Open Collections

UBC Undergraduate Research

Pathogenic Copy Number Variants (pCNVs) in Individuals diagnosed on the Autism Spectrum Disorder (ASD):.. Baniaga, Allan Dale 2010-07-22

You don't seem to have a PDF reader installed, try download the pdf

Item Metadata


AllanDaleBaniaga'sResearchPaper(cIRcle).pdf [ 773.05kB ]
JSON: 1.0107202.json
JSON-LD: 1.0107202+ld.json
RDF/XML (Pretty): 1.0107202.xml
RDF/JSON: 1.0107202+rdf.json
Turtle: 1.0107202+rdf-turtle.txt
N-Triples: 1.0107202+rdf-ntriples.txt
Original Record: 1.0107202 +original-record.json
Full Text

Full Text

 Page 1 of 11  Pathogenic Copy Number Variants (pCNVs) in Individuals diagnosed on the Autism Spectrum Disorder (ASD): A Closer lok at Candidate Genes  Baniaga, Allan Dale1 1The author is a former undergraduate student at the University of British Columbia, Vancouver, BC, Canada, V6T 1Z4  The genetic basis for autism spectrum disorders (ASDs) is wel established, and its heterogenetic nature provides us with substantial evidence for the many chromosomal aberations asociated with this complex disorder. However, litle is known about the genes that occupy the diferent chromosomal regions and the gene networks they participate in as they relate to phenotypes asociated with ASDs. Here, the author reports candidate genes that may be implicated with the observed clinical phenotypes in 9 patients diagnosed with an ASD identified to have pathogenic copy number variants (pCNVs) through aray-comparative genomic hybridization (CGH). Formal clinical asesments, which include a full physical examination, a medical history report, as wel as a family history, were administered by a clinical geneticist unaware of the aray-CGH results. Candidate genes were then compiled through the genome browser of the Database of Genomic Variants website and subsequently narowed down utilizing the SUSPECTS database. Additional information on each candidate gene was obtained through the NCBI, iHOP, and metalife databases. The author’s findings suggest a number of genes involved in neurodevelopment as wel as craniofacial and systemic features that may acount for the observed phenotypes in the 9 afected patients.  Abbreviations: ASD – Autism Spectrum Disorder; CGH – Comparative Genomic Hybridization; FISH – Fluorescence In Situ Hybridization; pCNVs – Pathogenic Copy Number Variants; qPCR – Quantitative Polymerase Chain Reaction  Keywords: Autism; Chromosome; Disorder; Genetics; Interactions; Networks; Phenotype   Introduction:  Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterized by impairments in communication, social interaction, and repetitive behavior, and have a prevalence as high as 60 per 10,00 individuals by recent estimates (Baird et al., 200; Bertrand et al., 201; Chakrabarti et al., 2001; Chakrabarti et al., 205). The heritability of ASD has also been well established over the years, particularly through comparing monozygotic (MZ) and dizygotic (DZ) concordance rates which, when taken colectively with family studies, clearly point to an important genetic liability for autism (Newschaffer et al., 207). Although current estimates show that clinical genetic evaluation can positively identify a specific etiology in up to 40% of individuals with an ASD (Shaefer and Mendelsohn, 208), litle is understod in terms of the genotype-phenotype correlations for the vast majority of genetic abnormalities found in affected individuals. Most candidate genes for specific clinical phenotypes and the posible gene networks and interactions they participate in have yet to be clearly determined. To address this, the current paper reports posible candidate genes associated with particular pathogenic copy number variants (pCNVs) in 3 pairs of individuals, 2 pairs of which had de novo changes, and a pair of brothers who inherited the same X-linked deletion from their unaffected mother. Three other individuals were also Page 2 of 11 Pathogenic Copy Number Variants (pCNVs) in Individuals diagnosed on the Autism Spectrum Disorder: A Closer lok at Candidate Genes  identified to have unique copy number changes not shared with other affected individuals in the cohort. Array-CGH, FISH, and RT-qPCR data were gathered from previous experiments, as well as detailed phenotypic descriptions for these affected individuals. From these, candidate genes in each unbalanced region were compiled through the use of various databases so as to provide a genetic basis for their clinical presentation.   Methods and Materials:  Identification of Pathogenic Copy Number Variants (pCNVs)  A total of nine subjects were identified to have pCNVs by colaborators through various genetic testing methods. Low resolution array-CGH findings were confirmed by FISH and RT-qPCR methods which were also used to refine breakpoints and determine the origins of the changes when parents were available for testing.  