Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death

Abstract

Aims: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic cardiac disorder characterized by unexplained left ventricular hypertrophy. It can cause a wide spectrum of clinical manifestations, ranging from asymptomatic to heart failure and sudden cardiac death (SCD). Approximately half of HCM cases are caused by variants in sarcomeric proteins, including α-tropomyosin (TPM1). In this study, we aimed to characterize the clinical and molecular phenotype of HCM in an Iranian pedigree with SCD.

Methods and results: The proband and available family members underwent comprehensive clinical evaluations, including echocardiography, cardiac magnetic resonance (CMR) imaging and electrocardiography (ECG). Whole-exome sequencing (WES) was performed in all available family members to identify the causal variant, which was validated, and segregation analysis was conducted via Sanger sequencing. WES identified a novel missense variant, c.761A>G:p.D254G (NM_001018005.2), in the TPM1 gene, in the proband, his father and one of his sisters. Bioinformatic analysis predicted it to be likely pathogenic. Clinical features in affected individuals were consistent with HCM.

Conclusions: The identification of a novel TPM1 variant in a family with HCM and SCD underscores the critical role of genetic screening in at-risk families. Early detection of pathogenic variants can facilitate timely intervention and management, potentially reducing the risk of SCD in individuals with HCM.

Keywords: genetic; hypertrophic cardiomyopathy; tropomyosin; variant; whole‐exome sequencing.

Figure 1

The family pedigree and genetic analysis of pathogenic variants are depicted. (A) The pedigree of the family shows a novel variant c.761A>G:p.D254G was detected in the affected proband, with one of his sisters and his father as heterozygous and his mother and another sister as wild genotypes in both allele positions. (B) The chromatogram shows a region of TPM1 exon 7 that contains an A‐to‐G mutated base that results in the substitution of aspartic acid for glycine at codon 254. Sequence from normal individuals is shown in the top panel and from affected individuals in the bottom panel.

Figure 2

Cardiac magnetic resonance imaging of a patient with hypertrophic cardiomyopathy. (A) A four‐chamber true fast imaging with steady‐state precession image at end‐diastole shows left ventricular hypertrophy with asymmetric thickening of the interventricular septum. IVS, interventricular septum; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. (B) A four‐chamber phase‐sensitive inversion‐recovery late gadolinium enhancement image shows patchy mid‐myocardial enhancement in the basal and mid‐interventricular septum. White arrows indicate areas of gadolinium enhancement. (C) A short‐axis phase‐sensitive inversion‐recovery late gadolinium enhancement image again demonstrates patchy mid‐myocardial enhancement in the mid‐interventricular septum, which is consistent with myocardial fibrosis. White arrows indicate areas of gadolinium enhancement.

Figure 3

(A) The figure shows the schematic structures of the original (left) and the mutant (right) amino acids by HOPE amino acid analysis. The backbone, which is the same for each amino acid, is coloured red. The side chain, unique for each amino acid, is coloured green. Each amino acid has its own specific size, charge and hydrophobicity value. The mutant residue is smaller than the wild‐type residue. The wild‐type residue charge was NEGATIVE, and the mutant residue charge was NEUTRAL. The mutant residue is more hydrophobic than the wild‐type residue. A new amino acid (glycine) is very flexible and can disturb the required rigidity of the protein at this position. In addition, the charge of the wild‐type residue is lost by this mutation. This can cause a loss of interactions with other molecules. (B) Only this residue type was found at this position via UniProt protein alignment among four various species. The wild‐type residue is highly conserved. Mutation of a 100% conserved residue is usually damaging to the protein. The mutant and wild‐type residues are not very similar. Based on this conservation information, this mutation is probably damaging to the protein. The mutated residue is located on the surface of a domain with an unknown function. The residue was not found to be in contact with other domains, the function of which is known within the used structure. However, contact with other molecules or domains is still possible and might be affected by this mutation.