Whole-exome sequencing of pathogenic genes in a family with congenital heart disease: A case report

Abstract

Rationale: Congenital heart disease (CHD) is the most common birth defect and an important cause of noninfectious deaths in infants and children. It has high prevalence globally, placing an enormous burden on society and families. Studies of individuals with hereditary or sporadic CHD have provided strong evidence for its genetic basis. The aim of this study was to identify causative gene variants in a Chinese family with congenital heart disease.

Patient concerns and diagnoses: Three generations of a CHD family were recruited. Proband III.9 was diagnosed with congenital heart disease at age 11 months, and the echocardiogram showed arterial ductus arteriosus, with a left-to-right shunt at the level of the arteries. Precedent III.10 was a twin of Proband III.9 who was diagnosed with congenital heart disease at age 11 months, in whom the echocardiogram revealed an arterial ductus arteriosus, an unenclosed patent ductus arteriosus, and a left to right shunt at the level of the arteries (second figure). III.8 was diagnosed with congenital heart disease at age 15, but echocardiography in this study showed no abnormalities. No cardiac abnormalities were detected in any of his parents, grandparents, or maternal grandparents. We performed whole-exome sequencing on CHD sufferers and their unexpressing family members to investigate the genetic causes of CHD in this family line. Exome sequencing identified 4 mutation sites in this family line. The variant c.3245A>G (p.His1082Arg) of the AMER1 gene was consistent with concomitant X-chromosome recessive inheritance, the variant c.238G>C (p.Val80Leu) of the KCNE1 gene was consistent with autosomal accessory inheritance, and the other 2 variants did not conform to the law of the mode of inheritance of the disease.

Outcomes: The first identified variant, c.3245A>G (p.His1082Arg) of the AMER1 gene, with X-chromosome recessive inheritance, and the variant c.238G>C (p.Val80Leu) of the KCNE1 gene, which has been reported as autosomal dominant, may be the causative agent of CHD in this family line. These findings broaden the genetic scope of congenital heart disease and could help in the development of targeted drugs for the treatment of congenital heart disease.

Figure 1.

Genealogical map of the family lineage of congenital heart disease. Boxes are males, circles are females, and black represents patients with congenital heart disease.

Figure 2.

Ultrasonographic findings of the twin probands in this family line. (A and B) Proband III.9, ultrasonographic images showed an unobstructed arterial duct with a left-to-right shunt at the level of the arteries, which was diagnosed as CHD. (C and D) Proband III.10, ultrasonographic images showed an unobstructed arterial duct with a left-to-right shunt at the level of the arteries, which was diagnosed as CHD.

Figure 3.

Four genes identified by whole-exome sequencing that may be associated with CHD and the genotypes of the variants carried by each family member, as well as the corresponding amino acid changes.

Figure 4.

Schematic representation of the structural domains of AMER1 and KCNE1 proteins and the locations of the mutation sites in the structural domains of the proteins identified by whole-exome sequencing in this lineage. (A) AMER1 contains 3 APC-binding domains, A1–A3, that have no obvious sequence similarity to each other, 2 N-terminal phosphatidylinositol (4,5) bisphosphate-binding domains (M1 and M2), which can take up APC from the microtubule to the plasma membrane and are membrane-localized structural domains, and an arginine–glutamate–alanine (REA) motif that interacts directly with armadillo repeats of β-connexin and negatively regulates Wnt signaling. (B) KCNE1 is a single-transmembrane protein that regulates the voltage-gated potassium channel KCNQ1 by slowing its activation and enhancing its conductance. Upon activation, the positively charged voltage sensor of the VSD senses changes in membrane potential and moves outward within the membrane, opening the pore through VSD-PD coupling. The transmembrane structural domain (TM) of KCNE1 slows the activation of the channel by connecting the voltage sensor to the S4–S5 junction of the pore structural domain and restricting its movement.