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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Whole gene sequencing identifies deep-intronic variants with potential functional impact in patients with

Rita Mendes de Almeida1, Joana Tavares1, Sandra Martins1

  • 1Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

Plos One
|August 11, 2017
PubMed

Insights

Deep intronic variants in hypertrophic cardiomyopathy (HCM) genes are often missed. This study developed a whole-gene sequencing strategy to identify these variants, revealing their contribution to HCM pathogenesis.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cardiovascular Medicine

Background:

  • High-throughput sequencing has advanced genetic disease identification, yet ~50% of hypertrophic cardiomyopathy (HCM) cases lack identified causal mutations.
  • Conventional sequencing often misses pathogenic mutations in deep intronic regions, hindering diagnosis.
  • Deep intronic variants are a potential source of unexplained genetic contributions to HCM.

Purpose of the Study:

  • To develop a whole-gene sequencing approach for identifying deep intronic variants in HCM.
  • To prioritize these intronic variants for their potential role in HCM development.
  • To investigate the contribution of intronic variation to HCM pathogenesis.

Main Methods:

  • Whole-genome sequencing of 26 HCM-associated genes in 16 unrelated patients.
  • Analysis focused on deep intronic regions beyond standard exonic and exon-intron boundary sequencing.
  • Prioritization of variants based on predicted impact on splicing or transcription factor binding.

Main Results:

  • Likely pathogenic deep intronic variants were identified in VCL, PRKAG2, and TTN genes.
  • These variants were found to be 3-fold more prevalent in the patient cohort compared to European populations.
  • A patient with compound heterozygous mutations (MYBPC3 splice site and deep intronic VCL) demonstrated clinical HCM, while carriers of only the MYBPC3 mutation did not.

Conclusions:

  • A framework for analyzing complete intronic sequences of HCM genes was established.
  • Deep intronic variants are suggested to contribute significantly to the HCM phenotype.
  • This approach aids in prioritizing variants for further functional and mechanistic studies.
Abstract

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