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Submicroscopic deletions of 11q24-25 in individuals without Jacobsen syndrome: re-examination of the… Tyson, Christine; Qiao, Ying; Harvard, Chansonette; Liu, Xudong; Bernier, Francois P; McGillivray, Barbara; Farrell, Sandra A; Arbour, Laura; Chudley, Albert E; Clarke, Lorne; Gibson, William; Dyack, Sarah; McLeod, Ross; Costa, Teresa; VanAllen, Margot I; Yong, Siu-li; Graham, Gail E; MacLeod, Patrick; Patel, Millan S; Hurlburt, Jane; Holden, Jeanette J; Lewis, Suzanne M; Rajcan-Separovic, Evica Nov 11, 2008

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ralssBioMed CentMolecular CytogeneticsOpen AcceResearchSubmicroscopic deletions of 11q24-25 in individuals without Jacobsen syndrome: re-examination of the critical region by high-resolution array-CGHChristine Tyson1, Ying Qiao1,2, Chansonette Harvard1, Xudong Liu3,4, Francois P Bernier5, Barbara McGillivray2, Sandra A Farrell6, Laura Arbour7, Albert E Chudley8, Lorne Clarke2, William Gibson2, Sarah Dyack9, Ross McLeod5, Teresa Costa10, Margot I VanAllen2, Siu-li Yong2, Gail E Graham11, Patrick MacLeod7, Millan S Patel2, Jane Hurlburt2, Jeanette JA Holden3,4, Suzanne ME Lewis2 and Evica Rajcan-Separovic*1Address: 1Department of Pathology and Laboratory Medicine and Child and Family Research Institute (CFRI), UBC, Vancouver, BC, Canada, 2Department of Medical Genetics, UBC, Vancouver, BC, Canada, 3Departments of Psychiatry and Physiology, Queens University, Kingston, ON, Canada, 4Autism Research Program and Cytogenetics and DNA Research Laboratory, Ongwanada, Kingston, ON, Canada, 5Department of Medical Genetics, University of Calgary, AB, Canada, 6Medical Genetics, Credit Valley Hospital, Mississauga, Ontario, Canada, 7Department of Medical Genetics, Victoria General Hospital, Victoria, BC, Canada, 8Section of Genetics and Metabolism, Children's Hospital, Manitoba, Canada, 9IWK Grace Health Centre, PO Box 3070, Halifax, Nova Scotia, Canada, 10Medical Genetics, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Québec, Canada and 11Eastern Ontario Regional Genetics Program, Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, CanadaEmail: Christine Tyson - Christine.Tyson@fraserhealth.ca; Ying Qiao - yqiao@interchange.ubc.ca; Chansonette Harvard - charvard@interchange.ubc.ca; Xudong Liu - liux@post.queensu.ca; Francois P Bernier - Francois.Bernier@CalgaryHealthRegion.ca; Barbara McGillivray - bmcgillivray@cw.bc.ca; Sandra A Farrell - sfarrell@cvh.on.ca; Laura Arbour - Laura.arbour@viha.ca; Albert E Chudley - AChudley@exchange.hsc.mb.ca; Lorne Clarke - lclarke@cw.bc.ca; William Gibson - wgibson@cw.bc.ca; Sarah Dyack - Sarah.Dyack@iwk.nshealth.ca; Ross McLeod - Ross.McLeod@CalgaryHealthRegion.ca; Teresa Costa - teresa.costa.hsj@ssss.gouv.qc.ca; Margot I VanAllen - mvallen@cw.bc.ca; Siu-li Yong - slyong@cw.bc.ca; Gail E Graham - GGraham@cheo.on.ca; Patrick MacLeod - macleodpatrick@shaw.ca; Millan S Patel - mpatel@cw.bc.ca; Jane Hurlburt - jhurlburt@cw.bc.ca; Jeanette JA Holden - holdenj@post.queensu.ca; Suzanne ME Lewis - slewis@cw.bc.ca; Evica Rajcan-Separovic* - eseparovic@cw.bc.ca* Corresponding author    AbstractBackground: Jacobsen syndrome is a rare contiguous gene disorder that results from a terminaldeletion of the long arm of chromosome 11. It is typically characterized by intellectual disability, avariety of physical anomalies and a distinctive facial appearance. The 11q deletion has traditionallybeen identified by routine chromosome analysis. Array-based comparative genomic hybridization(array-CGH) has offered new opportunities to identify and refine chromosomal abnormalities inregions known to be associated with clinical syndromes.Results: Using the 1 Mb BAC array (Spectral Genomics), we screened 70 chromosomally normalchildren with idiopathic intellectual disability (ID) and congenital abnormalities, and identified fivePublished: 11 November 2008Molecular Cytogenetics 2008, 1:23 doi:10.1186/1755-8166-1-23Received: 12 June 2008Accepted: 11 November 2008This article is available from: http://www.molecularcytogenetics.org/content/1/1/23© 2008 Tyson et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 