Individuals identified to harbor pCNVs found at genomic loci are associated with other disorders, and they also fulfiled CNV criteria strongly sugesting their pathogenicity (Fan et al., 207; Lee et al., 207). Several criteria were used to distinguish benign CNVs (bCNVs) from potentially pathogenic ones (pCNVs), including: a de novo origin (or maternally inherited X-linked in male probands), the involvement of multiple genes not known to vary in databases, the overlap with a gene or region that leads to a clinical phenotype when unbalanced, or if the affected region is >1Mb and overlaps well characterized genes (Fan et al., 207; Lee et al., 207). This is in contrast to benign CNVs (bCNVs) which are found in at least 2 healthy individuals in independent studies found on the Database of Genomic Variants website [htp:/].  Aray-CGH   PUREGENE DNA Isolation Kits (Gentra, Mineapolis, MN) were utilized to extract DNA from peripheral blod and were matched to normal male and female control DNAs (Promega, Madison, WI) as a reference. Both sample and reference DNAs were then subsequently hybridized using the 1-Mb BAC array (Tyson et al., 205) [Spectral Genomics, Houston, TX] through dye swap methods. Spectralware 2 software (Spectral Genomics) was then utilized for data analysis, and clones bearing a significant gain or los were identified through the use of the established values of 1.2 and 0.8, respectively, as cut-offs.  FISH   Deletions and duplications of BAC DNA clones identified by array-CGH were confirmed through FISH analyses (Rajcan-Separovic et al., 207). A Zeis Axioplan 2 fluorescence microscope and the MacProbe software (Aplied Imaging, Santa Clara, CA) were then utilized to view the slides and capture the images, respectively.  Real-Time Quantitative PCR (RT-qPCR)  RT-qPCR (Qiao et al., 207) was employed to confirm the pCNVs. The ABI Prism 790HT system (Aplied Biosystems) using SYBR Green I detection was utilized to assess the RT-qPCR products. The primers used can be made available upon request.  Phenotypic Data  A spectrum of clinical characteristics modified from the De Vries scoring method were taken into account, and includes prenatal and postnatal growth abnormalities that are indicative of subtelomeric rearrangements, not in exclusion of other characteristics. A spectrum of clinical and physical characteristics were noted for each participant by a professional Clinical Geneticist (M.E.S.L.) blinded to the array results. These include micro- and macrocephaly, prenatal and postnatal growth abnormalities, craniofacial dysmorphisms, systemic anomalies, and the presentation of medical co-morbidities such as seizures, intellectual disabilities (ID), and gastro-intestinal (GI) problems. Pregnancy and postnatal  Page 3 of 11  histories were also colected at the time of the appointment.  Identification of Candidate Genes  A general list of candidate genes were compiled for each proband through the Database of Genomic Variants website (htp:/, and were subsequently narrowed down further using the SUSPECTS database (htp:/ The major premise of SUSPECTS is that genes associated with complex traits wil participate in the same gene networks and exhibit similar expression patterns, and the program achieves this by ranking candidate genes in their posible involvement with the trait of interest.  Information on each candidate gene identified by SUSPECTS was colected through the NCBI website (htp:/, specifically loking at the Entrez Gene record and the database of Genotype and Phenotype (dbGaP) entry (when available) for each gene. Further information regarding genotype-phenotype relationships were gathered from the iHOP website (htp:/ which compiles a list of all known functions, interactions, and diseases the gene of interest is associated with. The metalife database (http:/ was also utilized to complement the gene ontology information colected from the iHOP website and gives an informative summary of all the research done on the gene of interest as well as linking them to various phenotypes associated with the gene.   Results:  Table 1 summarizes the candidate genes for each subject pair sharing the same pathogenic CNV, as well as the candidate genes for individuals bearing unique pCNVs. Known gene ontologies for each candidate gene are also listed in Table 1. A list of shared and unique phenotypes was also compiled in Table 2 for each pair and unique individuals bearing a particular pathogenic CNV. Figure 1 is a schematic diagram summarizing all of the candidate genes found on the various chromosomes.  