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

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.

Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years

“…Therefore, the frequency of heart and lymphatic problems in Turner syndrome may be best explained by a combination of copy number variation of X chromosome genes and altered expression of autosomal genes that also contribute to congenital defects in the general population. Recent studies identified autosomal gene mutations or epigenetic changes in women with Turner syndrome who have cardiac abnormalities, providing the first evidence to support this hypothesis (Corbitt et al, ; Prakash et al, ; Rajpathak, Vellarikkal, Patowary, Sivasubbu, & Deobagkar, ; Trolle et al, ).…”

A rare case in literature: Isochromosome Xq in Klinefelter syndrome

“…For Turner syndrome, because of the relatively high incidence of isochromosome Xq (15%), finding a statistically significant difference is easier. Congenital heart disease and hearing loss incidence found to be lower among nonmosaic isochromosome Xq carrier females (46,X,i(Xq)) compared to classical Turner syndrome (45,X)(Cameron‐ Pimblett, Rosa, King, Davies, & Conway, ; Prakash et al, ). But there was no significant difference for diabetes mellitus, hypertension or body mass index between these two groups (Cameron‐ Pimblett et al, ).…”

Fetal cardiac intervention—Perspectives from a single center

“…And remarkably, there is a higher rate of sex chromosome anomalies in the few females (45, X, 45, X/46, XX) as well as occasionally in those presenting as males (46, XY, 45, X). While a predominance of males and Turner syndrome females with left ventricle outflow tract anomalies including HLHS has been noted in the literature, the degree to which 46, XY or 45, X predominates the AS‐eHLHS cohort is intriguing. Further work is needed at the level of sequencing especially in the pseudo‐autosomal region to understand these patterns.…”