9(page number not for citation purposes)cases with submicroscopic abnormalities believed to contribute to their phenotypes. Here, weprovide detailed molecular cytogenetic descriptions and clinical presentation of two unrelatedMolecular Cytogenetics 2008, 1:23 http://www.molecularcytogenetics.org/content/1/1/23subjects with de novo submicroscopic deletions within chromosome bands 11q24-25. In subject 1the chromosome rearrangement consisted of a 6.18 Mb deletion (from 128.25–134.43 Mb) and anadjacent 5.04 Mb duplication (from 123.15–128.19 Mb), while in subject 2, a 4.74 Mb interstitialdeletion was found (from 124.29–129.03 Mb). Higher resolution array analysis (385 K Nimblegen)was used to refine all breakpoints. Deletions of the 11q24-25 region are known to be associatedwith Jacobsen syndrome (JBS: OMIM 147791). However, neither of the subjects had the typicalfeatures of JBS (trigonocephaly, platelet disorder, heart abnormalities). Both subjects had ID,dysmorphic features and additional phenotypic abnormalities: subject 1 had a kidney abnormality,bilateral preauricular pits, pectus excavatum, mild to moderate conductive hearing loss andbehavioral concerns; subject 2 had macrocephaly, an abnormal MRI with delayed myelination, fifthfinger shortening and squaring of all fingertips, and sensorineural hearing loss.Conclusion: Two individuals with ID who did not have the typical clinical features of Jacobsensyndrome were found to have deletions within the JBS region at 11q24-25. Their rearrangementsfacilitate the refinement of the JBS critical region and suggest that a) deletion of at least 3 of the 4platelet function critical genes (ETS-1, FLI-1 and NFRKB and JAM3) is necessary forthrombocytopenia; b) one of the critical regions for heart abnormalities (conotruncal heart defects)may lie within 129.03 – 130.6 Mb; c) deletions of KCNJ1 and ADAMTS15 may contribute to the renalanomalies in Jacobsen Syndrome; d) the critical region for MRI abnormalities involves a region from124.6 – 129.03 Mb. Our results reiterate the benefits of array-CGH for description of newphenotype/genotype associations and refinement of previously established ones.BackgroundArray-based comparative genomic hybridization (array-CGH) technology has vastly improved the resolution ofcytogenetic analysis, resulting in the detection of patho-genic genomic imbalances in 9–17% of individuals withnormal chromosomes and undefined causes of intellec-tual disability (ID) [1,2]. It has led not only to the descrip-tion of new microdeletion/microduplication syndromes(for review see Slavotinek, 2008 [3]) but has also facili-tated a more accurate genotype-phenotype correlation incases of well established syndromes [4,5].Jacobsen syndrome (JBS: OMIM 147791) was one of thefirst recognised contiguous gene syndromes, resultingfrom a terminal deletion of the long arm of chromosome11 [6]. The typical clinical findings include thrombocyto-penia, developmental delay, congenital heart disease andshort stature [7]. Dysmorphic features include hyperte-lorism, ptosis, down slanting palpebral fissures, broadnasal bridge with short nose, thin upper lip and low set,malformed ears. In most cases, the partial monosomy of11q is the result of a simple terminal deletion of 11q, withbreakpoints usually occurring at or distal to 11q23.3. Inaround 25% of cases the 11q23.3 breakpoint has beenlocalized to the FRA11B fragile site in 11q23.3 [7,8]. In anumber of these patients it was demonstrated that therewas a CCG triplet repeat expansion and expression of thisfragile site in one of the parents [9]. Several other JBS dele-tion breakpoints in the 11q23.3-qter region were alsoshown to localize to CCG repeat expansions [10]. Intersti-monosomy was due to an unbalanced translocation (forexample, Zahn et al. [12]). Several studies have provideda genotype-phenotype correlation in an attempt to iden-tify critical regions for the most common physical abnor-malities seen in Jacobsen syndrome [7,8].We report here the clinical and molecular cytogeneticfindings in two subjects with submicroscopic rearrange-ments involving the 11q24-25 JBS critical region, detectedwhile screening 70 children with