t t l e  and 2 years  live until  overlap  defects  (0-4).  in either  their f i r s t  in c l i n i c a l  Less than 18% of birthday.  and c a p i l l a r y haemangiomata. different  There  s i g n s between the two  i n the major area of developmental/mental  other signs are  due to the d i f f e r e n c e  are  chromosome m a t e r i a l which i s  1972; 1973).  19 73)  Magenis et  al.,  there are  reports  i n the  of p a r t i a l  trisomy  for chromosome 14 (Short et a l . ,  and 15 (Webb et a l . , 1972;  The p a r t i a l  It may be  t r i s o m i c i n each p a t i e n t .  Bucher et a l . ,  These two forms of p a r t i a l  clinically.  of  they appear i n g r e a t e r than 50% of  proposed these d i f f e r e n c e s  syndromes i n l i v e b i r t h s  is  patients  However, while the m a j o r i t y  shown i n Table 6.  For comparison,  tri-  retardation  the trisomy -13 i n d i v i d u a l s as  Muldal et a l . ,  There  may be the reason why these c h i l d r e n have  (0-3)  somy -13 p a t i e n t s  except  and no c o n g e n i t a l heart  as  19 71; Parker and A l f i , 1973;  C r a n d a l l et  trisomy cannot be  trisomy 14 cases have  common to a m a j o r i t y of autosomal  1972;  aberrations.  somy -14 case d e s c r i b e d by Short et a l . , ( 1 9 7 2 )  al.,  distinguished  abnormalities The p a r t i a l  tri-  had phenotypic  95 anomalies  such as microphthalmia with h y p e r t e l o r i s m ,  nasal  b e a k i n g , h y p o p l a s t i c mandible, short neck, b a r r e l c h e s t , k y p h o t i c spine  i n a d d i t i o n to the a b n o r m a l i t i e s  m a j o r i t y of autosomal a partial  aberrations.  common to a  Muldal et a l . ( 1 9 7 3 )  trisomy 14 karyotype i n a mentally r e t a r d e d  scent with short s t a t u r e .  The p a r t i a l  found adole-  trisomy 15 cases tend  to be moderately r e t a r d e d and h y p e r a c t i v e , to have any growth r e t a r d a t i o n  and  they do not seem  and have minimal p h y s i c a l ab-  normalities. The b i r t h weights significantly 1972).  o f autosomal  trisomy i n f a n t s  are  lower than those of normal newborns (Chen et  The order of d e c r e a s i n g b i r t h weights  trisomy 13>tri-somy 18.  The proband's  (0-3)  is  al.,  trisomy 21 >  b i r t h weight was  1960 grams, which i s  lower than the 2480 gram mean mentioned  by Smith (1970).  should be r e c a l l e d that  at  38 weeks  It  gestation.  The b i r t h weight of 0-4 was 3494 grams  which was above the mean b i r t h weight. lated cases,  t h i s weight was  Although these are  these b i r t h weights may r e f l e c t  t i c m a t e r i a l which i s  trisomic,  weight and the l a r g e r  chromosome p o r t i o n i n the t r i s o m i c  The defects in variable  of m i d - f a c e ,  degree as  a feature  appear to be the consequence ( t h i r d week)  as 0-3 has  the amount of  gene-  the lower b i r t h state.  eye and f o r e b r a i n , which occur of the trisomy -13 (Smith, 1970) ,  of a s i n g l e  defect  i n the e a r l y  development of the p r e c h o r d a l mesoderm.  derm i s not only necessary f o r  iso-  the morphogenesis  This  of the  meso-  mid-face,  but e x e r t s an i n d u c t i v e r o l e on the subsequent development of the prosencephalon,  the f o r e p a r t  of the b r a i n .  