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1.  Genes and biological processes commonly disrupted in rare and heterogeneous developmental delay syndromes 
Human Molecular Genetics  2010;20(5):880-893.
Rare copy number variations (CNVs) are a recognized cause of common human disease. Predicting the genetic element(s) within a small CNV whose copy number loss or gain underlies a specific phenotype might be achieved reasonably rapidly for single patients. Identifying the biological processes that are commonly disrupted within a large patient cohort which possess larger CNVs, however, requires a more objective approach that exploits genomic resources. In this study, we first identified 98 large, rare CNVs within patients exhibiting multiple congenital anomalies. All patients presented with global developmental delay (DD), while other secondary symptoms such as cardiac defects, craniofacial features and seizures were varyingly presented. By applying a robust statistical procedure that matches patients’ clinical phenotypes to laboratory mouse gene knockouts, we were able to strongly implicate anomalies in brain morphology and, separately, in long-term potentiation as manifestations of these DD patients’ disorders. These and other significantly enriched model phenotypes provide insights into the pathoetiology of human DD and behavioral and anatomical secondary symptoms that are specific to DD patients. These enrichments set apart 103 genes, from among thousands overlapped by these CNVs, as strong candidates whose copy number change causally underlies approximately 46% of the cohort's DD syndromes and between 59 and 80% of the cohort's secondary symptoms. We also identified significantly enriched model phenotypes among genes overlapped by CNVs in both DD and learning disability cohorts, indicating a congruent etiology. These results demonstrate the high predictive potential of model organism phenotypes when implicating candidate genes for rare genomic disorders.
doi:10.1093/hmg/ddq527
PMCID: PMC3033180  PMID: 21147756
2.  Recurrent interstitial 1p36 deletions: evidence for germline mosaicism and complex rearrangement breakpoints 
Deletions of chromosome 1p36 are one of the most frequently encountered subtelomeric alterations. Clinical features of monosomy 1p36 include neurocognitive impairment, hearing loss, seizures, cardiac defects, and characteristic facial features. The majority of cases have occurred sporadically, implying that genomic instability plays a role in the prevalence of the syndrome. Here we report two siblings with mild phenotypic features of the deletion syndrome, including developmental delay, hearing loss and left ventricular noncompaction (LVNC). Microarray analysis using bacterial artificial chromosome and oligonucleotide microarrays indicated the deletions were identical, suggesting germline mosaicism. Parental phenotypes were normal, and analysis by fluorescence in situ hybridization (FISH) did not show mosaicism. These small interstitial deletions were not detectable by conventional subtelomeric FISH analysis. To investigate the mechanism of deletion further, the breakpoints were cloned and sequenced, demonstrating the presence of a complex rearrangement. Sequence analysis of genes in the deletion interval did not reveal any mutations on the intact homologue that may have contributed to the LVNC seen in both children. This is the first report of apparent germline mosaicism for this disorder. Thus, our findings have important implications for diagnostic approaches and for recurrence risk counseling in families with a child with monosomy 1p36. In addition, our results further refine the minimal critical region for LVNC and hearing loss.
doi:10.1002/ajmg.a.33733
PMCID: PMC3058890  PMID: 21108392
1p36; deletion; germline mosaicism; LVNC; hearing loss
3.  A de novo 8.8-Mb Deletion of 21q21.1-q21.3 in an Autistic Male with a Complex Rearrangement Involving Chromosomes 6, 10, and 21 
We report here on a normal-appearing male with pervasive developmental disorder who was found to have a de novo, apparently balanced complex rearrangement involving chromosomes 6, 10, and 21: 46,XY,ins(21;10)(q11.2;p11.2p13)t(6;21)(p23;q11.2). Further analysis by high-density oligonucleotide microarray was performed, showing an 8.8-Mb heterozygous deletion at 21q21.1-q21.3. Interestingly, the deletion is distal to the translocation breakpoint on chromosome 21. The deletion involves 19 genes, including NCAM2 and GRIK1, both of which are associated with normal brain development and function, and have been considered as possible candidate genes in autism and other neurobehavioral disorders. This case underscores the utility of genomewide microarray analysis for the detection of copy number alterations in patients with apparently balanced complex rearrangements and abnormal phenotypes.
doi:10.1002/ajmg.a.33176
PMCID: PMC2801886  PMID: 20034085
complex chromosome rearrangement; microarray; microdeletion; pervasive developmental disorder-not otherwise specified
4.  A 781-kb Deletion of 13q12.3 in a Patient with Peters Plus Syndrome 
doi:10.1002/ajmg.a.32980
PMCID: PMC2736557  PMID: 19610101
Peters plus syndrome; multiple congenital anomalies; microdeletion; microarray; congenital disorders of glycosylation
5.  Identification of familial and de novo microduplications of 22q11.21–q11.23 distal to the 22q11.21 microdeletion syndrome region 
Human Molecular Genetics  2009;18(8):1377-1383.
Deletions of the 22q11.2 region distal to the 22q11.21 microdeletion syndrome region have recently been described in individuals with mental retardation and congenital anomalies. Because these deletions are mediated by low-copy repeats (LCRs), located distal to the 22q11.21 DiGeorge/velocardiofacial microdeletion region, duplications are predicted to occur with a frequency equal to the deletion. However, few microduplications of this region have been reported. We report the identification of 18 individuals with microduplications of 22q11.21–q11.23. The duplication boundaries for all individuals are within LCRs distal to the DiGeorge/velocardiofacial microdeletion region. Clinical records for nine subjects reveal shared characteristics, but also several examples of contradicting clinical features (e.g. macrocephaly versus microcephaly and upslanting versus downslanting palpebral fissures). Of 12 cases for whom parental DNA samples were available for testing, one is de novo and 11 inherited the microduplication from a parent, three of whom reportedly have learning problems or developmental delay. The variable phenotypes and preponderance of familial cases obfuscate the clinical relevance of the molecular data and emphasize the need for careful parental assessments and clinical correlations.
doi:10.1093/hmg/ddp042
PMCID: PMC2664143  PMID: 19193630
6.  Copy number variation at 1q21.1 associated with neuroblastoma 
Nature  2009;459(7249):987-991.
Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in cancer, we performed a genome-wide association study (GWAS) of CNVs in the childhood cancer neuroblastoma, a disease where SNP variations are known to influence susceptibility1,2. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at 550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. We identified a common CNV at 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets (Pcombined = 2.97 × 10−17; OR = 2.49, 95% CI: 2.02 to 3.05). This CNV was validated by quantitative PCR, fluorescent in situ hybridization, and analysis of matched tumor specimens, and was shown to be heritable in an independent set of 713 cancer-free trios. We identified a novel transcript within the CNV which showed high sequence similarity to several “Neuroblastoma breakpoint family” (NBPF) genes3,4 and represents a new member of this gene family (NBPFX). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a novel NBPF gene in early tumorigenesis of this childhood cancer.
doi:10.1038/nature08035
PMCID: PMC2755253  PMID: 19536264

Results 1-6 (6)