idiopathic ID and phys-ical anomalies, using a whole-genome 1 Mb BAC array.The recurrent 11q24-25 rearrangements and associatedphenotypes which are seen in our two patients are com-pared to those found in patients with Jacobsen syndrome.MethodsSubject recruitmentTwo subjects with 11q rearrangements were identifiedamongst 70 children with idiopathic ID having i) normalkaryotypes by routine cytogenetic testing at 500–550band level resolution, ii) negative Fragile X testing byDNA analysis, iii) a phenotype score ≥ 3 on the checklistpresented by DeVries et al [13]and iv) both parents avail-able for testing. Clinical geneticists across Canadarecruited subjects for genomic screening according to theabove criteria.G-banded Chromosome AnalysisMetaphase chromosomes were prepared from peripheralblood samples using standard methods. GTG bandingPage 2 of 9(page number not for citation purposes)tial deletions of 11q23.3-qter are rarely reported [11], asare cases of Jacobsen syndrome where the partial 11qwas performed according to standard procedures.Molecular Cytogenetics 2008, 1:23 http://www.molecularcytogenetics.org/content/1/1/231 Mb BAC Array-CGHArray-CGH was performed as previously described usingthe Spectral Genomics 1 Mb array [14]. The images wereanalyzed using SPECTRALWARE BAC Array Analysis Soft-ware v.2.0 (Spectral Genomics, Houston, TX). The posi-tions of BAC clones were established using the database ofgenomic variants http://projects.tcag.ca/variation/,human genome build 35.FISHFluorescence in situ hybridization (FISH) was performedwith BAC DNA clones (Spectral Genomics, Houston, TX)or commercially available pre-labeled BAC clones (TheCentre for Applied Genomics, Toronto) to confirm anydeletions or duplications found by 1 Mb array-CGH[14,15]. Slides were viewed on a Zeiss Axioplan 2 fluores-cence microscope, and images captured using MacProbesoftware (Applied Imaging, Santa Clara, CA). For eachprobe, at least 10 metaphase cells were analyzed. Inter-phase nuclei (50–100) were screened blindly in the caseof microduplications.High Resolution Array-CGHHigh resolution whole genome analysis was performed torefine the boundaries of rearrangements found by 1 Mbarray-CGH, and also offered a second independent meansof confirming the result. High-resolution Nimblegen 385K array-CGH was performed courtesy of Nimblegen.ResultsSubject 1 (Figure 1a)Clinical descriptionSubject 1 is the product of a second pregnancy to a non-consanguineous 32 year old mother and 34 year oldfather, both of northern European descent. She was bornat 39 weeks gestation with a birth weight of 6 lb 11 oz. Shewas noted at birth to have a single umbilical artery, bilat-eral preauricular pits, bilateral simian creases, and ultra-sound in early infancy showed an absent right kidney.Physical examination at 1 month of age showed an activealert female without dysmorphic facies; Occipital-frontalhead circumference (OFC), length and weight were 50th,75th and 25–50th percentiles, respectively. Neurologicalexam was normal. However, later assessment showed herdevelopmental milestones were delayed: she walked atnearly 2 years, and began putting two words together at 21/2 years. Audiology testing demonstrated mild to moder-ate conductive hearing loss in the left ear, and a less severeright-sided loss. At 38 months, she was mildly unusual inappearance with a broad nasal root, widely set eyes, andpreauricular pits. OFC was reduced to the 5th percentile,relative to maintenance of height and weight approximat-ing the 50th percentiles. Her voice was noted to be mono-tone and nasal in quality. At age 6 1/2 years, concernswere noted regarding social skills, with difficulty makingfriends, an inability to concentrate and impulsiveness. Shewas noted to have difficulty with gross motor skills. Hersystemic health was otherwise uncomplicated. At thistime, OFC, height and weight were 25th, 25th and 5th per-centiles, respectively. She had an unusual facies with aprominent forehead, receding hairline, and fine hairwhich grew slowly. She had a high nasal root, squarishnose, long philtrum, straight mouth and narrow uppervermilion border. She had a pectus excavatum, and wasmildy