Three Novel Pathogenic Variants in Unrelated Vietnamese Patients with Cardiomyopathy

Abstract

Background: Cardiomyopathy, including dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), is a major cause of heart failure (HF) and a leading indication for heart transplantation. Of these patients, 20-50% have a genetic cause, so understanding the genetic basis of cardiomyopathy will provide knowledge about the pathogenesis of the disease for diagnosis, treatment, prevention, and genetic counseling for families. Methods: This study collected nine patients from different Vietnamese families for genetic analysis at The Cardiovascular Center, E Hospital, Hanoi, Vietnam. The patients were diagnosed with cardiomyopathy based on clinical symptoms. Whole-exome sequencing (WES) was performed in the Vietnamese patients to identify variants associated with cardiomyopathy, and the Sanger sequencing method was used to validate the variants in the patients' families. The influence of the variants was predicted using in silico analysis tools. Results: Nine heterozygous variants were detected as a cause of disease in the patients, three of which were novel variants, including c.284C>G, p.Pro95Arg in the MYL2 gene, c.2356A>G, p.Thr786Ala in the MYH7 gene, and c.1223T>A, p.Leu408Gln in the DES gene. Two other variants were pathogenic variants (c.602T>C, p.Ile201Thr in the MYH7 gene and c.1391G>C, p.Gly464Ala in the PTPN11 gene), and four were variants of uncertain significance in the ACTA2, ANK2, MYOZ2, and PRKAG2 genes. The results of the in silico prediction software showed that the identified variants were pathogenic and responsible for the patients' DCM. Conclusions: Our results contribute to the understanding of cardiomyopathy pathogenesis and provide a basis for diagnosis, treatment, prevention, and genetic counseling.

Keywords: Vietnamese patients; cardiomyopathy; dilated cardiomyopathy (DCM); hypertrophic cardiomyopathy (HCM); pathogenic variants; whole-exome sequencing (WES).

Figure 1

Sanger sequencing result confirms p.Pro95Arg in the MYL2 gene in family members of patient P2 (A); p.Gly464Ala variant in the PTPN11 gene in family members of patient P5 (B); p.Arg208His in the ACTA2 gene in family members of patient P6 (C); and p.Thr786Ala in the MYH7 gene in family members of patient P7 (D).

Figure 2

Multiple alignment of the proteins from human and other species by Clustal-X2. Multiple alignments of the MYL2, MYOZ2, MYH7, PTPN11, ACTA2, PRKAG2, and DES proteins at the positions of variants based on amino acid sequences from different species, including Homo sapiens, Cricetulus griseus, Sus scrofa, Canis lupus, Equus caballus, Bos taurus, Mus musculus, Gallus gallus, and Rattus norvegicus.

Figure 3

Three-dimensional structure of the proteins predicted by Swiss-Pdb Viewer. (A) Mutant type of MYL2 protein with the formation of one more strong H bond (in green color) between Arg95 and Thr98. (B) Mutant type of PTPN11 protein with the formation of one more strong H bond (in green color) between Ala464 and Gly467. (C) Mutant type of ACTA2 protein with the formation of one more weak H bond (in pink color) between His208 and Thr204. (D) Mutant type of MYH7 protein with the loss of two strong H bonds (in green color) between Ala786 with Ser782 and Arg783. (E) Mutant type of DES protein with the formation of one more weak H bond (in pink color) between Gln408 and Tyr405.