Subjects A and B  The affected, unrelated pair share almost identical 2p15-16.1 deletions and both are of de novo origin. The affected region has been further defined to be from positions 56,80,00 to 63,20,00 for subject A, and from 5,50,00 to 63,40,00 for subject B on chromosome 2 confirmed through RT-qPCR and/or FISH methods.  Candidate genes for both subjects within the overlapping regions include PEX13 and OTX1, which are involved in Peroxisome Biogenesis Disorders and brain and sensory organ development as well as iner ear morphogenesis, respectively.  Subjects C and D  Subject D is the aunt of subject C, and both individuals share the same deletion at the 14q1.2 locus and duplication at the 15q1-12 locus. An unbalanced product of a reciprocal cryptic 14q/15q translocation represents this finding. A perfect overlap at the 14q1.2 and 15q11-12 regions between both subjects was found (19,570,792 to 20,341,734 and 20,536,416 to 30,830,821, respectively).   Of particular note, several candidate genes are implicated with nervous system development, which include CYFIP1, NDN, UBE3A, APBA2, GREM1, and SCG5, all of which are found on the shared 15q1-12 site. Several candidate genes found on the same locus are also implicated with Angelman syndrome as well as Prader-Wili syndrome, and includes the NIPA1/NIPA2, SNRPN, UBE3A, and ATP10A genes.  Subjects E and F  Subjects E and F are brothers who share the Page 4 of 11 Pathogenic Copy Number Variants (pCNVs) in Individuals diagnosed on the Autism Spectrum Disorder: A Closer lok at Candidate Genes  Table 1 Subject(s) Candidate Gene(s)1 Pathogenic CNV(s) and cytoband(s)2 Origin Genomic Region (bp)2 Gene Ontology3 A, B 1.PEX13 2.OTX1 del 2p15-16.1 de novo A=56,800,000/63,200,000 B=55,500,000/63,400,000 1.Peroxisome Biogenesis Disorders 2.Brain and sensory organ development, Inner ear morphogenesis C, D 1a.NP 2a.NIPA1/NIPA2   b.CYFIP1   c.NDN   d.SNRPN   e.UBE3A   f.ATP10A   g.GABRB3   h.GABRA5   i.GABRG3   j.APBA2   k.CHRFAM7A   l.GREM1   m.SCG5 1.del 14q11.2   2.dup 15q11-12      Both translocations  1. 19,570,792/20,341,734 2. 20,536,416/30,830,821  1a.Purine nucleoside phosphorylase     activity 2a.Prader-Wili/Angelman syndrome   b.Nervous system development   c.Neuron development   d.RNA splicing, Prader-Wili     Syndrome   e.Brain development, Angelman      Syndrome   f.Angelman Syndrome  g,h,i.GABA-A receptor activity  j.Nervous system development   k.Role in failure to thrive in infants   l.Bone and Nervous System    development  m.Neuropeptide signaling, hormone     secretion regulation E, F 1.PHF8 2.WNK3 del Xp11.2 (highly skewed X-inactivation) familial inherited 53,970,960 /54,326,640 1.X-linked mental retardation 2.Protein amino acid phosphorylation G 2a.SEMA5A   b.CT5   c.CTNND2  1.del 3p24.3-25     2.del 5p15.2 novo novo  1. 15,780,358 /15,940,642       2. 9,334,790 /11,738,791 2a.Axonal guidance, Nervous system     development  b.Chaperon protein binding  c.Neuron adhesion, synaptic     plasticity H  1.GTF2I  dup 7q11.23 unknown origin 72,200,000/73,767,523 1.General transcription factor,   Wiliams-Beuren syndrome I 1. L3MBTL4 dup 18p11.3 de novo 5,910,725/6,063,460 1.Cel adhesion, platelet activation,   integrin complex component 1Confirmed through Database of Genomic Variants website and subsequently narrowed down with SUSPECTS database 2Affected region confirmed by RT-qPCR and/or FISH 3Information gathered colectively from the NCBI, iHOP, and metalife databases  Page 5 of 11  Table 2 1ID = Intelectual Disability    Subject(s) Shared Phenotypes Unique Phenotypes A, B Severe ID1, microcephaly (<2%), craniofacial dysmorphisms (short forehead, high and broad nasal root), other systemic dysmorphisms (bilateraly tight heel cords, oral motor dysfunction), abnormal brain imaging A=Prenatal growth retardation, B=Seizure disorder, postnatal smal stature (<5%) C, D Craniofacial dysmorphisms (strabismus, flat occiput, prominent alar cartilage), no other systemic dysmorphisms C=Moderate ID, respiratory distres and poor suck and     feding dificulties (postnatal) D=Mild ID, seizure disorder, floppy infant (postnatal) E, F Moderate ID, craniofacial dysmorphisms (flat occiput, coarse asymmetric face [right side > left side fulnes], micrognathia, unilateral cleft lip), other systemic dysmorphisms (pes planus, bone anomalies) E=Prominent metopic suture, prominent finger pads F=Long slender fingers, macrocephaly at birth, mild     hyperoptic refractive eror G N/A G=Moderate ID, seizure disorder, macrocephaly (>98%),    postnatal large stature (>98%), craniofacial     dysmorphisms (coarse facial features, frontal bossing,     prominent supra-orbital ridge), other systemic     dysmorphsims (prominent finger