hyperextensible. She was noted to be remarkablylike her mother in her facial appearance. When examinedat 9 years 1 month she had shown reasonable intervalgrowth, lean habitus, mild pectus excavatum, and star-Facial features and physical abnormalities in subject 1 (a) and 2(b)igure 1abSubject 1Subject 2Page 3 of 9(page number not for citation purposes)Facial features and physical abnormalities in subject 1 (a) and 2(b).Molecular Cytogenetics 2008, 1:23 http://www.molecularcytogenetics.org/content/1/1/23tling blue eyes. She continued to have behavioral con-cerns including impulsive behaviour and difficulty withstrangers. Psychoeducational testing, including the WAISIII (Weschler Adult Intelligence Scales – Version III), at age16 indicated a borderline verbal score, a performancescore in the mild disability range and a full score withinthe mild ID range. When seen at age 17 years 10 monthsshe was noted to have long facies, remarkable blue eyes,an overhanging nose with a bulbous tip, well markedphiltrum, and protuberant lower lip. She had mildly shortD4 and D5 metacarpals. OFC, height and weight were atthe 2nd, 10th and < 5th percentiles, respectively. She hadrapid speech that was difficult to understand. A renalultrasound done at age 18 documented a left kidney ofnormal size and location, and a smaller ectopic right kid-ney. Other investigations included an ophthalmologyexam, which noted intermittent exotropia with mild myo-pia. Karyotype, FISH for 22q11.2/13 microdeletions, Frag-ile X studies, urinary organic acids and serum amino acidswere all normal.Array CGHA 5.04 Mb duplication (from 123.15–128.19 Mb) andadjacent 6.18 Mb deletion (from 128.25–134.43 Mb) at11q24.2-25 were detected (Figure 2). FISH using BACclones RP11-164A10 (dup), RP11-50B3 (dup), RP11-206H9 (del) and RP11-469N6 (del) mapping within theduplication and deletion regions confirmed the imbal-ances in the patient, and showed them to be de novo (Fig-ure 2). The duplication probes showed a discordant (1:2)signal pattern in ~90% of interphase nuclei in subject 1and < 20% nuclei in the parents, while the deletion probesshowed a single signal in 100% of subject 1's interphaseand metaphase cells (compared to < 20% nuclei in par-ents). The number of analyzed cells was 20–100.Subject 2 (Figure 1b)Clinical descriptionThis male child was initially seen in the Genetics Clinic at8 months of age with developmental delay: specifically,the inability to sit unsupported or pull himself into sittingposition, and macrocephaly (OFC > 98th percentile). Hewas delivered at term following an uneventful pregnancyand his weight and OFC at that time were both at the 25thpercentile. At an early age he was noted to have a combi-nation of motor and language delays as well as difficultieswith socialization. MRI scans of the brain have shown evi-dence of abnormal white matter lesions, which werethought to be due to delayed myelination rather than aprogressive leukodystrophy. At age 7 years the patient wasre-assessed due to ongoing concerns regarding his devel-opment, as well his physical appearance. His medical his-tory was unremarkable except for mild sensorineuralaide to help with some specific learning problems in read-ing as well as behavioral issues. His social interaction hadimproved significantly. His height, weight and OFC were10–25th, 50th and 98th percentiles, respectively. He had rel-ative macrocephaly with a prominent forehead (Figure1b), a round face with a broad nose and slightly broadnasal tip with a well-grooved philtrum. His right ear wasnoted to be slightly smaller than the left and he had over-folding of the helices. His hands showed some 5th fingershortening and squaring of the fingertips (Figure 1b). Hisphysical appearance was not consistent with a diagnosa-ble syndrome and a routine karytype as well as subtelom-eric FISH analysis and Fragile X testing were normal. Inreviewing the family history, his brother also has ID butwith an otherwise very different, abnormal phenotypeand an array detected de novo duplication of 19p13.3 (~3Mb). There was no evidence of 11q24-25 abnormality inthis brother. His parents and two older brothers are allhealthy without any cognitive or