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Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield.

ABSTRACT: 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.

SUBMITTER: Geng J

PROVIDER: S-EPMC4378009 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield.

Geng Juan J Picker Jonathan J Zheng Zhaojing Z Zhang Xiaoqing X Wang Jian J Hisama Fuki F Brown David W DW Mullen Mary P MP Harris David D Stoler Joan J Seman Ann A Miller David T DT Fu Qihua Q Roberts Amy E AE Shen Yiping Y

BMC genomics 20141217

<h4>Background</h4>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 coh ...[more]

PMID: 25516202

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Project description:Congenital heart disease (CHD) is the most common congenital malformation in fetuses and neonates, which also represents a leading cause of mortality. Although significant progress has been made by emerging advanced technologies in genetic etiology diagnosis, the causative genetic mechanisms behind CHD remain poorly understood and more than half of CHD patients lack a genetic diagnosis. Unlike carefully designed large case-control cohorts by multicenter trials, we designed a reliable strategy to analyze case-only cohorts to utilize clinical samples sufficiently. Combined low-coverage whole-genome sequencing (WGS) and whole-exome sequencing (WES) were simultaneously conducted in a patient-only cohort for identifying genetic etiologies and exploring candidate, or potential causative CHD-related genes. A total of 121 sporadic CHD patients were recruited and 34.71% (95% CI, 26.80 to 43.56) was diagnosed with genetic etiologies by low-coverage WGS and WES. Chromosomal abnormalities and damaging variants of CHD-related genes could explain 24.79% (95% CI, 17.92 to 33.22) and 18.18% (95% CI, 12.26 to 26.06) of CHD patients, separately, and 8.26% (95% CI, 4.39 to 14.70) of them have simultaneously detected two types of variants. Deletion of chromosome 22q11.2 and pathogenic variants of the COL3A1 gene were the most common recurrent variants of chromosomal abnormalities and gene variants, respectively. By in-depth manual interpretation, we identified eight candidate CHD-causing genes. Based on rare disease-causing variants prediction and interaction analysis with definitive CHD association genes, we proposed 86 genes as potential CHD-related genes. Gene Ontology (GO) enrichment analysis of the 86 genes revealed regulation-related processes were significantly enriched and processes response to regulation of muscle adaptation might be one of the underlying molecular mechanisms of CHD. Our findings and results provide new insights into research strategies and underlying mechanisms of CHD.

Dataset Information

Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield.

Publications

Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield.

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