Molecular autopsy and subsequent functional analysis reveal de novo DSG2 mutation as cause of sudden death

• Published in: European journal of medical genetics Vol. 64; no. 11; p. 104322
• Main Authors: Simons, Eline, Labro, Alain, Saenen, Johan, Nijak, Aleksandra, Sieliwonczyk, Ewa, Vandendriessche, Bert, Dąbrowska, Małgorzata, Van Craenenbroeck, Emeline M., Schepers, Dorien, Van Laer, Lut, Loeys, Bart L., Alaerts, Maaike
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Masson SAS 01.11.2021
• Subjects: Animals; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - pathology; Arrhythmogenic right ventricular cardiomyopathy; CHO Cells; Clinical report; Cricetinae; Cricetulus; Death, Sudden, Cardiac - etiology; Desmoglein 2 - genetics; Desmoglein 2 - metabolism; Heart Rate; Humans; Inherited cardiac arrhythmia; KCNQ1 Potassium Channel - genetics; KCNQ1 Potassium Channel - metabolism; Male; Middle Aged; Molecular autopsy; Mutation, Missense; Sudden cardiac death; Inherited cardiac arrhythmia; Molecular autopsy; Arrhythmogenic right ventricular cardiomyopathy; Clinical report; Sudden cardiac death
• ISSN: 1769-7212; 1878-0849
• DOI: 10.1016/j.ejmg.2021.104322

Sudden cardiac death (SCD) is a common cause of death in young adults. In up to 80% of cases a genetic cause is suspected. Next-generation sequencing of candidate genes can reveal the cause of SCD, provide prognostic management, and facilitate pre-symptomatic testing and prevention in relatives. Here we present a proband who experienced SCD in his sleep for which molecular autopsy was performed. We performed a post-mortem genetic analysis of a 49-year-old male who died during sleep after competitive kayaking, using a Cardiomyopathy and Primary Arrhythmia next-generation sequencing panel, each containing 51 candidate genes. Autopsy was not performed. Genetic testing of the proband resulted in missense variants in KCNQ1 (c.1449C > A; p.(Asn483Lys)) and DSG2 (c.2979G > T; p.(Gln993His)), both absent from the gnomAD database. Familial segregation analysis showed de novo occurrence of the DSG2 variant and presence of the KCNQ1 variant in the proband's mother and daughter. KCNQ1 p.(Asn483Lys) was predicted to be pathogenic by MutationTaster. However, none of the KCNQ1 variant carrying family members showed long QTc on ECG or Holter. We further functionally analysed this variant using patch-clamp in a heterologous expression system (Chinese Hamster Ovary (CHO) cells) expressing the KCNQ1 mutant in combination with KCNE1 wild type protein and showed no significant changes in electrophysiological function of Kv7.1. Based on the above evidence, we concluded that the DSG2 p.(Gln993His) variant is the most likely cause of SCD in the presented case, and that there is insufficient evidence that the identified KCNQ1 p.(Asn483Lys) variant would confer risk for SCD in his mother and daughter. Fortunately, the DSG2 variant was not inherited by the proband's two children. This case report indicates the added value of molecular autopsy and the importance of subsequent functional study of variants to inform patients and family members about the risk of variants they might carry.