This type of  96 defect has been r e f e r r e d to as severity et a l . ,  from c y c l o p i a ( T a y s i and T i n a z t e p e , 1972; 1973)  to cebocephaly and l e s s severe  The c l i n i c a l tends  expression  cal  Fujimoto  translocation  concerning the short  whether by r e c i p r o -  r e s u l t i n g i n a monocentric t r a n s l o c a t i o n chromo-  some or by c e n t r i c fusion r e s u l t i n g i n a d i c e n t r i c there i s  always a l o s s  t i o n to t h i s  arms  Independent of the mechanism  formation of the t(Dq Dq) t r a n s l o c a t i o n s , translocation  in  forms.  of the t(13p;14p)  to confuse p r e v i o u s assumptions  of the a c r o c e n t r i c chromosomes. of  arhinencephaly and v a r i e s  translocation,  of some s h o r t arm m a t e r i a l .  assumption i s  the rare  The excep-  f i n d i n g of a complete  reci-  p r o c a l t r a n s l o c a t i o n w i t h the r e s u l t i n g formation of the t(Dp Dp) fragment.  D e l e t i o n of the s h o r t arm of the D-group chromosomes  have been r e p o r t e d f o r chromosomes 13 (Bias and MigQon, L i e b e r et a l . ,  1967; Emerit et a l . ,  some 14 (Emerit et a l . , 1974).  The general  1968; Brogger,  1 9 6 9 ; ) , chromo-  1972), and chromosome 15 (Hoo et  c o n c l u s i o n was that the short  showed no phenotypic e f f e c t  arm m a t e r i a l from the two chromosomes  material  S i m i l a r conclusions  were reached when i t was noted that most t(Dq Dq) carriers  al.,  arm of the D-  group chromosomes does not c o n t a i n important genetic and the l o s s has no g e n e t i c consequence.  1967;  translocation  due to the l o s s of i n v o l v e d i n the  short  translocation.  The s h o r t arms of the a c r o c e n t r i c chromosomes were shown to c o n t a i n the n u c l e o l a r - o r g a n i z e . r r e g i o n s , cells  (Ferguson-Smith and Handmaker, 1961)  first  in mitotic  and l a t e r  i n human  97 m e i o t i c chromosomes  (Ferguson&Smith, 1964).  s t a i n i n g of n u c l e o l u s o r g a n i z e r s  (N banding)  phase chromosomes (Matsui and S a s k i , shown to be r e s t r i c t e d c e n t r i c chromosomes.  By d i f f e r e n t i a l  1973),  to the s a t e l l i t e  of human metathe N bands were  regions  of a l l  acro-  No s t a i n was observed i n any other chromo-  some or chromosomal r e g i o n s , t i o n of chromosomes 1, method was used p r i o r  i n c l u d i n g the secondary  9, and 16.  constric-  When a q u i n a c r i n e - f l u o r e s c e n t  to the N s t a i n i n g ,  i t showed u n e q u i v o c a l l y  that N bands were l o c a t e d e x c l u s i v e l y on tiie s a t e l l i t e s no banding on the centromeres, short arms,  or s t a l k  with  of the  satellite. From the reports  p r e v i o u s l y mentioned on the s h o r t arm  d e l e t i o n evidence and the exact p o s i t i o n s ganizers  for the D group chromosomes, c e r t a i n proposals  made concerning the t(13p;14p) of pedigree a)  can be  t r a n s l o c a t i o n i n the 0-4  female  5:  i t may be that the l o s s of these short a r m - n u c l e o l a r organizer regions has no e f f e c t if  p h e n o t y p i c a l l y on the p a t i e n t but  these regions are i n excess there may be some type of  cause and e f f e c t b)  of the n u c l e o l u s or-  relationship  expressed;  there may be an important gene or gene sequence  located  close  to the centromere i n the long arm of chromosome 13 and t h i s gene or gene sequence may be i n c l u d e d i n the t(13p;14p) location.  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Factors A f f e c t i n g the Q u a l i t y of G Bands Produced by T r y p s i n i n Human Chromosomes. Cytobios 6, 47-54 (1972).  107 Webb, G . C , O.M. Carson, M.K. Robson, D . B . P i t t i A P a r t i a l DTrisomy/Normal Mosaic Female. J . m'ed. Genet. 