Genetic Modifiers Predisposing to Congenital Heart Disease in the Sensitized Down Syndrome Population

Abstract

Background About half of people with Down syndrome (DS) exhibit some form of congenital heart disease (CHD). However, trisomy for human chromosome 21 (Hsa21) alone is insufficient to cause CHD as half of all people with DS have a normal heart, suggesting that genetic modifiers interact with dosage sensitive gene(s) on Hsa21 to result in CHD. We hypothesize that a threshold exists in both Down syndrome and euploid populations for the number of genetic perturbations that can be tolerated before CHD results. Methods and Results We ascertained a group of individuals with DS and complete atrioventricular septal defect (AVSD) and sequenced two candidate genes for CHD, CRELD1, which is associated with AVSD in people with or without DS, and HEY2, whose mouse ortholog produces septal defects when mutated. Several deleterious variants were identified but the frequency of these potential modifiers was low. We crossed mice with mutant forms of these potential modifiers to the Ts65Dn mouse model of Down syndrome. Crossing loss-of-function alleles of either Creld1 or Hey2 onto the trisomic background caused a significant increase in the frequency of CHD, demonstrating an interaction between the modifiers and trisomic genes. We showed further that although either of these mutant modifiers is benign by itself, they interact to affect heart development when inherited together. Conclusions Using mouse models of Down syndrome and of genes associated with congenital heart disease we demonstrate a biological basis for an interaction that supports a threshold hypothesis for additive effects of genetic modifiers in the sensitized trisomic population.

What people with Down Syndrome can teach us about cardiopulmonary disease

“…Similarly, haploinsufficiency of the heart morphogen Tbx5 (chromosome 12) results in different left-right cardiac patterning when on a trisomic background in Ts65Dn mice [138]. Collectively, these studies raise the possibility that overdosage of Hsa21 genes combined with perturbed expression of non-Hsa21 genetic modifiers may drive AVSD (and perhaps other developmental morbidities) in Down syndrome [139]. In this regard, many of the deleterious gene variants involving CHD identified to date involve the VEGF-A pathway [140].…”

Gender differences in the prevalence of congenital heart disease in Down’s syndrome: a brief meta-analysis

“…Numerous factors may contribute to the development of different cardiac malformations in DS. Some are being unraveled recently in animal models [5]. However, until now, there has been few reports looking into the association of gender with CHD and DS.…”

“…The reported prevalence of these defects varies among studies [8][9][10][11][12][13][14]. This could reflect inherent characteristics of the studied populations, such a higher frequency of genetic variances that predispose to the presence of AVSD [5,[15][16][17][18][19].…”

Insights into the Genetic Structure of Congenital Heart Disease from Human and Murine Studies on Monogenic Disorders

“…This hypothesis was tested by sequencing CRELD1, a cause of non-DS AVSD defect (Robinson et al 2003), in DS patients with this form of CHD (Maslen et al 2006;Li et al 2012). Out of 135 patients sequenced, three individuals had two predicted damaging missense mutations, one of which had been previously identified in individuals with nonsyndromic AVSD.…”

“…Out of 135 patients sequenced, three individuals had two predicted damaging missense mutations, one of which had been previously identified in individuals with nonsyndromic AVSD. The genetic interaction of CRELD1 with dosage-sensitive loci that cause DS was studied by crossing the heterozygous Creld1 mice with a murine model of DS (Ts65Dn) (Li et al 2012). Although Ts65Dn rarely (,5%) had septal defects and Creld1 þ/2 mice were phenotypically normal, Ts65Dn::Creld1 þ/2 mice had increased frequency of septal defects (33%).…”