Autosomal and X chromosome structural variants are associated with congenital heart defects in Turner syndrome: The NHLBI GenTAC registry

Siddharth K Prakash, Carolyn A Bondy, Cheryl L Maslen, Michael Silberbach, Angela E Lin, Laura Perrone, Giuseppe Limongelli, Hector I Michelena, Eduardo Bossone, Rodolfo Citro, BAVCon Investigators, GenTAC Registry Investigators, Scott A Lemaire, Simon C Body, Dianna M Milewicz, Siddharth K Prakash, Carolyn A Bondy, Cheryl L Maslen, Michael Silberbach, Angela E Lin, Laura Perrone, Giuseppe Limongelli, Hector I Michelena, Eduardo Bossone, Rodolfo Citro, BAVCon Investigators, GenTAC Registry Investigators, Scott A Lemaire, Simon C Body, Dianna M Milewicz

Abstract

Turner Syndrome (TS) is a developmental disorder caused by partial or complete loss of one sex chromosome. Bicuspid aortic valve and other left-sided congenital heart lesions (LSL), including thoracic aortic aneurysms and acute aortic dissections, are 30-50 times more frequent in TS than in the general population. In 454 TS subjects, we found that LSL are significantly associated with reduced dosage of Xp genes and increased dosage of Xq genes. We also showed that genome-wide copy number variation is increased in TS and identify a common copy number variant (CNV) in chromosome 12p13.31 that is associated with LSL with an odds ratio of 3.7. This CNV contains three protein-coding genes (SLC2A3, SLC2A14, and NANOGP1) and was previously implicated in congenital heart defects in the 22q11 deletion syndrome. In addition, we identified a subset of rare and recurrent CNVs that are also enriched in non-syndromic BAV cases. These observations support our hypothesis that X chromosome and autosomal variants affecting cardiac developmental genes may interact to cause the increased prevalence of LSL in TS. © 2016 Wiley Periodicals, Inc.

Keywords: Turner syndrome; X chromosome; congenital heart defects; genomics; valvular heart disease.

Figures

Figure 1. Larger Ascending Aortic Diameters in… — **Figure 1. Larger Ascending Aortic Diameters in Subjects with BAV**
Box-and- whisker plots of the aortic size index (ASI), the maximum diameter of the ascending aorta divided by body surface area (mm/m2), stratified by the presence (+) or absence (−) of bicuspid aortic valve (BAV). Levene's test verified equal variances.

Figure 2. 12p31.31 Copy Variant is Enriched… — **Figure 2. 12p31.31 Copy Variant is Enriched in TS Subjects with LSL**
Locus plot of 12p13.31 illustrates enrichment of CNVs in TS cases with LSL (green) compared with TS cases without LSL (red). The scale in kilobases, hg19 genomic coordinates (7.9-8.2 Mb) and RefSeq gene structures are included to provide the genomic context.

Source: PubMed

Autosomal and X chromosome structural variants are associated with congenital heart defects in Turner syndrome: The NHLBI GenTAC registry

Abstract

Figures

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