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Rare genetic mutations in Pakistani patients with dilated cardiomyopathy

Muhammad Shakeel1, Muhammad Irfan1, Ishtiaq Ahmad Khan1

  • 1Jamil-ur-Rahman Center for Genome Research, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.

Gene
|June 11, 2018
PubMed

Insights

Genetic factors contribute to dilated cardiomyopathy (DCM), a heart failure cause. Whole exome sequencing identified detrimental variants in cardiac genes, including MYOM3, offering potential for DCM risk assessment and precision therapy.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Genomics

Background:

  • Dilated cardiomyopathy (DCM) is a primary cause of heart failure and necessitates heart transplantation.
  • Genetic factors are implicated in up to 50% of DCM cases, yet its complex pathophysiology remains incompletely understood.
  • Idiopathic DCM presents a significant challenge due to its heterogeneity and unclear underlying mechanisms.

Purpose of the Study:

  • To identify genetic variants associated with idiopathic DCM through whole exome sequencing.
  • To investigate the role of rare deleterious variants in cardiac-expressed genes in DCM pathogenesis.
  • To explore potential genetic markers for risk assessment and targeted therapies in DCM.

Main Methods:

  • Whole exome sequencing of five unrelated idiopathic DCM patients to an average depth of 100×.
  • In silico analysis using SIFT, Polyphen2, and CADD to predict the deleteriousness of single nucleotide variants (SNVs).
  • Analysis of allele frequencies and linkage disequilibrium to identify potentially pathogenic variants and their association with DCM.

Main Results:

  • Sequencing identified 494 rare missense SNVs predicted as deleterious.
  • Loss-of-function variants in C2orf40, MYOM3, and TMED4, a frameshift insertion in RTKN2, and a splice site deletion in SLC6A6 were found.
  • A stop-gained variant in MYOM3 (rs143187236) was in perfect linkage disequilibrium with a neighboring missense variant, highlighting MYOM3's role.
  • Variants rs375563861 (C2orf40), rs143187236 (MYOM3), and rs564181443 (RTKN2) showed significantly higher allele frequencies in South Asians.

Conclusions:

  • Whole exome sequencing revealed multiple rare, deleterious variants in genes critical for cardiac function in idiopathic DCM patients.
  • Specific variants in MYOM3, C2orf40, and RTKN2 may play a significant role in DCM pathophysiology, particularly in South Asian populations.
  • These identified pathogenic variants hold promise for improving risk stratification and enabling precision medicine approaches for DCM management.

Keywords:
Deleterious variantExome sequencingMyomesin 3

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