Novel loci for non-syndromic coarctation of the aorta in sporadic and familial cases.

TitleNovel loci for non-syndromic coarctation of the aorta in sporadic and familial cases.
Publication TypeJournal Article
Year of Publication2015
AuthorsMoosmann J, Uebe S, Dittrich S, Rüffer A, Ekici AB, Toka O
JournalPLoS One
Volume10
Issue5
Paginatione0126873
Date Published2015
ISSN1932-6203
KeywordsAdolescent, Adult, Aortic Coarctation, Child, Child, Preschool, Chromosomes, Human, X, DNA Copy Number Variations, Female, Genetic Loci, Humans, Infant, Male, Middle Aged, Pedigree, Septins, TRPM Cation Channels
Abstract

BACKGROUND: Coarctation 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. METHODS: We 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. RESULTS: We 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. CONCLUSION: Of 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.

DOI10.1371/journal.pone.0126873
Alternate JournalPLoS ONE
Citation Key1649
PubMed ID25984793