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Genetics of HCM and Role of Genetic Testing

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Hypertrophic Cardiomyopathy

Abstract

Since 1989, major advances have been made in our understanding of the genetic basis of HCM. Our genetic advances have led to a complete redefinition of HCM as a complex medical genetic disorder of the sarcomere. To date, over 1300 mutations in at least 8 disease genes have been identified in patients with HCM. This genetic information has had its greatest impact in the setting of predictive testing in at-risk family members. The genetic testing process in HCM requires a multidisciplinary approach, which includes the cardiologist, genetic counselor, geneticists, and patient support groups. Careful phenotyping of HCM patients, comprehensive pre- and post- test genetic counseling, careful interpretation of the genetic reports, and systematic application of the genetic result in the setting of the HCM family are all key components of care. The latest genetic technologies, including whole genome sequencing, will likely translate to a greater understanding of the genetic and molecular underpinnings of HCM.

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Author information

Authors and Affiliations

  1. Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia

    Christopher Semsarian

  2. Sydney Medical School, University of Sydney, Sydney, NSW, Australia

    Christopher Semsarian & Jodie Ingles

  3. Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, NSW, Australia

    Christopher Semsarian & Jodie Ingles

Authors
  1. Christopher Semsarian
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  2. Jodie Ingles
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Corresponding author

Correspondence to Christopher Semsarian .

Editor information

Editors and Affiliations

  1. Westchester Medical Center, Valhalla, NY, USA

    Srihari S. Naidu

Questions

Questions

  1. 1.

    The most common form of inheritance in HCM is:

    1. A.

      Autosomal dominant

    2. B.

      Autosomal recessive

    3. C.

      X-linked

    4. D.

      Maternal

    5. E.

      None of the above

  • Answer: A

  • HCM can be inherited in all the listed modes, but the majority (at least 70%) is inherited as an autosomal dominant trait. The clinical importance of this relates to the fact that in autosomal dominant inheritance, 50% of the offspring of affected HCM individuals will also be affected, hence the importance of clinical and genetic screening of first-degree relatives.

  1. 2.

    The most common genes implicated in HCM relate to:

    1. A.

      Calcium regulation

    2. B.

      Desmosome function

    3. C.

      Ion channel function

    4. D.

      Sarcomere function

    5. E.

      Mitochondrial energy utilization

  • Answer: D

  • All the established genes in which mutations cause HCM encode sarcomere or sarcomere-related proteins. The two most common genes are MYH7 and MYBPC3. Mutations in HCM sarcomere genes can influence calcium regulation, desmosome function, ion channel function, and energy utilization as part of the molecular pathogenesis of HCM.

  1. 3.

    Genetic testing in HCM can be useful for:

    1. A.

      Diagnosis

    2. B.

      Screening family members

    3. C.

      Diagnosing HCM “phenocopies”

    4. D.

      Reproductive decisions

    5. E.

      All of the above

  • Answer: E

  • Genetic testing has many benefits in HCM. While the main role relates to cascade or predictive testing in screening family members (option B), it can also assist in clarifying diagnosis (e.g., HCM vs athlete’s heart), diagnosing HCM phenocopies such as Fabry or Danon disease, and can help in decisions regarding family planning.

  1. 4.

    Which one of the following statements is true regarding a variant of uncertain significance (VUS):

    1. A.

      VUS can be used clinically in genetic testing of family members.

    2. B.

      VUS is the cause of HCM.

    3. C.

      The clinical significance and pathogenicity of the VUS remains unknown.

    4. D.

      VUS findings are rare.

    5. E.

      None of the above.

  • Answer: C

  • VUS are commonly seen with genetic testing in HCM and represent findings of variants where the clinical and pathogenic significance remains unclear. Therefore VUS findings should not be used for genetic screening in the family since its pathogenic, disease-causing role is unknown.

  1. 5.

    Genetic testing in HCM can be useful in the setting of reproductive decisions in the following way:

    1. A.

      Preimplantation genetic diagnosis

    2. B.

      Prenatal testing

    3. C.

      Genetic testing at birth

    4. D.

      Genetic testing in childhood

    5. E.

      All of the above

  • Answer: E

  • Genetic testing in HCM can have clinical utility from conception through to old age. A pathogenic genetic result for HCM in a proband can be used to test embryos preimplantation by IVF to ensure a baby who does not carry the mutation. A pathogenic genetic result for HCM in a proband can also be used prenatally (by chorionic villous sampling) to see whether the fetus carries the HCM mutation. In life, genetic testing can be performed at birth, during childhood, or at any stage during adulthood. Importantly, pretest and posttest cardiac genetic counseling is essential in all instances where genetic testing in HCM is being considered.

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Semsarian, C., Ingles, J. (2019). Genetics of HCM and Role of Genetic Testing. In: Naidu, S. (eds) Hypertrophic Cardiomyopathy. Springer, Cham. https://doi.org/10.1007/978-3-319-92423-6_6

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  • DOI: https://doi.org/10.1007/978-3-319-92423-6_6

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-92422-9

  • Online ISBN: 978-3-319-92423-6

  • eBook Packages: MedicineMedicine (R0)

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