learning disabilities andthere were no reported paternity concerns.Array CGHA 4.74 Mb interstitial deletion was found at 11q24.2-24.3(from 124.29–129.03 Mb) (Figure 2). FISH using BACclones RP11-50B3 and RP11-206H9 confirmed the dele-tion and showed it to be de novo (Figure 2), as all 10 met-aphases in subject 2 showed a hybridization signal ononly one chromosome 11 homologue (compared to 10parental metaphases which all showed signals on bothchromosome 11 homologues).DiscussionWe report the constellation of clinical and molecularcytogenetic features of two individuals with ID who havede novo submicroscopic rearrangements of chromosome11q24-25. These two individuals are of particular interestsince their deletions lie within the region that is com-monly deleted in patients with Jacobsen syndrome [16].Other than ID, neither of our patients exhibits the mostcharacteristic features of Jacobsen syndrome, which typi-cally include thrombocytopenia or pancytopenia, cranio-facial abnormalities (trigonocephaly) and cardiac defects[6]). As a result, it is possible to re-examine and refine thechromosomal regions responsible for the different pheno-types found in both our patients, and those with JBS.Paris-Trousseau syndrome (PTS)This is the most common clinical finding (94%) in JBSpatients, and is characterized by thrombocytopenia andplatelet dysfunction. The critical region has been nar-rowed down to the 6.8 Mb terminal portion of 11q (distalto D11S1351, i.e. from 127.6 to 134.4 Mb) [7], and con-tains three genes associated with hematopoiesis (ETS-1,Page 4 of 9(page number not for citation purposes)hearing loss. He attended a regular classroom and wasable to complete grade level work but required a full-timeFLI-1 and NFRKB), and the JAM3 gene which is expressedin platelets [17] (Figure 3). Deletion of FLI-1, in particu-Molecular Cytogenetics 2008, 1:23 http://www.molecularcytogenetics.org/content/1/1/23Page 5 of 9(page number not for citation purposes)11q24-25 rearrangements found in subjects 1 and 2Figure 211q24-25 rearrangements found in subjects 1 and 2. (a) Nimblegen array (385 K) profiles of chromosome 11 showed a 5.04 Mb duplication and a 6.18 Mb deletion detected in subject 1. FISH confirmation of the duplication of clone RP11-50B3 (b) and deletion of clone RP11-206H19 (AP003775.3) (c) in subject 1. (d) Nimblegen array (385 K) profiles of chromosome 11 showed a 4.74 Mb deletion of chromosome 11q24.2-24.3 in subject 2. FISH confirmation of the deletion of clones RP11-50B3 and RP11-206H19 (AP003775.3) in subject 2 is shown in (e) and (f), respectively. Arrow indicates duplicated chromosome and arrowhead the deleted chromosomes.e fDeletiond0                 20               40                 60        80               100              120  Position (Mb)DeletionDuplicationa0                 20               40                 60        80               100              120   Position (Mb)cbMolecular Cytogenetics 2008, 1:23 http://www.molecularcytogenetics.org/content/1/1/23Page 6 of 9(page number not for citation purposes)11q24.1-25 region, showing the previously defined [7] critical regions for some of the common Jacobsen syndrome features, and the location of t e rearrangements detected in the present subjects 1 and 2Figur 311q24.1-25 region, showing the previously defined [7] critical regions for some of the common Jacobsen syn-drome features, and the location of the rearrangements detected in the present subjects 1 and 2. Chromosome bands are shown on the left, and the megabase (Mb) position on the right, with the positions and functions of some genes of interest. The patients' deletions are represented by red vertical lines, and the duplication of subject 1 by a blue vertical line. The 780 Kb region of deletion overlap between these two patients is shown by a red shaded box, and includes the CpG island 4929 (black arrow) that contains a (CCG)6 repeat. A third red vertical line labeled 'W' shows the size of the interstitial deletion reported by Wenger et al [11]. The critical regions [7] for MRI abnormalities (MRI), heart defects (H) and Paris-Trousseau syn-drome (PTS) are shown by three vertical grey lines, with the