pads, bilateral tight     heel cords, slight toe walking)  H N/A H=Moderate ID, craniofacial dysmorphisms    (plagiocephaly, brachycephaly, prognathia), other     systemic dysmorphisms (GI: unusual dark stool colour,     walks on heels, occasional enuresis), normal brain      imaging I N/A  I=Mild ID, hightened blood presure (during pregnancy),    craniofacial dysmorphisms (mild bilateral epicanthal    folds, ears bilateraly protuberant, slight malar    flatening), other systemic dysmorphisms (slight    metatarsus varus when walking)  Page 6 of 11 Pathogenic Copy Number Variants (pCNVs) in Individuals diagnosed on the Autism Spectrum Disorder: A Closer lok at Candidate Genes   same Xp1.2 deletion that is familial inherited, and the precise genomic region was found to be from 53,970,960 to 54,326,640 on the X chromosome. Of particular note, the mother was confirmed to have a very skewed X-inactivation, perhaps implying dosage imbalance problems in both siblings. Potential candidate genes in the affected region of both subjects E and F include PHF8, which is associated with X-linked mental retardation, as well as the WNK3 gene which is involved in protein amino acid phosphorylation.  Subject G  The affected individual harbors two deletions at the 3p24.3-25 and 5p15.2 regions, with both regions of de novo origin. The precise affected region for the chromosome 3 deletion was found to be from 15,780,358 to 15,940,642, and the chromosome 5 deletion is from 9,34,790 to 1,738,791, as confirmed by FISH and/or RT-qPCR.  In relation to the observed phenotypes, several candidate genes that may play a role in the pathogenesis of classical autism includes SEMA5A and CTNND2, both of which are located on chromosome 5 and are involved in axonal guidance and neuron adhesion and synaptic plasticity, respectively. CCT5 was also identified by SUSPECTS to be another candidate gene on the same chromosome, and is involved with chaperon protein binding in neurons.  Subject H  Subject H is an individual with a unique 7q1.23 duplication of unknown origin that is not found in other subjects presenting with pathogenic CNVs. The affected genomic region was found to be from 72,20,00 to 73,767,523 through FISH and/or RT-qPCR methods. Of particular note, the GTF2I candidate gene was identified by the SUSPECTS database which is known to be as a general transcription factor, as well as being implicated with Wiliams-Beuren syndrome.  Subject I  This affected individual was identified to have a duplication of de novo origin at the 18p1.3 region which was further refined to be from 5,910,725 to 6,063,460 on chromosome 18. L3MBTL4 was the sole candidate gene identified that may account for the observed phenotypes, and is known to be involved in cell adhesion, platelet activation, as well as being a component of the integrin complex.   Discusion:  Subjects A and B: 2p15-16.1 deletion  Several characteristics shared by both subjects include intellectual disability as well as por oral motor skils and por muscle tone,  Page 7 of 11  which overlap with certain Peroxisome Biogenesis Disorder (PBD) phenotypes, thus making the PEX13 gene on chromosome 2 a posible culprit for the observed phenotypes. Since both subjects are stil alive, Refsum’s disease is the most likely out of all the other PBDs as its prognosis is the most hopeful in terms of living past the early childhod years. However, normal laboratory evidence of phytanic acid and long chain fatty acids, both of which are found in elevated levels in affected individuals due to faulty enzymes during the alpha oxidation of phytanic acid and fatty acid oxidation, were found for both individuals harboring the overlapping 2p15-16.1 deletion (Rajcan-Separovic et al., 207). Nonetheless, the posibility of PEX13 contributing to part of the observed phenotypes, in particular those involved with neurodevelopment (in keeping with microcephaly in both subjects) and por muscle tone, cannot be completely ruled out, as well as other candidate genes in the deleted region.  Another candidate gene that may be responsible for neurodevelopment as well as sensory organ development is OTX1, a transcription factor that was recently found to be essential in cerebellum development (de Haas et al., 206). The observed large ears, relative to the microcephaly in both subjects, may also be in part due to the los of function of the OTX1 gene. Furthermore, evidence sugests that the OTX1 gene dictates the segregation of the saccule and the utricle during iner ear morphogenesis (Beisel et al., 205), and its los of function due to the deletion may perhaps indeed be responsible for the hyperacusis observed in subject A as well as the bilateral sensorineural los (mild to moderate in the left ear and slight to mild in the right ear) observed in subject B.  