Identification of a novel heterozygous SOX9 variant in a Chinese family with congenital heart disease

Abstract

Background: Previous studies of individuals with hereditary or sporadic congenital heart disease (CHD) have provided strong evidence for a genetic basis for CHD. The aim of this study was to identify novel pathogenic genes and variants in a Chinese CHD family.

Methods: Three generations of a family with CHD were recruited. We performed whole exome sequencing for the affected individuals and the proband's unaffected aunt to investigate the genetic causes of CHD in this family. Heterozygous variants carried by the proband and her maternal grandmother, but not the proband's aunt, were selected. The frequencies of the variants detected were assessed using public databases, and their influences on protein function were predicted using online prediction software. The candidate variant was further confirmed by Sanger sequencing of other members of the family.

Results: On the basis of the family's pedigree, the mode of inheritance was speculated to be autosomal dominant with incomplete penetrance. We identified a novel heterozygous missense variant in SOX9 in all affected individuals and one asymptomatic family member, suggesting an inheritance pattern with incomplete penetrance. The variant was not found in any public database. In addition, the variant was highly conserved among mammals, and was predicted to be deleterious by online software programs.

Conclusions: We report for the first time a novel heterozygous missense variant in SOX9 (NM_000346:c.931G>T:p.Gly311Cys) in a Chinese CHD family. Our results provide further evidence supporting a causative role for SOX9 variants in CHD.

Keywords: SOX9; congenital heart disease; incomplete penetrance; missense variant; whole exome sequencing.

FIGURE 1

Echocardiogram images from patient III‐1 showing the apex of the heart. (a, b) Apical four‐chamber view showing a large ventricular septal defect (VSD) prior to surgery and the repaired VSD after surgery, respectively. (c, d) Apical three‐chamber view showing an atrial septal defect (ASD) prior to surgery and the repaired ASD after surgery, respectively. Ao, aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle

FIGURE 2

Genetic analysis of the missense variant in SOX9. (a): Pedigree of the family with CHD. The filled black symbols represent the affected members. The asymptomatic individual harboring the variant is indicated by the symbol with a central black spot. The arrow denotes the proband. (b): Sanger sequencing results from the proband, her mother, and her grandmother. The heterozygous c.931G>T variant in the SOX9 gene was identified in the proband and her grandmother, but not in her mother. (c): Amino acid alignment of the SOX9 protein from several organisms. The position of Gly311 residue (highlighted by a red box) was highly conserved among different species. (d): The location of the variant in the intron‐exon structure of SOX9. The arrow denotes the mutated site