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Picker, Jonathan

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Picker

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Jonathan

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Picker, Jonathan
Author's Publications: search.filters.isAuthorOfPublication.3d3de038-78fa-4858-bf36-b319d08da242

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    Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield
    (BioMed Central, 2014) Geng, Juan; Picker, Jonathan; Zheng, Zhaojing; Zhang, Xiaoqing; Wang, Jian; Hisama, Fuki; Brown, David W; Mullen, Mary P; Harris, David; Stoler, Joan; Seman, Ann; Miller, David; Fu, Qihua; Roberts, Amy; Shen, Yiping
    Background: Congenital heart defects (CHD), as the most common congenital anomaly, have been reported to be frequently associated with pathogenic copy number variants (CNVs). Currently, patients with CHD are routinely offered chromosomal microarray (CMA) testing, but the diagnostic yield of CMA on CHD patients has not been extensively evaluated based on a large patient cohort. In this study, we retrospectively assessed the detected CNVs in a total of 514 CHD cases (a 422-case clinical cohort from Boston Children's Hospital (BCH) and a 92-case research cohort from Shanghai Children’s Medical Center (SCMC)) and conducted a genotype-phenotype analysis. Furthermore, genes encompassed in pathogenic/likely pathogenic CNVs were prioritized by integrating several tools and public data sources for novel CHD candidate gene identification. Results: Based on the BCH cohort, the overall diagnostic yield of CMA testing for CHD patients was 12.8(pathogenic CNVs)-18.5% (pathogenic and likely pathogenic CNVs). The diagnostic yield of CMA for syndromic CHD was 14.1-20.6% (excluding aneuploidy cases), whereas the diagnostic yield for isolated CHD was 4.3-9.3%. Four recurrent genomic loci (4q terminal region, 15q11.2, 16p12.2 and Yp11.2) were more significantly enriched in cases than in controls. These regions are considered as novel CHD loci. We further identified 20 genes as the most likely novel CHD candidate genes through gene prioritization analysis. Conclusion: The high clinical diagnostic yield of CMA in this study provides supportive evidence for CMA as the first-line genetic diagnostic tool for CHD patients. The CNVs detected in our study suggest a number of CHD candidate genes that warrant further investigation. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-1127) contains supplementary material, which is available to authorized users.
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    Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy
    (BioMed Central, 2013) McLaughlin, Heather M; Kelly, Melissa A; Hawley, Pamela P; Darras, Basil; Funke, Birgit; Picker, Jonathan
    Background: Variants in the desmin gene (DES) are associated with desminopathy; a myofibrillar myopathy mainly characterized by muscle weakness, conduction block, and dilated cardiomyopathy. To date, only ~50 disease-associated variants have been described, and the majority of these lead to dominant-negative effects. However, the complete genotypic spectrum of desminopathy is not well established. Case presentation: Next-generation sequencing was performed on 51 cardiac disease genes in a proband with profound skeletal myopathy, dilated cardiomyopathy, and respiratory dysfunction. Our analyses revealed compound heterozygous DES variants, both of which are predicted to lead to a loss-of-function. Consistent with recessive inheritance, each variant was identified in an unaffected parent. Conclusions: This case report serves to broaden the variant spectrum of desminopathies and provides insight into the molecular mechanisms of desminopathy, supporting distinct dominant-negative and loss-of-function etiologies.