Molecular autopsy and family screening in a young case of sudden cardiac death reveals an unusually severe case of FHL1 related hypertrophic cardiomyopathy

Abstract

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.

Cardiomyopathy‐associated mutations in the RS domain affect nuclear localization of RBM20

“…Total RNA was isolated from 30 mg of left ventricular myocardium using a commercial kit (RNeasy, Qiagen, Hilden, Germany) as previously reported (Gaertner‐Rommel et al, 2019). Purity and integrity were assessed by agarose gel electrophoresis.…”

The emergency medical service has a crucial role to unravel the genetics of sudden cardiac arrest in young, out of hospital resuscitated patients

“…In patient #06 genetic analysis led to the identification of a de novo nonsense mutation in FHL1. 9 MYBPC3 encodes the cardiac myosin binding protein C which is one of the major genes associated with HCM. Approximately 35% of the known HCM-associated mutations are found within MYBPC3.…”

“…After signing a second informed consent form, the DNA was isolated from the blood sample for NGS panel analysis as previously reported. 9 The ethics committees of the Ruhr-University Bochum, situated in Bad Oeynhausen, Germany, and the responsible local Medical Association in Mü nster, Germany, gave approval (file numbers: 2017-232 or 2017-514-b-S, respectively). The study followed the principles of the conference of Helsinki.…”

“…10 DNA integrity was analysed by agarose gel electrophoresis. Paired end DNA-sequencing was used with a commercial DNA panel comprising 174 genes as previously reported 9 and classified according to the recent recommendations of the guidelines of the American College of Medical Genetics (ACMG). 11,12 In cases of suspected familial disposition whole exome analysis was additionally performed.…”

Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies

“…For example, HCM is mainly caused by mutations in genes encoding sarcomeric proteins such as MYH7 or MYBPC3 (Figure 1). Further mutations in other genes, encoding sarcomere proteins, like TPM1 [38], TNNC1 [39], TNNI3 [40], TNNT2 [38], FHL1 [41,42], or ACTC1 [43], have also been identified in patients with HCM (Table 1). In addition, in rare cases, mutations in genes encoding for Z-disc proteins, like ACTN2 [44] or FLNC [45], or genes encoding for proteins involved in the Ca 2+ -homeostasis like PLN [46], are also known to cause HCM (see Figure 1).…”