Left-sided congenital heart disease (CHD) encompasses a spectrum of malformations that range from bicuspid aortic valve to hypoplastic left heart syndrome.It contributes significantly to infant mortality and has serious implications in adult cardiology.Although left-sided CHD is known to be highly heritable, the underlying genetic determinants are largely unidentified.In this study, we sought to determine the impact of structural genomic variation on left-sided CHD and compared multiplex families (464 individuals with 174 affecteds (37.5%) in 59 multiplex families and 8 trios) to 1,582 wellphenotyped controls.73 unique inherited or de novo CNVs in 54 individuals were identified in the left-sided CHD cohort.After stringent filtering, our gene inventory reveals 25 new candidates for LS-CHD pathogenesis, such as SMC1A, MFAP4, and CTHRC1, and overlaps with several known syndromic loci.Conservative estimation examining the overlap of the prioritized gene content with CNVs present only in affected individuals in our cohort implies a strong effect for unique CNVs in at least 10% of left-sided CHD cases.Enrichment testing of gene content in all identified CNVs showed a significant association with angiogenesis.In this first family-based CNV study of left-sided CHD, we found that both co-segregating and de novo events associate with disease in a complex fashion at structural genomic level.Often viewed as an anatomically circumscript disease, a subset of left-sided CHD may in fact reflect more general genetic perturbations of angiogenesis and/or vascular biology.
Abstract Background Recent advances in genomic technologies have facilitated genome-wide investigation of human genetic variations. However, most efforts have focused on the major populations, yet trio genomes of indigenous populations from Southeast Asia have been under-investigated. Results We analyzed the whole-genome deep sequencing data (~30×) of five native trios from Malaysia, and discovered approximately 6.9 million single nucleotide variants (SNVs), 1.2 million small insertions and deletions (indels), and 9,000 copy number variants (CNVs) in the 15 samples. We found 2.7% SNVs, 2.3% indels and 22% CNVs were novel, implying the insufficient coverage of population diversity in existing databases. We identified a higher proportion of novel variants in the Orang Asli (OA) samples, i.e., the indigenous people from Peninsular Malaysia, than that of the North Bornean (NB) samples, likely due to more complex demographic history and long-time isolation of the OA groups. We used the pedigree information to identify autosomal de novo variants and estimated the mutation rates to be 0.81×10-8–1.33×10-8 , 1.0×10-9–2.9×10-9 , and ~0.001 per site per generation for SNVs, indels, and CNVs, respectively. The trio-genomes also allowed for accurate haplotype phasing with high accuracy, which serves as references to the future genomic studies of OA and NB populations. In addition, high-frequency inherited CNVs specific to OA or NB were identified. One example was a 50-kb duplication in DEFA1B detected only in the Negrito trios, implying plausible effects on host defense against the exposure of diverse microbial in tropical rainforest environment of these hunter-gatherers. The CNVs shared between OA and NB groups were much fewer than those specific to each group. Nevertheless, we identified a 142-kb duplication in AMY1A in all the 15 samples, and this gene is associated with the high-starch diet. Moreover, novel insertions shared with archaic hominids were identified in our samples. Conclusion Our study presents a full catalogue of the genome variants of the native Malaysian populations, which is a complement of the genome diversity in Southeast Asians. It implies specific population history of the native inhabitants, and demonstrated the necessity of more genome sequencing efforts on the multi-ethnic native groups of Malaysia and Southeast Asia.
Next generation sequencing technologies have enabled a rapid expansion toward the understanding of inherited disorders, cancer biology, drug development, and treatment resistance. Exome sequencing has been increasingly and successfully applied in the clinical research setting for identifying common single nucleotide variants, copy number variations, and small insertions or deletions as well as rare de novo mutations that may explain Mendelian, complex, and rare genetic disorders. Recent advancement in rapid and low-cost exome sequencing make it an attractive alternative to traditional targeted gene panel sequencing for clinical research, while maintaining the possibility of discovering mutations in genes previously not associated with a disorder. Furthermore, the exome encompasses approximately 1% of the genome, yet contains approximately 85% of disease-causing mutations, making exome sequencing easier and cheaper than whole genome sequencing for identifying disease-causing variants in research. Researchers are now applying proband-father-mother (trio) exome sequencing to uncover variants that potentially either cause or modify the condition under study. In this webinar, the audience will learn about the current applications of exome sequencing in clinical research and its impact on the future of health care.
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