proximal molecular marker indicated at the top of each line. A 1.57 Mb refined critical region for conotruncal heart defects is represented by two arrowheads (from the distal end of subject 2's deletion to the distal end of the deletion seen in the patient reported by Wenger et al [11].ROBO4FEZ1NEPH2ETS-1FLI-1KCNJ1BARX2NFRKBRICSJAM3KCNJ5Genes11q24.111q24.211q24.311q25D11S2090D11S707D11S1351S1 S2MRI H PTS WCpGMaintains vascular integretyAxonal developmentExpressed in brain and kidney podocytes. Supports hematopoietic stem cellsRegulates numerous gene involved in stem cell development, cell senescence and death, and tumorigenesisTranscription factor in hematopoiesis, deletions contribute to Paris-Trousseau SyndromeExpressed in kidneys, associated with antenatal Bartter syndrome type 2Potassium channel, expressed in heartHighest expression in brain and ovary.  Expressed duringneuronal development. Involved in synaptic adhesionHomeobox transcription factor expressed in neural and craniofacial regions. Regulates hair folicle remodelingInvolved in T-cell activation Expressed in peripheral nerves and heartADAMTS15 Expressed in fetal liver and kidney Molecular Cytogenetics 2008, 1:23 http://www.molecularcytogenetics.org/content/1/1/23lar, is thought to be at least partly responsible for theplatelet/megakaryocyte defects observed in PTS patients[18]. The absence of PTS in subject 2, in association withthe deletion of the ETS-1 and FLI-1 genes but the presenceof the NFRKB and JAM3 genes, would suggest that the lat-ter two genes, or other as yet unidentified genes, may besufficient for normal platelet development and function(Figure 3). PTS also was absent in subject 1, whose termi-nal deletion includes NFRKB and JAM3 and who hasduplication of ETS-1 and FLI-1. Therefore, it is likely thatthe platelet dysfunction and/or thrombocytopenia com-monly observed in JBS might result from the combinedeffect of deletion of least three of these genes, and thatdeletion of only two of these genes is insufficient to causethe PTS phenotype. This is consistent with the finding ofthrombocytopenia in a patient with an interstitial dele-tion of 11q24, which included ETS-1, FLJ-1, NFRKB, butexcluded JAM3 (Wenger et al, [11]). In addition, as sug-gested by Penny et al [8], the genetic background of theindividual might influence the expression PTS, sincearound 6% of patients with 11q terminal deletions do nothave thrombocytopenia.Craniofacial abnormalitiesBased on deletion mapping in JBS patients [8], a regioninfluencing craniofacial development was speculated tomap distal to D11S1351 (127.6 Mb), with BARX2(128.75 Mb) as a potential candidate gene, since it isexpressed in the neural and craniofacial structures duringdevelopment [19]. BARX2 is further implicated here by itslocation within the small (780 Kb) area of deletion over-lap for our two patients (Figure 3), both of whom displaysome of the facial dysmorphism (broad nasal root and aprominent forehead) that is seen in a significant propor-tion of JBS patients.Cardiac abnormalitiesA variety of serious cardiac abnormalities is observed inindividuals with JBS, and genes which influence cardiacdevelopment are believed to lie distal to D11S707 (125.8Mb) [7] (Figure 3). Together, the deletions of subjects 1and 2 span this entire critical region, yet neither individ-ual has any heart anomaly. While the concurrent duplica-tion in subject 1 may be able to somehow "compensate"for the loss of any heart-function related genes, the iso-lated interstitial deletion in subject 2 may be helpful torefine this critical region. When taken together with thesubject reported by Wenger et al [11], a patient withconotruncal heart defects and a larger interstitial 11q24deletion, one can see that one area critical to cardiacanomalies may reside in a 1.57 Mb region between129.03 – 130.6 (i.e. from the distal end of subject 2's dele-tion to the distal end of Wenger's deletion, Figure 3). Thisple, polymorphisms in SNX19 have been reported to beassociated with coronary disease [20], while ADAMTS8 isinvolved in regulating angiogenesis [21]. As suggested byWenger et al [11], a second JBS cardiac critical regionresponsible for