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1.  Mosaic Trisomy 17: Variable Clinical and Cytogenetic Presentation 
Mosaic trisomy 17 is rare with only 28 cases reported and the clinical presentation is highly variable. The diagnosis is most commonly made by prenatal karyotype and in most cases is followed by a normal postnatal karyotype on blood lymphocytes. We present two cases of mosaic trisomy 17 diagnosed prenatally, with follow up in multiple tissues at birth. In the first case, trisomy 17 was identified in all amniocytes, and at birth standard results of chromosome analysis in peripheral blood were normal, but mosaic trisomy 17 was identified (50–75%) in skin fibroblasts by genome-wide SNP array analysis. This patient presented with minor anomalies, congenital heart disease, asymmetry, intestinal malrotation and died on day 9 of life. In the second patient amniocentesis after ultrasound finding of tetralogy of Fallot showed mosaic trisomy 17. Postnatally, results of a SNP array were normal in blood, buccal mucosa and skin. It is possible that the cardiac defect is related to trisomy 17 in key tissues during heart development, although at birth the aneuploidy could not be identified in tissues that are routinely analyzed for diagnosis. These cases add to our understanding of mosaic trisomy 17, highlighting the failure to diagnose this aneuploidy in peripheral blood.
PMCID: PMC3197730  PMID: 21998853
Mosaic trisomy 17; SNP microarray analysis; tissue specific mosaicism
2.  Genomic Alterations in Biliary Atresia Suggests Region of Potential Disease Susceptibility in 2q37.3 
Biliary atresia (BA) is a progressive, idiopathic obliteration of the extrahepatic biliary system occurring exclusively in the neonatal period. It is the most common disease leading to liver transplantation in children. The etiology of BA is unknown, although infectious, immune and genetic causes have been suggested. While the recurrence of BA in families is not common, there are more than 30 multiplex families reported and an underlying genetic susceptibility has been hypothesized. We screened a cohort of 35 BA patients for genomic alterations that might confer susceptibility to BA. DNA was genotyped on the Illumina Quad550 platform, which analyzes over 550,000 single nucleotide polymorphisms (SNPs) for genomic deletions and duplications. Areas of increased and decreased copy number were compared to those found in control populations. In order to identify regions that could serve as susceptibility factors for BA, we searched for regions that were found in BA patients, but not in controls. We identified two unrelated BA patients with overlapping heterozygous deletions of 2q37.3. Patient 1 had a 1.76 Mb (280 SNP), heterozygous deletion containing thirty genes. Patient 2 had a 5.87 Mb (1,346 SNP) heterozygous deletion containing fifty-five genes. The overlapping 1.76 Mb deletion on chromosome 2q37.3 from 240,936,900 to 242,692,820 constitutes the critical region and the genes within this region could be candidates for susceptibility to BA.
doi:10.1002/ajmg.a.33332
PMCID: PMC2914625  PMID: 20358598
Biliary atresia; copy number variation; deletion 2q37.3
3.  Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis 
Human Molecular Genetics  2010;19(7):1263-1275.
Mosaic aneuploidy and uniparental disomy (UPD) arise from mitotic or meiotic events. There are differences between these mechanisms in terms of (i) impact on embryonic development; (ii) co-occurrence of mosaic trisomy and UPD and (iii) potential recurrence risks. We used a genome-wide single nucleotide polymorphism (SNP) array to study patients with chromosome aneuploidy mosaicism, UPD and one individual with XX/XY chimerism to gain insight into the developmental mechanism and timing of these events. Sixteen cases of mosaic aneuploidy originated mitotically, and these included four rare trisomies and all of the monosomies, consistent with the influence of selective factors. Five trisomies arose meiotically, and three of the five had UPD in the disomic cells, confirming increased risk for UPD in the case of meiotic non-disjunction. Evidence for the meiotic origin of aneuploidy and UPD was seen in the patterns of recombination visible during analysis with 1–3 crossovers per chromosome. The mechanisms of formation of the UPD included trisomy rescue, with and without concomitant trisomy, monosomy rescue, and mitotic formation of a mosaic segmental UPD. UPD was also identified in an XX/XY chimeric individual, with one cell line having complete maternal UPD consistent with a parthenogenetic origin. Utilization of SNP arrays allows simultaneous evaluation of genomic alterations and insights into aneuploidy and UPD mechanisms. Differentiation of mitotic and meiotic origins for aneuploidy and UPD supports existence of selective factors against full trisomy of some chromosomes in the early embryo and provides data for estimation of recurrence and disease mechanisms.
doi:10.1093/hmg/ddq003
PMCID: PMC3146011  PMID: 20053666
4.  SNP array mapping of 20p deletions: Genotypes, Phenotypes and Copy Number Variation 
Human mutation  2009;30(3):371-378.
The use of array technology to define chromosome deletions and duplications is bringing us closer to establishing a genotype/phenotype map of genomic copy number alterations. We studied 21 patients and 5 relatives with deletions of the short arm of chromosome 20 using the Illumina HumanHap550 SNP array to 1) more accurately determine the deletion sizes, 2) identify and compare breakpoints, 3) establish genotype/phenotype correlations and 4) investigate the use of the HumanHap550 platform for analysis of chromosome deletions. Deletions ranged from 95kb to 14.62Mb, and all of the breakpoints were unique. Eleven patients had deletions between 95kb and 4Mb and these individuals had normal development, with no anomalies outside of those associated with Alagille syndrome. The proximal and distal boundaries of these eleven deletions constitute a 5.4MB region, and we propose that haploinsufficiency for only 1 of the 12 genes in this region causes phenotypic abnormalities. This defines the JAG1 associated critical region, in which deletions do not confer findings other than those associated with Alagille syndrome. The other 10 patients had deletions between 3.28Mb and 14.62Mb, which extended outside the critical region, and notably, all of these patients, had developmental delay. This group had other findings such as autism, scoliosis and bifid uvula. We identified 47 additional polymorphic genome-wide copy number variants (>20 SNPs), with 0–5 variants called per patient. Deletions of the short arm of chromosome 20 are associated with relatively mild and limited clinical anomalies. The use of SNP arrays provides accurate high-resolution definition of genomic abnormalities.
doi:10.1002/humu.20863
PMCID: PMC2650004  PMID: 19058200
SNP array analysis; 20p deletion; copy number variants; Alagille syndrome; haploinsufficiency; JAG1

Results 1-4 (4)