Subjects C and D: 14q11.2 deletion and 15q11-12 duplication  Both subjects present strikingly similar characteristics, most notably sharing several craniofacial dysmorphisms (strabismus, flat occiput, prominent alar cartilage) and presentation of intellectual disability (subject C has moderate ID while subject D has mild ID). These findings sugest an underlying genomic basis that may be responsible for the shared pathogenesis, and indeed, both a deletion and a duplication arising through a reciprocal cryptic 14q/15q translocation were found whose affected genomic areas were found to have perfect overlap between the two relatives (Table 1).  Candidate genes that may be implicated with cephalic development were found in the duplicated 15q1-12 region and as such, dosage effects may be at play here in terms of over-expression of a particular gene and/or altered regulation of a gene that may exert its effects on adjacent genes involved in the same gene network. The highly conserved CYFIP1 gene may be one such gene. Through co-localization experiments, there is evidence that the products of the CYFIP1 gene do indeed interact with FMRPs [Fragile X mental retardation proteins] (Schenck et al., 201). Although the functions of the CYFIP1 proteins are currently unknown, the extraction of CYFIP1 proteins at the synaptosome of the distal portion of dendrites sugests that they also interact with the small GTPase Rac1 where it also localizes (Schenck et al., 201). Rac1 is known to be essential for dendritic spine maturation as well as maintenance (Nakayama et al., 200), and a duplication of the CYFIP1 gene with whom it interacts may have direct or indirect effects on the maturation and maintenance of these structures. One posibility is that improper dosage of the CYFIP1 gene product could directly alter expression levels of Rac1 and other genes in the network involved in dendrite formation. This would have major implications for neurodevelopment and could thus be responsible for the shared ID and ASD observed in both subjects.  Several other candidate genes that may be responsible for the shared dysmorphisms include UBE3A and APBA2. Most notably, maternally derived duplications of the 15q1-13 region results in changes to UBE3A expression observed in autistic individuals, whereas the duplication is not present in normal individuals (Veenstra-VanderWeele et al., 199). In addition, GREM1 may also be the culprit gene for the observed bone fractures in subject D and the ligamentous laxity in subject C, as over-expression of the gene in transgenic mice analogous to that of a duplication event resulted in a 20-30% reduction in bone mineral density as well as formation of bone fractures (Gazzerro et al., 205). It has been well established that Page 8 of 11 Pathogenic Copy Number Variants (pCNVs) in Individuals diagnosed on the Autism Spectrum Disorder: A Closer lok at Candidate Genes  deletions in the 15q1-13 region result in Prader-Wili syndrome (PWS) as well as Angelman syndrome (AS) (Ditrich et al., 1992) in which several of the phenotypes overlap with those present in both subjects. These include reduced fetal movements, respiration and feeding difficulties, strabismus, and intellectual disability (Holm et al., 193). NIPA1/NIPA2, NDN, SNRPN, UBE3A, ATP10A, and the Gamma acid receptor family (GABA) were identified by SUSPECTS in the duplicated 15q11-12 region to be implicated in autistic disorder in both subjects. There is evidence that a marker in the gene for the gamma aminobutyric acid receptor subunit of GABRB3 was found to have linkage disequilibrium with autistic disorder, making this gene as well as other members of the gene family a prime candidate gene (Cook et al., 198). Furthermore, the role of benzodiazepine as a GABA receptor agonist in treating autistic phenotypes such as anxiety disorders and seizures sugest a potential role of the GABA gene family in the presentation of these phenotypes beyond the normal inhibitory neurotransmiter GABA function (Cook et al., 198). Aditional studies need to be conducted in the future so as to precisely disect the roles of the GABA gene family as well as others that exhibit linkage disequilibrium with autistic disorders.  Subjects E and F: Xp11.2 deletion  Both brothers share the same familial inherited Xp1.2 deletion, and a posible candidate gene that may account for the shared moderate ID is PHF8. The PHF8 gene encodes a PHD finger protein which has been shown through truncation mutation experiments to cause X-linked mental retardation (XLMR) with or without cleft lip/cleft palate presentation (Laumonier et al., 205). The PHD finger protein has also been thought to regulate and modify chromatin structure (Jensen et al., 205), which has major implications in terms of altered transcription levels and neurodevelopment in individuals with mutations or deletions of the PHF8 gene.  