Molecular autopsy and clinical family screening in a case of sudden cardiac death reveals ACTN2 mutation related to hypertrophic/dilated cardiomyopathy and a novel LZTR1 variant associated with Noonan syndrome

Mol Genet Genomic Med. 2022 Jul;10(7):e1954. doi: 10.1002/mgg3.1954. Epub 2022 Jun 3.

Abstract

Background: Genetic cardiac diseases are the main trigger of sudden cardiac death (SCD) in young adults. Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiomyopathy and accounts for 0.5 to 1% of SCD cases per year.

Methods: Herein, we report a family with a marked history of SCD focusing on one SCD young adult case and one pediatric case with HCM.

Results: For the deceased young adult, postmortem whole-exome sequencing (WES) revealed a missense variant in the ACTN2 gene: c.355G > A; p.(Ala119Thr) confirming the mixed hypertrophic/dilated cardiomyopathy phenotype detected in the autopsy. For the pediatric case, WES allowed us the identification of a novel frameshift variant in the LZTR1 gene: c.1745delT; p.(Val582Glyfs*10) which confirms a clinical suspicion of HCM related to Noonan syndrome.

Conclusion: The present study adds further evidence on the pathogenicity of ACTN2: p. Ala119Thr variant in SCD and expands the mutational spectrum of the LZTR1 gene related to Noonan syndrome.

Keywords: ACTN2 gene; HCM/DCM; LZTR1 gene; Noonan syndrome; postmortem whole-exome sequencing; sudden cardiac death.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actinin / genetics
  • Autopsy
  • Cardiomyopathy, Dilated*
  • Cardiomyopathy, Hypertrophic* / diagnosis
  • Cardiomyopathy, Hypertrophic* / genetics
  • Child
  • Death, Sudden, Cardiac / etiology
  • Humans
  • Mutation
  • Noonan Syndrome* / genetics
  • Transcription Factors / genetics
  • Young Adult

Substances

  • ACTN2 protein, human
  • LZTR1 protein, human
  • Transcription Factors
  • Actinin