TY  - JOUR
A1  - Scheiper-Welling, Stefanie
A1  - Tabunscik, Monika
A1  - Groß, Theresa Elisa
A1  - Jenewein, Tina
A1  - Beckmann, Britt-Maria
A1  - Niess, Constanze
A1  - Gradhand, Elise
A1  - Wunder, Cora
A1  - Schneider, Peter M.
A1  - Rothschild, Markus A.
A1  - Verhoff, Marcel A.
A1  - Kauferstein, Silke
T1  - Variant interpretation in molecular autopsy: a useful dilemma
T2  - International journal of legal medicine
N2  - Sudden cardiac death (SCD) in adolescents and young adults may be the first manifestation of an inherited arrhythmic syndrome. Thus identification of a genetic origin in sudden death cases deemed inconclusive after a comprehensive autopsy and may help to reduce the risk of lethal episodes in the remaining family. Using next-generation sequencing (NGS), a large number of variants of unknown significance (VUS) are detected. In the majority of cases, there is insufficient evidence of pathogenicity, representing a huge dilemma in current genetic investigations. Misinterpretation of such variants may lead to inaccurate genetic diagnoses and/or the adoption of unnecessary and/or inappropriate therapeutic approaches. In our study, we applied current (ACMG) recommendations for variant classification in post-mortem genetic screening of a cohort of 56 SCD victims. We identified a total 53 rare protein-altering variants (MAF < 0.2%) classified as VUS or worse. Twelve percent of the cases exhibited a clinically actionable variant (pathogenic, likely pathogenic or VUS – potentially pathogenic) that would warrant cascade genetic screening in relatives. Most of the variants detected by means of the post-mortem genetic investigations were VUS. Thus, genetic testing by itself might be fairly meaningless without supporting background data. This data reinforces the need for an experienced multidisciplinary team for obtaining reliable and accountable interpretations of variant significance for elucidating potential causes for SCDs in the young. This enables the early identification of relatives at risk or excludes family members as genetic carriers. Also, development of adequate forensic guidelines to enable appropriate interpretation of rare genetic variants is fundamental.
KW  - Sudden death
KW  - Sudden cardiac death
KW  - Post-mortem genetic screening
KW  - Molecular autopsy
KW  - VUS
KW  - Inherited arrhythmic syndrome
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/69580
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-695800
SN  - 1437-1596
SN  - 0937-9827
N1  - Open Access funding enabled and organized by Projekt DEAL. We thank the Dr. Rolf M. Schwiete Foundation for supporting this work.
VL  - 136
IS  - 2
SP  - 475
EP  - 482
PB  - Springer ; HeinOnline
CY  - Berlin ; Heidelberg ; Getzville, NY
ER  -