Abstract

BackroundCoarctation of the aorta (CoA) accounts for 5-8% of all congenital heart defects. CoA can be detected in up to 20% of patients with Ullrich-Turner syndrome (UTS), in which a part or all of one of the X chromosomes is absent. The etiology of non-syndromic CoA is poorly understood. In the present work, we test the hypothesis that rare copy number variation (CNV) especially on the gonosomes, contribute to the etiology of non-syndromic CoA.MethodsWe performed high-resolution genome-wide CNV analysis using the Affymetrix SNP 6.0 microarray platform for 70 individuals with sporadic CoA, 3 families with inherited CoA (n=13) and 605 controls. Our analysis comprised genome wide association, CNV burden and linkage. CNV was validated by multiplex ligation-dependent probe amplification.ResultsWe identified a significant abundance of large (>100 kb) CNVs on the X chromosome in males with CoA (p=0.005). 11 out of 51 (~ 22%) male cases had these large CNVs. Association analysis in the sporadic cohort revealed 14 novel loci for CoA. The locus on 21q22.3 in the sporadic CoA cohort overlapped with a gene locus identified in all familial cases of CoA (candidate gene TRPM2). We identified one CNV locus within a locus with high multipoint LOD score from a linkage analysis of the familial cases (SEPT9); another locus overlapped with a region implicated in Kabuki syndrome. In the familial cases, we identified a total of 7 CNV loci that were exclusively present in cases but not in unaffected family members.ConclusionOf all candidate loci identified, the TRPM2 locus was the most frequently implicated autosomal locus in sporadic and familial cases. However, the abundance of large CNVs on the X chromosome of affected males suggests that gonosomal aberrations are not only responsible for syndromic CoA but also involved in the development of sporadic and non-syndromic CoA and their male dominance.

Highlights

  • Recent studies of sporadic, non-syndromic congenital anomalies implicated rare de novo variants and copy number variation (CNV) as their etiology [1,2,3]

  • We identified a significant abundance of large (>100 kb) CNVs on the X chromosome in males with Coarctation of the aorta (CoA) (p=0.005). 11 out of 51 (~ 22%) male cases had these large CNVs

  • We identified one CNV locus within a locus with high multipoint LOD score from a linkage analysis of the familial cases (SEPT9); another locus overlapped with a region implicated in Kabuki syndrome

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Summary

Introduction

Non-syndromic congenital anomalies implicated rare de novo variants and copy number variation (CNV) as their etiology [1,2,3]. Several groups associated CNVs with the pathogenesis of congenital heart disease (CHD), including pulmonary atresia, tetralogy of Fallot, and left-sided outflow tract obstruction [4,5,6,7,8]. Left-sided outflow tract obstruction represents the most severe cardiac malformation syndrome, including bicuspid aortic valve (BAV), aortic valve stenosis (AS), coarctation of the aorta (CoA), and hypoplastic left heart syndrome (HLHS). In this study we focus on CoA, which represents the third most frequent cardiac malformation with a prevalence of ~8% of all CHD. A locus on 8p22-23.1 was implicated in to the pathogenesis of KS [18,19,20,21,22]

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