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Title: Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns

item LI, ALEXANDER - University Of Texas Health Science Center
item HANCHARD, NEIL - Children'S Nutrition Research Center (CNRC)
item FERNBACH, SUSAN - Baylor College Of Medicine
item AZAMIAN, MAHSHID - Baylor College Of Medicine
item NICOSIA, ANNARITA - Baylor College Of Medicine
item ROSENFELD, JILL - Baylor College Of Medicine
item MUZNY, DONNA - Baylor College Of Medicine
item D'ALESSANDRO, LISA - Baylor College Of Medicine
item MORRIS, SHAINE - Baylor College Of Medicine
item LEWIN, MARK - Seattle Children'S Research Institute

Submitted to: Genome Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/12/2017
Publication Date: 10/31/2017
Citation: Li, A.H., Hanchard, N.A., Furthner, D., Fernbach, S., Azamian, M., Nicosia, A., Rosenfeld, J., Muzny, D., D'Alessandro, L.C., Morris, S., Jhangiani, S., Parekh, D.R., Franklin, W.J., Lewin, M., Towbin, J.A., Penny, D.J., Fraser, C.D., Martin, J.F., Eng, C., Lupski, J.R., Gibbs, R.A., Boerwinkle, E., Belmont, J.W. 2017. Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns. Genome Medicine. 9(1):95.

Interpretive Summary: Congenital Heart Disease (CHD) remains the number one cause of infant mortality in the United States; yet the causes for CHD, remain understudied and poorly defined. In this study, we used next-generation DNA sequencing to surveyed the regions of the DNA that code for specific proteins (genes). Variants that were rare in large population databases, and were likely to adversely affect the resulting protein were identified as candidate genes. These genes converged upon different ways of inheriting disease (recessive, dominant, X-linked) and identified new candidates genes for this class of disease.

Technical Abstract: Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes. Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases. Gene variants that were not observed in a comparably sequenced control dataset of 5492 samples without severe CVM were then subjected to targeted validation in cases and parents. Whole exome sequencing data from 4593 individuals referred for clinical sequencing were used to bolster evidence for the role of candidate genes in CVMs and LSLs. Our analyses revealed 28 candidate variants in 27 genes, including 17 genes not previously associated with a human CVM disorder, and revealed diverse patterns of inheritance among LOF carriers, including 9 confirmed de novo variants in both novel and newly described human CVM candidate genes (ACVR1, JARID2, NR2F2, PLRG1, SMURF1) as well as established syndromic CVM genes (KMT2D, NF1, TBX20, ZEB2). We also identified two genes (DNAH5, OFD1) with evidence of recessive and hemizygous inheritance patterns, respectively. Within our clinical cohort, we also observed heterozygous LOF variants in JARID2 and SMAD1 in individuals with cardiac phenotypes, and collectively, carriers of LOF variants in our candidate genes had a four times higher odds of having CVM (odds ratio'='4.0, 95% confidence interval 2.5-6.5). Our analytical strategy highlights the utility of bioinformatic resources, including human disease records and model organism phenotyping, in novel gene discovery for rare human disease. The results underscore the extensive genetic heterogeneity underlying non-syndromic LSLs, and posit potential novel candidate genes and complex modes of inheritance in this important group of birth defects.