8, 52 2527 (1971). W i l s o n , J . A . A P r o s p e c t i v e Cytogenetic Study of Recurrent A b o r t i o n . J . Med. Genet. 6, 5-13 (1969). Wilson,  J . A . F e r t i l i t y i n Balanced Heterozygotes f o r a F a m i l i a l C e n t r i c Fusion T r a n s l o c a t i o n , t(Dq Dq). J . med. Genet. :8, 175-178 (1971).  Y o s h i d a , M . C , N. Nomoto, M. S a s a k i . Quinacrine Fluorescence P a t t e r n s i n Somatic Chromosomes of a t(15q;15q) C a r r i e r . Humangenetik 15, 66-70 (1972). Yunis, J . J . , M. A l t e r , E . B . Hook, M. Mayer. F a m i l i a l D/D Transl o c a t i o n . New. E n g l . J . Med. 271, 1133-1137 (1964). Yunis, J . J . , 0. Sanchez. G-Banding and Chromosome Chromosoma 44, 15-23 (1973).  Structure.  Zeuthen, E . , J . N i e l s e n . D/D T r a n s l o c a t i o n i n Males Examined f o r M i l i t a r y S e r v i c e . J . med. Genet. 10, 356-361 (1973). Zink, V . , R. R i x , K . P . Grosse, G. Schwanitz. Ring Chromosome D13. K a s u i s t i k und U b e r s i c h t . Klm. P a d i a t r . 185, 192197 (1973).  108  APPENDIX A :  LEUKOCYTE CULTURE METHOD  1) C u l t u r e s were grown i n p l a s t i c ,  sterile,  disposible  tubes with  screw tops c o n t a i n i n g 5 cc of Gibco chromosome medium IA. each tube was added 5-4 drops of venous blood 0.25  cc)  To  (approximately  and the c u l t u r e s were then incubated at  5 7 ° C f o r 72  hours. 2)  Colcemid i n a f i n a l the c u l t u r e s the c e l l s . sealed  5) A f t e r  c o n c e n t r a t i o n of 0.02  approximately one hour p r i o r to the h a r v e s t The c e l l s were then gently resuspended  of  i n the  tube. the i n c u b a t i o n p e r i o d was completed the contents  tube were emptied i n t o a c e n t r i f u g e , and  ug/ml was added to  c e n t r i f u g e d at  of the  covered with P a r a f i l m M]_  800 rpm f o r 8 minutes.  The supernatant  was  removed and d i s c a r d e d and the c e l l s were suspended i n 5 cc of hypotonic s o l u t i o n  (0. 075 M. KC1)  at room temperature  for  2-5  minutes. 4) The c e l l s were then c e n t r i f u g e d at the supernatant supernatant cells  was removed and d i s c a r d e d .  (approximately  were suspended,  t i o n of the f i x a t i v e acetic (2-5  acid).  drops)  800 rpm f o r 8 minutes and  2-5 drops) was l e f t ,  i n which the  i n order to reduce clumping on the addi(5:1 absolute methyl a l c o h o l :  The f i r s t  and the c e l l s  with a PSsteur p i p e t t e . ger volumes u n t i l  A small amount of  glacial  amount of f i x a t i v e was added s l o w l y were immediately g e n t l y  agitated  More f i x a t i v e was then added i n l a r -  approximately 5 cc of f i x a t i v e  had been  added and then the tubes were allowed to stand at room temperature  109 for approximately 20 minutes. 5) The c e l l s  were then c e n t r i f u g e d and the supernatant  moved and d i s c a r d e d . cells  times a f t e r 6) A f t e r  re-  Fresh f i x a t i v e was used to wash the  which were suspended i n 5 cc of f i x a t i v e  centrifuged.  was  and then  This washing procedure was u s u a l l y done 2-3 the i n i t i a l  fixation.  the f i n a l wash, the supernatant was removed and d i s -  carded and the c e l l s were suspended  i n 5-6 drops of  fresh  7) The suspended c e l l s were then p l a c e d on p r e c l e a n e d ,  cold,  fixative.  wet s l i d e s .  The s l i d e s were then flamed, a i r - d r i e d and  s t o r e d at room temperature  until  required.  