flow defects may be located distal to 130.6Mb. This region contains JAM3, previously identified as acandidate gene for the JBS cardiac phenotype [22]. It isevident that the 11q JBS region is likely to contain anumber of genes involved in cardiac function, whichwould account for the variety, as well as the presence/absence of heart defects observed in these patients.Indeed, genes outside the refined critical region (129.04Mb to 11qter), such as ROBO4 (maintains vascular integ-rity) and KCNJ5 (highly expressed in heart) may also con-tribute to the cardiac defects that are observed in some JBSpatients with larger deletions of 11q.Kidney abnormalitiesGrossfeld et al [7] found structural defects of the kidney tooccur in 8% of JBS patients. Two genes in 11q24.3, KCNJ1and ADAMTS15, both of which are expressed in kidney,are potentially responsible for the renal anomalies foundin subject 1. The KCNJ1 gene (at 128.2 Mb) lies within herduplication/deletion breakpoint, which might have dis-rupted the function of this gene, while ADAMTS15 lieswithin her terminal deletion region (Figure 3). In addi-tion, the contribution of her 11q24.1-3 duplication, aregion which includes NEPH2 (a gene which is known tobe expressed in kidney podocytes and whose proteininteracts with podocin), is unclear.MRI abnormalities51% of JBS patients have abnormal brain imaging, withthe critical region lying distal to 124.6 Mb (D11S2090)[7] (Figure 3). A region common to both this criticalregion and the deletion of subject 2, who has abnormalwhite matter lesions on MRI, is from 124.6 – 129.03 Mb.Potential candidate genes include FEZ1, predominantlyexpressed in the brain and involved in axonal outgrowth[23], and RICS, expressed during neural development andwhich may regulate dendritic spine morphology andstrength [24].In summary, although the large number of 11q24-25genes that are imbalanced in subjects 1 and 2 (> 100)makes identification of genes responsible for specific phe-notypic features challenging, the small 11q24-25 rear-rangement sizes within the larger 11q JBS critical regionare important contributors to understanding specific phe-notype-genotype correlations. The high number of candi-date genes located within the large, cytogenetically visibleJBS deletions makes it likely that many of the typical fea-tures seen in JBS are due not just to monosomy of singlePage 7 of 9(page number not for citation purposes)small region contains several genes of interest; for exam- genes, but to the cumulative effect of a combination ofMolecular Cytogenetics 2008, 1:23 http://www.molecularcytogenetics.org/content/1/1/23contiguous genes, or possible gene-gene interaction. Thisseems the most likely scenario, particularly when one con-siders the discrepancies that exist between phenotypes ofsome individuals, their deletion sizes, and the criticalregions that are defined by the majority of patients with aparticular phenotype. One should also keep in mind thatthe critical regions defined by Grossfeld et al [7] andPenny et al [8] were based on conventional karyotypesand a selection of DNA markers from the 11q terminalregion. The use of whole genome array-CGH should facil-itate a more accurate assessment of the types and sizes ofchromosomal rearrangements in JBS.The occurrence of a terminal deletion of 11q24.3 to11qter, and duplication of 11q24.2-24.3 in subject 1 is arare instance of a more complex rearrangement of 11q24-25 region. The duplicated region almost certainly willcontribute to the patient's phenotype together with theconcurrent deletion. Similarly, the effect of the deletionon the phenotypic expression of the 11q24.1-24.3 dupli-cation should be taken into consideration when subject 1is compared to other patients with duplications involving11q24. In a review of 11q duplications, Delobel et al [25],showed that patients with interstitial duplications involv-ing 11q23.3-24 do not have heart abnormalities, but com-monly exhibit microcephaly, growth retardation, scoliosisand strabismus, which, except for the growth retardation,were not seen in our subject 1. The simultaneous occur-rence of deletion and duplication in the 11q24-25 regionin subject 1 may suggest the