Abstract
Cardiovascular malformations (CVM) are common birth defects (incidence of 2–5/100 live births). Although a genetic basis is established, in most cases the cause remains unknown. Analysis of whole exome sequencing (WES) in left sided CVM case and trio series has identified large numbers of potential variants but evidence of causality has remained elusive except in a small percentage of cases. We sought to determine whether variant segregation in families would aid in novel gene discovery. The objective was to compare conventional and co-segregation approaches for WES in multiplex families. WES was performed on 52 individuals from 4 multiplex families ascertained by probands with hypoplastic left heart syndrome (HLHS). We identified rare variants with informatics support (RVIS, minor allele frequency ≤0.01 and Combined Annotation Dependent Depletion score ≥20) in probands. Non-RVIS variants did not meet these criteria. Family specific two point logarithm of the odds (LOD) scores identified co-segregating variants (C-SV) using a dominant model and 80% penetrance. In families, 702 RVIS in 668 genes were identified, but only 1 RVIS was also a C-SV (LOD ≥ 1). On the other hand, there were 109 non-RVIS variants with LOD ≥ 1. Among 110 C-SV, 97% were common (MAF > 1%). These results suggest that conventional variant identification methods focused on RVIS, miss most C-SV. For diseases such as left sided CVM, which exhibit strong familial transmission, co-segregation can identify novel candidates.
Highlights
Cardiovascular malformations (CVM) are the most common birth defects with an incidence of 2 to 5 per 100 live births (Benson, 2002)
A conventional approach that relies on documentation of rare variants with informatics support (RVIS) was compared to an approach based on variant co-segregation (C-SV) with CVM in families using existing linkage analysis methods
In terms of variants identified by the 2 approaches, we found little overlap
Summary
Cardiovascular malformations (CVM) are the most common birth defects with an incidence of 2 to 5 per 100 live births (Benson, 2002). HLHS is a severe form of CVM characterized by hypoplasia of the left ventricle and ascending aorta in addition to atresia or hypoplasia of the aortic and mitral valves. Bicuspid aortic valve (BAV) is the most common CVM, affecting 1–2% of the population. The prevailing view is that BAV and HLHS are developmentally related, Segregation for Exome Discovery and that the two phenotypes represent extremes of a spectrum of CVM involving structures on the left side of the heart; related phenotypes include abnormalities of the aorta, mitral valve and heart chamber septa (Brenner et al, 1989; Loffredo et al, 2004; McBride et al, 2005; Hoang et al, 2018). Exome data for left sided CVM case series and trios has identified large numbers of potential variants but definitive evidence of causality has remained elusive except in a small percentage of cases (Russell et al, 2018)
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