Another candidate gene that may be implicated with the observed moderate ID in both subjects is WNK3, as it has been shown to occupy the critical linkage region on Xp1.2, and thus may also play a critical role in neurodevelopmental disorders such as XLMR (Ropers et al., 203). However, future studies need to be conducted so as to determine whether the WNK3 deletions could account for the differences in autism occurrence in the cases presented here in comparison to the PHF8 deletion cases, or whether deletion size differences affect interaction with neighboring genes.  Subject G: 3p24.3-25 and 5p15.2 deletions  Subject G is an affected individual identified to harbor unique deletions at the 3p24.3-25 and 5p15.2 regions. Several phenotypes unique to subject G in relation to the deletions include moderate ID, macrocephaly (>98%), postnatal large stature (>98%), and several craniofacial dysmorphisms (coarse facial features, frontal bosing). SEMA5A, a candidate gene identified by SUSPECTS, may account for the observed moderate ID and macrocephaly as it is known to be involved in axonal guidance and nervous system development (Adams et al., 196). The gene occupies the 5p15.2 region and experimental evidence shows that axonal development and formation of synapses may be affected by changes in SEMA5A expression (Jones et al., 202). Furthermore, deletions from the 5p band are also implicated with the Cri-du-chat phenotype, and haploinsufficiency of SEMA5A may be responsible for the intellectual disability in individuals exhibiting the phenotype (Simmons et al., 198). A deletion at the 5p15.2 region may thus have major implications in SEMA5A expression levels as not enough products are made to maintain proper axonal development and synapse formation, posibly leading to the observed macrocephaly and moderate ID in subject G.  CCT5 is another candidate gene that was identified by SUSPECTS to be likely involved in neurodevelopment as the chaperon protein product of CCT5 was found to have an additional role in polymerization as well as maintenance of cytoskeletal proteins in neurons (Bourke et al., 202). Deletions in the 5p15.2 region would thus have profound effects on proper neurodevelopment due to a lack of CCT5 chaperone proteins essential for proper neuron functioning. The CTNND2 gene, which is also found on 5p15.2, was also identified as a posible candidate for the shared macrocephaly  Page 9 of 11  and moderate ID phenotypes. Mutational experiments sugest a specialized role for the CTNND2 protein as mutations in the gene result in learning and synaptic plasticity deficits (Israely et al., 204). Furthermore, a strong correlation between a hemizygous deletion of the CTND2 gene and severe mental retardation in individuals with Cri-du-chat syndrome (CDCS) was found (Medina et al., 200), further underlying the critical role of CTNND2 regarding intellectual disability in subjects manifesting a deletion in the 5p15.2 region associated with CDCS. Moreover, delta catenin (the protein product of CTNND2) was also found to co-bind with kaiso to the promoter sites of rapsyn [a synapse protein necessary for segregating acetylcholine receptors at the neuromuscular area] (Rodova et al., 204).  Deletion of the CTND2 gene on 5p15.2 would thus have adverse effects on proper rapsyn functioning, and this may attribute to the seizures, delays in motor milestones, as well as failure to thrive observed in the affected individual.  Subject H: 7q11.23 duplication  Subject H is an isolated case that does not share any pathogenic CNVs or cytogenetic bands with the other cases here, but several others have been reported. A unique 7q1.23 duplication of unknown origin was found, and GTF2I was the sole candidate gene identified by SUSPECTS that may be implicated with the unique phenotypes associated with the affected genomic region. Structural features of 7q1.23 render this region susceptible to genomic rearrangement and deletions, yielding various CNVs that are also involved with Wiliams-Beuren syndrome [WBS] (Cuscó et al., 208). Several characteristics are shared by the subject with WBS which include intellectual disability, hyperacusis, as well as genito-urinary problems (Sammour et al., 2006) [subject has a history of enuresis]. Furthermore, GTF2I was also shown to be involved in toth development at the bud and early bell stage (Ohazama and Sharpe, 207), and thus may also account for the carious as well as early los of teeth in the subject. Moreover, hemizygosity of GTF2I was found to be sufficient to account for a number of features associated with WBS, including visuospatial deficits (Edelmann et al., 207), which may contribute to the astigmatism and myopia observed in subject H.  