The Burden of Recurrent and Ancestral Mutations in Families with Hypertrophic Cardiomyopathy — ASN Events
  1. Schedule
  2. Poster Session 2
  3. The Burden of Recurrent and Ancestral Mutations in Families with Hypertrophic Cardiomyopathy

The Burden of Recurrent and Ancestral Mutations in Families with Hypertrophic Cardiomyopathy (#238)

Samantha Barratt-Ross 1 2 , Richard Bagnall 1 2 , Jodie Ingles 1 2 3 , J. Peter Van Tintelen 4 , Chris Semsarian 1 2 3
  1. Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  2. Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, NSW, Australia
  3. Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
  4. Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, North Holland, the Netherlands

Purpose: Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous myocardial disease with over 1000 causal variants identified. Non-unique variants account for disease in many families. We sought to identify non-unique variants in Australian families to determine whether they arise from common ancestral mutations or recurrent mutation events.

Methods: Genetic test results of patients from apparently unrelated families with HCM were recorded. Haplotype analysis was performed in patients and family members who carry non-unique variants in myosin binding protein-C (MYBPC3) and myosin heavy chain beta (MYH7).

Results: Causal variants were found in 192/467 (41%) families. The most common single genetic cause of HCM is the recurrent MYBPC3 variant c.1504C>T, p.Arg502Trp. Non-unique variants accounted for 63% of these families. Thirteen variants were each identified in more than three families and alone accounted for 17% of HCM cases. Seven of 13 variants were recurrent. Two variants, MYBPC3 c.1928-2A>G and MYH7 c.2681A>G, p.Glu894Gly, were found on one haplotype in 6 families each, supportive of a single mutation inherited from a common ancestor.

Conclusion: The majority of families with HCM have a non-unique causal variant. Discovery of the genetic origins of human disease forms a fundamental basis for improved understanding of disease pathogenesis and phenotype development.

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