A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field

Abstract

The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 × ), NKX2-5 (6 × ), ZIC3 (3 × ), MLPA (2 × ) and ELN (4 × ). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era.

GATA4 variant identified by whole‐exome sequencing in a Japanese family with atrial septal defect: Implications for male sex development

“…In this regard, the absence of this variant in the public and in‐house databases, high pathogenicity predicted by the four in silico analyses, and gene information by OMIM and UCSC survey (Table S1), in conjunction with the previous description of the same variant in a French family with ASD2,12 indicate that this variant is responsible for the development of ASD2 in this Japanese family. According to the ACMG Standards and Guidelines,13 this variant is regarded as a “likely pathogenic variant,” because this variant is positive for PS1 (same amino acid change as an established pathogenic variant), PM2 (absent from controls), PP1 (co‐segregation with disease phenotype in multiple affected family members), and PP3 (multiple lines of computational evidence in support of a deleterious effect).…”

“…Previous studies have also revealed various GATA4 variants in familial forms of ASD2 with and without PS 5, 12. Thus, it is likely that GATA4 variants frequently cause ASD with and without PS and occasionally lead to other types of CHDs, depending on the effects of other multiple genetic and environmental factors.…”

“…However, since GATA4 binds to the AMH promoter and enhances AMH expression synergically with NR5A1,6 the GATA4 p.(R284H) variant may have primarily impaired AMH expression, with no clinically discernible deleterious effect on other Sertoli cell function including Sertoli‐germ cell interaction. Indeed, male subjects with the same p.(R284H) variant in the French family are fertile, although they have ASD2 12. Thus, the deleterious effect of GATA4 p.(R284H) variant on testicular function would remain at a subclinical level, if any.…”

“…The R284 residue was highly conserved (Figure 2C), and this variant was completely absent from the public and in‐house databases (Figure 2D) and was assessed to have high pathogenicity by all the four in silico pathogenic predictions (Figure 2E). Furthermore, this variant was found to be reported as the causative variant in a French family with ASD2 12. No other candidate variant for CHD was identified.…”

Unraveling De Novo Copy Number Variants in Congenital Heart Defects

“…12 Altogether, de novo CNV and point mutations could account for as much as ≈20% of CHD. This percentage is impressive, but what is even more notable is the fact that these discoveries concern essentially so-called sporadic CHD cases that represent the bottom of the iceberg because familial cases are estimated to account for only 4% to 9% of CHDs.…”