presence of low copy repeats(LCRs) which could lead to non-allelic homologousrecombination, comparable to the 1 pter deletion/dupli-cation event which can lead to 1 pter deletion syndrome[26]. The identity of such LCRs, however, remainsunknown, since a comparison of segmental duplicationswithin the 5 Mb region proximal to the duplication didnot reveal significant homology. It is intriguing to con-sider the possibility that subject 1's terminal deletion/duplication could also be a result of a terminal deletion,followed by at least one breakage-fusion-bridge cycle, aswas described for two cases with a terminal deletion/inverted duplication of 1 pter [27]. Detailed sequenceanalysis of the breakpoints in subject 1 would be requiredfor the understanding of the molecular mechanisms lead-ing to this rearrangement.It would be interesting to perform whole genome screen-ing of individuals with both typical and atypical Jacobsensyndrome, to test for the presence of complex rearrange-ments of the 11qter region and to rule out any additionalrearrangements elsewhere in the genome. The results ofsuch efforts would enhance our knowledge of the syn-drome by allowing more accurate phenotype/genotypeConclusionOur molecular cytogenetic and clinical findings in twosubjects with submicroscopic 11q24-25 rearrangementsfacilitate the refinement of the JBS critical region and sug-gest that a) deletion of at least 3 of the 4 platelet functioncritical genes (ETS-1, FLI-1 and NFRKB and JAM3) is nec-essary for thrombocytopenia; b) one of the critical regionsfor heart abnormalities (conotruncal heart defects) maybe within 129.03 – 130.6 Mb; c) deletions of KCNJ1 andADAMTS15 may contribute to the renal anomalies inJacobsen Syndrome d) the critical region for MRI abnor-malities involves a region from 124.6 – 129.03 Mb. Ourresults reiterate the benefits of array-CGH for descriptionof new phenotype/genotype associations and refinementof previously established ones.AbbreviationsID: intellectual disability; JBS: Jacobsen syndrome; array-CGH: array-based comparative genomic hybridization;OFC: occipital-frontal head circumference; FISH: fluores-cence in situ hybridization; WAIS lll: Weschler Adult Intel-ligence Scales – Version III; PTS: Paris-Trousseausyndrome; LCRs: low copy repeatsConsentWritten informed consent was obtained from the patientsfor publication of this case report and accompanyingimages. A copy of the written consent is available forreview by the Editor-in-Chief of this journal.Competing interestsThe authors declare that they have no competing interests.Authors' contributionsCT and YQ made substantial contributions to conceptionand design, or acquisition of data, or analysis and inter-pretation of data, and have been involved in drafting themanuscript or revising it critically for important intellec-tual content. CH made substantial contributions to con-ception and design, or acquisition of data, and analysisand interpretation of data. XL made contributions toacquisition of data and analysis and interpretation ofdata. LA, FPB, BM, SAF, AEC, LC, WG, SD, RM, TC, MVA,SLY, GEG, PM, MSP and JH made substantial contribu-tions to patient recruitment and acquisition of clinicaldata. JJAH, MESL and ESR made substantial contributionsto conception and design, acquisition of data, or analysisand interpretation of data, and have been involved indrafting the manuscript or revising it critically for impor-tant intellectual content. ERS also gave final approval ofthe version to be published. All authors read andapproved the final manuscript.Page 8 of 9(page number not for citation purposes)correlation.Molecular Cytogenetics 2008, 1:23 http://www.molecularcytogenetics.org/content/1/1/23AcknowledgementsThis work was supported by funding from the Canadian Institutes for Health Research (CIHR) (MOP 74502; PI: ERS), a CIHR Interdisciplinary Health Research Team grant (RT-43820) to ASD-CARC http://www.Autis mResearch.com (PI: JJAH), and the Ontario Mental Health Foundation (PI: JJAH). YQ is a trainee with the CIHR/NAAR-Autism Speaks STIHR Inter-Institute Autism Spectrum Disorders Training Program (PI: JJAH). 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