Case Report: Tetralogy of Fallot in a Chinese Family Caused by a Novel Missense Variant of MYOM2

Abstract

Background: Rare genetic variants have been identified to be important contributors to the risk of Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD). But relatively limited familial studies with small numbers of TOF cases have been reported to date. In this study, we aimed to identify novel pathogenic genes and variants that caused TOF in a Chinese family using whole exome sequencing (WES).

Methods: A Chinese family whose twins were affected by TOF were recruited for this study. A WES was performed for the affected twins, their healthy brother, and parents to identify the potential pathogenic mutated gene(s). Heterozygous variants carried by the twins, but not the unaffected brother, were retained. Public databases were used to assess the frequencies of the selected variants, and online prediction tools were accessed to predict the influences of these variants on protein function. The final candidate variant was further confirmed by Sanger sequencing in other members of the family.

Results: After several filtering processes, a heterozygous missense variant in the MYOM2 gene (NM_003970.4:c.3097C>T:p.R1033C) was identified and confirmed by Sanger sequencing in the affected twins and their unaffected father, suggesting an inheritance pattern with incomplete penetrance. The variant was found to be extremely rare in the public databases. Furthermore, the mutated site was highly conserved among mammals, and as shown using multiple online prediction tools, this variant was predicted to be a detrimental variant.

Conclusion: We assessed a family with TOF caused by a rare heterozygous missense variant of MYOM2. Our findings not only further confirm the significant role of genetics in the incidence of TOF but also expand the spectrum of the gene variants that lead to TOF.

Keywords: MYOM2; Tetralogy of Fallot; heterozygous variant; incomplete penetrance; whole exome sequencing.

Figure 1

Pedigree of the family with TOF. The filled black symbols represent the affected members.

Figure 2

Echocardiogram images from patients II:2 and II:3 showing the apex of the heart. (A) The ultrasonogram for the elder twin (II:2). (B) The ultrasonogram for the younger twin (II:3). LV, left ventricle; RV, right ventricle; Ao, aorta; RVOT, right ventricular out ow tract; PA, pulmonary artery.

Figure 3

Validation of the missense variant of MYOM2 in the family with TOF. (A) Sanger sequencing results from the probands, their brothers, and their unaffected parents. The heterozygous variant in the MYOM2 gene was identified in the twins, but not in their healthy brother. (B) The location of the variant in the protein structure of MYOM2. The arrow denotes the mutated site. (C) Amino acid alignment of the MYOM2 protein from several organisms. The position of Arg1033 residue (highlighted by a red box) was highly conserved among different species.

Figure 4

Wild-type and variant structure of MYOM2 protein. (A) Wild-type MYOM2 predicted 3D structure. (B) Mutation MYOM2 predicted 3D structure. Supplemental Figure 1 Echo images from the twins' father. The above 4 figures were taken from Cardiac ultrasound results. These figures illustrate the shape, structure, wall thickness, and function of the heart were all normal.