110 APPENDIX B: 1)  The a i r  FLUORESCENT BANDING TECHNIQUE d r i e d s l i d e s were p l a c e d i n a 0.5  s o l u t i o n of A t r e b i n Gurr) 2)  grams/100 ml  (quinacrine dihydrochloride) (G.T.  for a p e r i o d of time g r e a t e r than 20 minutes.  The s l i d e s were removed, r i n s e d i n d i s t i l l e d water and a c l e a n c o v e r s l i p was then a p p l i e d .  3)  The s l i d e s were then pressed between p i e c e s of b i b u l o u s paper and then the c o v e r s l i p was s e a l e d along i t s by p a r a f f i n  wax.  edges  Ill  APPEHDIA  1)  The a i r d r i e d the  first  Difco) to  from  Initially,  and  solution  The s l i d e s  tnrough  a series  length After  5-20 s e c o n d s  the s l i d e s  The s l i d e s depending  uere  men  were  were l e f t  water).  buffer  t n e Giemsa  in  dipped me d i um.  in xylol  i n t r y p s i n , for  This  was  o f U.91 later  o f one wash i n 1% CnCl2  were l e f t  t h e l o n g e s t be inf. tne s l i d e s  and s t a i n i n g  (1 cc  o f Giemsa  (pil b . 5 ) ,  30 c c  Giemsa s t a i n  d r y between b i b u l o u s  the banding  diluted  water.  stained  stain,  (1:250  saline  two washes  (pli 0 . 5 ) .  consisted  The s l i d e s  o f time, w i t h  solutions,  on t h e chro:nosores.  tiicn p u t t h r o u g h  The m o d i f i c a t i o n  water, b l o t t e d  of  (1 c c o f a 5% t r y p s i n  ( G u r r L 1 1 0 0 ) , 20 c c p h o s p h a t e h u f f e r  distilled  When  TECHNIQUE  made up i , i Hank's Ca and f'g f r e e  two washes o f d i s t i l l e d  stain  3)  trypsin  taken  and one o f p h o s p h a t e  modified.  4)  being  were  40 c c i n 0.9% s a l i n e ) .  saline  3)  slides  solution  periods 2)  T R Y P S I N - G Iii M S A ii A D D I N G  C:  were  in  stain  fora  variaole  5 minutes. rinsed  in distilled  p a p e r and a l l o w e d  was s a t i s f a c t o r y ,  and mounted i n a Pro-texx(Can  to a i r dry.  the s l i d e s  Lab) m o u n t i n g  were  112 APPENDIX D: 1)  C-BANDING TECHNIQUE  The a i r d r i e d s l i d e s  were taken through a s e r i e s of  the f i r s t  being 0. 03-0. 07 N NaOil i n 0.13 M N a C l .  were l e f t  in this  s o l u t i o n for 30-90 seconds  at  solutions,  The  slides  room tempera-  ture . 2)  The s l i d e s  were then r i n s e d i n d i s t i l l e d water and then taken  through two a l c o h o l washes  (701  and 991 methanol)  and allowed  to a i r d r y . 3)  The a i r d r i e d s l i d e s ( K H 2 P 0 4 , 6.63  were t r e a t e d i n Sorensen b u f f e r  (plf  6.8)  g, Na 2 HP0 A 7H 2 0, 2.56g; d i s t i l l e d H 2 0 to 1000 ml)  at 6 8 ° C for one hour. 4)  The heated s l i d e s tion  were then s t a i n e d i n b u f f e r e d Giemsa s o l u -  (50 ml d i s t i l l e d water,  1.5  pll with 0.2M Na 2 HP04 to 6 . 8 - 7 . 2 , stock 5)  ml 0.1M c i t r i c a c i d , 1.5  adjust  ml pure methanol, 5 ml  Giemsa ( G . T . Gurr) f o r 15 minutes).  Tne s l i d e s  were then r i n s e d i n d i s t i l l e d water,  b l o t t e d dry  between b i b u l o u s paper and a i r d r i e d . 6)  Tiie a i r d r i e d s l i d e s a Pro>texx(Can  were then dipped i n x y l o l  Lab) mounting medium.  and mounted i n  113 APPENDIX E :  STAINING TECHNOLOGY  The d i f f e r e n t i a l s t a i n i n g techniques now used i n  cytogenetics  have brought a new order of accuracy to chromosome i d e n t i f i c a t i o n . The techniques and the s p e c i f i c i t y of s t a i n i n g has been reviewed by a number of authors  (Pearson,  19 72; H i r s c h h o r n ,  19 73; H s u ,  1973) . C e r t a i n optimum c o n d i t i o n s are necessary  to get the maximum  from any of the three s t a i n i n g techniques used i n t h i s The f i r s t results  c o n d i t i o n which i s  is  to c o n t r o l  preparation.  