Subject I: 18p11.3 duplication   The affected subject harbors a unique duplication at the 18p1.3 region of de novo origin and presents several phenotypes that may be associated with the duplication. Of particular note, the candidate L3MBTL4 gene is known to be involved in platelet activation, and a dosage imbalance arising through a duplication may have direct or indirect consequences with regards to the observed heightened blod pressure during pregnancy. Furthermore, the role of the L3MBTL4 gene in cell adhesion, in particular as a component of the integrin complex which is known to be involved in mediating various intracellular signals, may indeed account for the craniofacial and systemic dysmorphisms as well as the mild ID observed in subject I. The implications of dosage effects through duplication of the 18p1.3 region need to be further investigated as well as the specific roles of L3MBTL4, as research on this region and its genes is limited to make any conclusive statements regarding genotype-phenotype relationships at this time.   Conclusions:  The identification of candidate genes on various chromosomes provide further insight as to how changes occurring at the gene level affects the phenotype at the organismal level. Autism spectrum disorders present an especially daunting task as its variability between different individuals sugests a multitude of genes that may interact with other candidate genes involved in the same or different gene networks. Aditional experiments need to be conducted in the future so as to uncover the functions of these genes, how their expression is regulated, and what gene networks they participate in. Only through understanding these finer details at the gene level can we then unravel the genetic bases of some of the phenotypes associated with classical autism.   Acknowledgements:  Page 10 of 11 Pathogenic Copy Number Variants (pCNVs) in Individuals diagnosed on the Autism Spectrum Disorder: A Closer lok at Candidate Genes  The author would like to thank Noemie Riendeau and Ying Qiao at the Child and Family Research Institute (CFRI) wet lab for all of their help in assisting with the CNV data, as well as for their insightful comments. A warm thank-you also goes out to Priscila Carrion and Lindsay Swinton at the dry lab for all of their help with the clinical files. The arrays and FISH data that were utilized by the author were done by Ying Qiao and Maryam Kochek, and the RT-qPCR was done by Xudong Liu at Queen’s University, all of which the author is grateful for having access to. And last, but certainly not least, the author would like to express his sincerest gratitude towards his mentor, Dr. Lewis, for allowing the author to undertake this directed studies project, as well as for all of her guidance with which this project would have never been posible without.   Coresponding Author:  Alan Dale Baniaga The University of British Columbia  247 East 29th Avenue  Vancouver, British Columbia  Canada V5R 1T8   REFERENCES:  Adams R H, Betz H, and Puschel A W (196) A novel class of murine semaphorins with homology to thrombospondin is differentially expressed during early embryogenesis, Mech Dev 57: 3–45. Baird G, Charman T, Baron-Cohen S, Cox A, Swettenham J, et al. (200) A screening instrument for autism at 18 months of age: a 6-year folow up study, J. Am. Acad. Child Adolesc. Psychiatry 39: 694–702. Beisel K W et al. (205) Development and evolution of the vestibular sensory apparatus of the mammalian ear, Journal of Vestibular Research 15(5-6): 25-41. Bertrand J, Mars A, Boyle C, Bove C, Yeargin-Alsop , Decoufle P (201) Prevalence of autism in a United States population: the Brick Township, NewJersey, investigation, Pediatrics 108: 15–61. Bourke G J, El Alami W, Wilson S J, Yuan A, Roobol A, Carden M J (202) Slow axonal transport of the cytosolic chaperonin CT with Hsc73 and actin in motor neurons, J Neurosci Res 68: 29–35. Chakrabarti S and Fombone E (201) Pervasive developmental disorders in preschol children, JAMA 285: 3093–99. Chakrabarti S and Fombone E (205) Pervasive developmental disorders in preschol children: confirmation of high prevalence, Am. J. Psychiatry 162: 13–41. Cook, E H Jr et al. (198) Linkage-Disequilibrium Mapping of Autistic Disorder, with 15q11-13 Markers, Am. J. Hum. Genet. 