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Familial Hypertrophic Cardiomyopathy - Identification of cause and risk stratification through exome sequencing
Amitabh Biswas1, Soumi Das2, Mitali Kapoor2
1Dept. of Anthropology, Delhi University, Delhi, India; College of Natural Sciences, Arba Minch University, Ethiopia.
Insights
Whole exome sequencing identified a rare TNNT2 gene variant in a family with hypertrophic cardiomyopathy (HCM). This genetic finding aids in understanding complex cardiac disease and sudden cardiac death risk.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Hypertrophic Cardiomyopathy (HCM) is a significant cause of sudden cardiac death, characterized by diverse clinical presentations and genetic heterogeneity.
- Genetic diagnosis of HCM is complex, but whole exome sequencing offers a powerful tool for identifying causative variants.
Purpose of the Study:
- To investigate the genetic underpinnings of hypertrophic cardiomyopathy in a multigenerational family with a history of sudden cardiac death.
- To demonstrate the utility of exome sequencing in diagnosing complex inherited cardiac conditions.
Main Methods:
- Whole exome sequencing (100× coverage) was performed on affected and unaffected family members.
- Variants were filtered based on inheritance patterns, rarity, and known disease associations.
- Segregated and prioritized variants were evaluated for clinical relevance.
Main Results:
- A rare, pathogenic variant (c.274C>T; p.Arg92Trp) in the troponin-T gene (TNNT2) was identified, exclusively present in affected individuals.
- While TNNT2 acts as a primary driver mutation, variants in KCNMB1, LPL, APOE, and other factors contribute to risk stratification within the family.
- The identified variant was absent in 200 control chromosomes.
Conclusions:
- Rare variants play a crucial role in the complex phenotypes and intrafamilial heterogeneity observed in hypertrophic cardiomyopathy.
- Whole exome sequencing is essential for diagnosing complex cardiomyopathies that may harbor private or rare mutations.
Background:
Hypertrophic Cardiomyopathy (HCM) with variable clinical presentations and heterogeneity is the common cause of sudden cardiac death. Genetic diagnosis is challenging in these complex diseases but exome sequencing as a genetic diagnostic tool provides explainable results.
Methods:
In a familial Hypertrophic Cardiomyopathy with multigenerational inheritance with apparent phenotype, had a history of sudden death and severe arrhythmia followed by implantation of Implantable cardioverter defibrillator (ICD). Exome sequencing (100×) trailed by effective filtering steps for exome variants on the basis of different parameters, segregated variants are prioritized for the disease and further clinical relevance are evaluated for the variants.
Results:
A rare causal variant in troponin-T gene (TNNT2, NM_000364.3;c.274C > T;p.Arg92Trp) is identified, shared by only affected members, absent in unaffected members and also in 200 unrelated control chromosomes. TNNT2 mutation act as a driver mutation but mutations in other disease-related genes, KCNMB1, LPL, APOE and other biochemical factors provides risk stratification within affected family members.
Conclusion:
This study contributes to the role of "rare variants" in complex disease phenotypes and heterogeneity within family and the necessity of whole exome targeted approaches in complex cardiomyopathy, which are known to harbor private mutations.
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