the s t a t e of h y d r a t i o n of the chromosome  (Yunis and Sanchez, 1973)  anol.  important to obtain good banding  This i s p a r t i c u l a r l y necessary  in a dessicant  or as  study.  f o r adequate G-bands  and may be achieved by s t o r i n g  i n the present  The second c o n d i t i o n which i s  slides  study by f i x a t i o n with methcritical  used i n making the chromosome p r e p a r a t i o n s .  is  the technique  The metaphase  cells  should be c r i s p and w e l l spread with a minimum of c y t o p l a s m i c . c o n tamination.  Adequate banding i s  acetic-methanol 3-4  (Crossen,  times w i t h t h i s  achieved by f i x a t i o n w i t h  fresh  1973; Yunis and Sanchez, 1973), washing  fixative  and f l a m e - a i r d r y i n g the  Too much heat makes c l e a r v i s u a l i z a t i o n of the G bands  slides. difficult  while too l i t t l e heat makes the v i s u a l i z a t i o n of the G bands impossible  as  the chromosomes have a shiny u n s t a i n a b l e  The t h i r d c o n d i t i o n which i s  appearance.  important for more d i s t i n c t  t i o n of the band and i n t e r - b a n d regions  is  the use of  separa-  elongated  "114 chromosomes. metaphase. such as  These are The use  obtained from mitoses a r r e s t e d  of lo\v c o n c e n t r a t i o n s  colcemid and the use  c o n d i t i o n which i s  of a r r e s t i n g  of short i n t e r v a l s  in o b t a i n i n g these elongated  chromosomes.  important,  is  i n KCl y i e l d s  results  chromosome.  fourth  Short periods  of 2  the best banding r e s u l t s . (Caspersson  et  i n banding p a t t e r n s which are unique for  al.,  each  Every chromosome i n the human complement can be  cognized through the combination of the p o s i t i o n , the b r i g h t n e s s and Barr  the  the type of hypotonic s o l u t i o n  The q u i n a c r i n e d i h y d r o c h l o r i d e technique 1969a,b)  agents  of one hour a s s i s t  Finally,  and the p e r i o d of s w e l l i n g of the n u c l e i . minutes  in early  of the q u i n a c r i n e bands.  the w i d t h , and  It was shown by E l l i s o n  (1972) t h a t q u i n a c r i n e d i h y d r o c h l o r i d e had a f f i n i t y  the A-T regions  of the chromosome i n s t e a d  of the G-C regions  o r i g i n a l l y proposed by Caspersson  et a l .  some drawbacks  t e c h n i q u e , namely:  fluorescence procedures  to the f l u o r e s c e n t  i s not permanent;  b)  the fluorescence  varies;  (1969a,b).  the more recent  r e v e a l more d e t a i l e d banding; and d) there  is  on exposure to the u l t r a - v i o l e t l i g h t .  re-  There a)  as  are  the  Giemsa-banding  c) the b r i g h t n e s s fading of the For t h i s  at  reason,  of  fluorescence cells  which possessed morphological c r o s s - o v e r s or were spread  too l a r g e  for a s i n g l e  Although  or double frame p i c t u r e were not a n a l y z e d .  the f l u o r e s c e n t for  the b r i g h t  human Y .  It  is  technique has fluorescence also useful  drawbacks,  it  is  extremely  useful  of the heterochromatin such as  i n the  for the i d e n t i f i c a t i o n of the polymerphic  115 centromeric f l u o r e s c e n t regions  marker or chromosome  of the human D and G group  The Giemsa-banding r e s u l t s different  techniques  Hirschhorn, induced.  