Universität zu Köln

Scheiper-Welling, Stefanie, Tabunscik, Monika, Gross, Theresa E., Jenewein, Tina, Beckmann, Britt M., Niess, Constanze, Gradhand, Elise, Wunder, Cora, Schneider, Peter M. ORCID: 0000-0003-0744-2349, Rothschild, Markus A., Verhoff, Marcel A. and Kauferstein, Silke (2022). Variant interpretation in molecular autopsy: a useful dilemma. Int. J. Legal Med., 136 (2). S. 475 - 483. NEW YORK: SPRINGER. ISSN 1437-1596

Full text not available from this repository.

Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Scheiper-Welling, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Tabunscik, Monika UNSPECIFIED UNSPECIFIED UNSPECIFIED Gross, Theresa E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jenewein, Tina UNSPECIFIED UNSPECIFIED UNSPECIFIED Beckmann, Britt M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Niess, Constanze UNSPECIFIED UNSPECIFIED UNSPECIFIED Gradhand, Elise UNSPECIFIED UNSPECIFIED UNSPECIFIED Wunder, Cora UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Peter M. UNSPECIFIED orcid.org/0000-0003-0744-2349 UNSPECIFIED Rothschild, Markus A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Verhoff, Marcel A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kauferstein, Silke UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-673640
DOI:	10.1007/s00414-021-02764-z
Journal or Publication Title:	Int. J. Legal Med.
Volume:	136
Number:	2
Page Range:	S. 475 - 483
Date:	2022
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1437-1596
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SUDDEN CARDIAC DEATH; EXPERT CONSENSUS STATEMENT; GENETICS; ARREST; CHANNELOPATHIES; NATIONWIDE; BURDEN; YOUNG Multiple languages Medicine, Legal Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67364