Open AccessMolecular autopsy and family screening in a young case of sudden cardiac death reveals an unusually severe case of FHL1 related hypertrophic cardiomyopathy
Author(s) -
GaertnerRommel Anna,
Tiesmeier Jens,
Jakob Thomas,
Strickmann Bernd,
Veit Gunter,
BachmannMennenga Bernd,
Paluszkiewicz Lech,
Klingel Karin,
Schulz Uwe,
Laser Kai T.,
Karger Bernd,
Pfeiffer Heidi,
Milting Hendrik
Publication year - 2019
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.841
Subject(s) - hypertrophic cardiomyopathy , medicine , sudden cardiac death , autopsy , genetic counseling , sudden death , penetrance , genetic testing , cardiomyopathy , family history , pathology , cardiology , genetics , heart failure , biology , gene , phenotype
Background Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy with a prevalence of about 1:200. It is characterized by left ventricular hypertrophy, diastolic dysfunction and interstitial fibrosis; HCM might lead to sudden cardiac death (SCD) especially in the young. Due to low autopsy frequencies of sudden unexplained deaths (SUD) the true prevalence of SCD and especially of HCM among SUD remains unclear. Even in cases of proven SCD genetic testing is not a routine procedure precluding appropriate risk stratification and counseling of relatives. Methods Here we report a case of SCD in a 19‐year‐old investigated by combined forensic and molecular autopsy. Results During autopsy of the index‐patient HCM was detected. As no other possible cause of death could be uncovered by forensic autopsy the event was classified as SCD. Molecular autopsy identified two (probably) pathogenic genetic variants in FHL1 and MYBPC3 . The MYBPC3 variant had an incomplete penetrance. The FHL1 variant was a de novo mutation. We detected reduced FHL1 mRNA levels and no FHL1 protein in muscle samples suggesting nonsense‐mediated mRNA decay and/or degradation of the truncated protein in the SCD victim revealing a plausible disease mechanism. Conclusion The identification of the genetic cause of the SCD contributed to the rational counseling of the relatives and risk assessment within the family. Furthermore our study revealed evidences for the pathomechanism of FHL1 mutations.