19 73)  have been d e r i v e d from so many  (Seabright,  1971;  some evidence  that  the DNA and the p r o t e i n which i s Evidence for t h i s the Q bands;  b)  includes:  a)  that a v a r i e t y  Pearson,  from DNA;  d) t h a t  with n u c l e a r p r o t e i n s  that  represent  G bands are  comparable  to  of compounds capable of i n d u c i n g c) urea i s  known to  cleave  actinomycin D which does not the guanine treatment;  which suggest a r g i n i n e - r i c h  react moiety e)  bio-  histones  b i n d G-C r i c h DNA.  the n o t i o n that dark G bands  A-T r i c h  the chromosome s t r u c t u r e  (or b r i g h t Q bands)  v i o u s l y as being u s e f u l  more i n f o r m a t i o n on  than the f l u o r e s c e n t  These cases are  similar  banding  dependent  time of exposure of the chromosomes  technique  to those mentioned pre-  examples f o r the f l u o r e s c e n t  The optimum t r y p s i n - b a n d i n g i s  the Giemsa s t a i n .  treat-  regions.  The Giemsa-banding technique p r o v i d e s  i n most cases.  are  (Hsu, 1973).  The i n d u c t i o n of G bands by actinomycin D p r e f i x a t i o n ment support  1973;  the banding i n v o l v e s both  can induce G bands without any p o s t - f i x a t i o n  preferentially  Hsu,  how the G bands  but does b i n d to DNA at  chemical i n v e s t i g a t i o n s  1972;  a s s o c i a t e d with i t  G bands have c h e l a t i n g p r o p e r t i e s ; proteins  satellite  chromosomes.  that no one knows e x a c t l y  There i s  3 and the  technique.  on the c o n c e n t r a t i o n and  to the t r y p s i n s o l u t i o n and  The pH of the s t a i n  seems to a f f e c t  the amount  116 of s t a i n i n g with the optimum range pH 6.5 which review f a c t o r s specificity 1973;  affecting  are numerous  Crossen,  Other  reports  the Giemsa banding and the banding  (Wang et  al.,  1973; Meisner et a l . ,  1972;  Yunis and Sanchez,  1973a,b).  The C-banding technique was f i r s t (1971).  - 6.8.  d e s c r i b e d by A r r i g h i  T h e i r method r e s u l t e d i n intense  s t a i n i n g with Giemsa at  the centromeric regions  of the chromosomes and the d i s t a l  the long arm of the Y .  The b a s i s  s e r v a t i o n of Pardue and G a l l repetitive  copies  other types localizes  for t h i s  2/3 of  technique was the ob-  (1970) that DNA c o n s i s t i n g of h i g h l y  of short segments renatures  of DNA a f t e r  and Hsu  more r a p i d l y than  alkaline denaturation.  i n the renatured p o r t i o n s  The Giemsa s t a i n  of the chromosome.  In the pre-  sent study the C-banding was used to t r y to i d e n t i f y the centromeric regions  i n the t(Dq Dq) t r a n s l o c a t i o n s  the t r a n s l o c a t i o n s  and determine whether  were monocentric or d i c e n t r i c .  The assumption  was made that the f a m i l i a l chromosome was i d e n t i c a l i n r e g a r d l e s s of the member of the family c a r r y i n g the  structure  translocation.  For t h i s reason C-banding was only done on one or two t r a n s l o c a t i o n carriers  i n each p e d i g r e e .  C-bands have been produced by methods  other than d e n a t u r a t i o n - r e n a t u r a t i o n  as p r o g r e s s i v e  trypsin  ment shows the decrease of G-banding and the appearance (Merrick et a l . ,  1973).  treat-  of C-bands  There has been evidence to show that chromo-  some p r o t e i n may have a r o l e i n C-banding as w e l l as banding (Chuprevich et a l . ,  1973).  i n Q and G  

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