62: 107–83. Cuscó I, Corominas R, Bayés M et al. (208) Copy number variation at the 7q1.23 segmental duplications is a susceptibility factor for the Wiliams-Beuren syndrome deletion, Genome Res 18(5): 683-94. Ditrich B et al. (192) Molecular diagnosis of the Prader-Wili and Angelman syndromes by detection of parent-of-origin specific DNA methylation in 15q1-13, Hum Genet 90: 313-15. Edelmann L et al. (207) An atypical deletion of the Wiliams–Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism, Journal of Medical Genetics 44: 136-43. Fan YS, Jayakar P, Zhu H, Barbouth D, Sacharow S, Morales A et al. (207) Detection of pathogenic gene copy number variations in patients with mental retardation by genome wide oligonucleotide array comparative genomic hybridization, Human mutation 28(11): 124-32. Gazzerro E et al. (205) Skeletal Overexpression of Gremlin Impairs Bone Formation and Causes Osteopenia, Endocrinology 146(2): 65–65. de Haas, T et al. (206) OTX1 and OTX2 Expression Correlates With the Clinicopathologic Classification of Meduloblastomas, Journal of Neuropathology & Experimental Neurology 65(2): 176-86. Holm V A et al. (193) Prader-Wili Syndrome: Consensus Diagnostic Criteria, Pediatrics 91: 398-402. Israely, I et al. (204) The neuronal adherens-junction protein Delta-Catenin is critical for  learning and synaptic plasticity, Curr Biol 14: 1657–63.  Page 11 of 11  Jensen L R et al. (205) Mutations in the JARID1C gene, involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation, Am J Hum Genet 76: 27–36. Jones L, Lopez-Bendito G, Grus P, Stoykova A, and Molnar Z (202) Pax6 is required for the normal development of the forebrain axonal conections, Development 129: 5041–52. Laumonier F et al. (205) Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate, J Med Genet 42: 780–86. Lee C, Iafrate AJ, Brothman AR (207) Copy number variations and clinical cytogenetic diagnosis of constitutional disorders, Nat Genet 39(7 Supl): S48-54. Medina M, Marinescu R C, Overhauser J, Kosik K S (200) Hemizygosity of delta-catenin (CTND2) is associated with severe mental retardation in cri-du-chat syndrome, Genomics 63(2): 157–64. Nakayama A Y, Harms M B, and Luo L (200) Small GTPases Rac and Rho in the Maintenance of Dendritic Spines and Branches in Hipocampal Pyramidal Neurons, The Journal of Neuroscience 20(14): 5329-38. Newschaffer, C J et al. (207) The Epidemiology of Autism Spectrum Disorders, Anu. Rev. Public Health 28: 235–58. Ohazama, A and Sharpe P T (207) TFII-I Gene Family During Toth Development: Candidate Genes for Toth Anomalies in Wiliams Syndrome, Developmental Dynamics 236(10): 2884–88. Qiao Y, Liu X, Harvard C, Nolin SL, Brown WT, Kochek M et al. (207) Large-scale copy number variants (CNVs): distribution in normal subjects and FISH/real-time qPCR analysis, BMC genomics 8: 167. Rajcan-Separovic E, Harvard C, Liu X, McGilivray B, Hall JG, Qiao Y et al. (207)  Clinical and molecular cytogenetic characterisation of a newly recognised microdeletion syndrome involving 2p15-16.1, J Med Genet 4(4): 269-76. Rodova M, Kelly K F, VanSaun M, Daniel J M, and Werle M J (204) Regulation of the Rapsyn Promoter by Kaiso and Delta-Catenin, Mol Cell Biol 24(16): 718–96. Ropers, H  et al. (203) Nonsyndromic X-linked mental retardation: where are the mising mutations?, Trends Genet. 19: 316-20. Sammour Z, Gomes C, Duarte R, Trigo-Rocha F, Srougi M (206) Voiding Dysfunction and the Wiliams-Beuren Syndrome: A Clinical and Urodynamic Investigation, The Journal of Urology 175(4): 1472-76. Schenck A et al. (201) A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P, PNAS 98(15): 8844-49. Shaefer G B and Mendelsohn N J (208) Clinical genetics evaluation in identifying the etiology of autism spectrum disorders, Genetics in Medicine 10(1): 4-12. Simmons A D, Puschel A W, McPherson J D, Overhauser J, and Lovett M (198) Molecular cloning and mapping of human semaphorin F from the Cri-du-chat candidate interval, Biochem Biophys Res Commun 242: 685–91. Tyson C, Harvard C, Locker R, Friedman JM, Langlois S, Lewis ME et al. (205) Submicroscopic deletions and duplications in individuals with intellectual disability detected by array-CGH, Am J Med Genet A 139(3): 173-85. Veenstra-VanderWeele J, Gonen D, Leventhal B L, and Cook Jr E H (199) Mutation screening of the UBE3A/E6-AP gene in autistic disorder, Molecular Psychiatry 4: 64-7.    


Citation Scheme:


Citations by CSL (citeproc-js)

Usage Statistics

Country Views Downloads
China 21 3
United Kingdom 11 0
France 8 0
Brazil 8 0
United States 4 29
Canada 2 0
Germany 1 0
City Views Downloads
Shenzhen 21 3
Unknown 20 0
Edinburgh 9 0
London 2 0
Vancouver 2 0
Ashburn 1 0

{[{ mDataHeader[type] }]} {[{ month[type] }]} {[{ tData[type] }]}
Download Stats



Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            async >
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:


Related Items