Cargando…

Variant interpretation in molecular autopsy: a useful dilemma

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 rem...

Descripción completa

Detalles Bibliográficos
Autores principales: Scheiper-Welling, Stefanie, Tabunscik, Monika, Gross, Theresa E., Jenewein, Tina, Beckmann, Britt M., Niess, Constanze, Gradhand, Elise, Wunder, Cora, Schneider, Peter M., Rothschild, Markus A., Verhoff, Marcel A., Kauferstein, Silke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847204/
https://www.ncbi.nlm.nih.gov/pubmed/35091851
http://dx.doi.org/10.1007/s00414-021-02764-z
_version_ 1784652002026848256
author Scheiper-Welling, Stefanie
Tabunscik, Monika
Gross, Theresa E.
Jenewein, Tina
Beckmann, Britt M.
Niess, Constanze
Gradhand, Elise
Wunder, Cora
Schneider, Peter M.
Rothschild, Markus A.
Verhoff, Marcel A.
Kauferstein, Silke
author_facet Scheiper-Welling, Stefanie
Tabunscik, Monika
Gross, Theresa E.
Jenewein, Tina
Beckmann, Britt M.
Niess, Constanze
Gradhand, Elise
Wunder, Cora
Schneider, Peter M.
Rothschild, Markus A.
Verhoff, Marcel A.
Kauferstein, Silke
author_sort Scheiper-Welling, Stefanie
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00414-021-02764-z.
format Online
Article
Text
id pubmed-8847204
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-88472042022-02-23 Variant interpretation in molecular autopsy: a useful dilemma Scheiper-Welling, Stefanie Tabunscik, Monika Gross, Theresa E. Jenewein, Tina Beckmann, Britt M. Niess, Constanze Gradhand, Elise Wunder, Cora Schneider, Peter M. Rothschild, Markus A. Verhoff, Marcel A. Kauferstein, Silke Int J Legal Med Original Article 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00414-021-02764-z. Springer Berlin Heidelberg 2022-01-29 2022 /pmc/articles/PMC8847204/ /pubmed/35091851 http://dx.doi.org/10.1007/s00414-021-02764-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Scheiper-Welling, Stefanie
Tabunscik, Monika
Gross, Theresa E.
Jenewein, Tina
Beckmann, Britt M.
Niess, Constanze
Gradhand, Elise
Wunder, Cora
Schneider, Peter M.
Rothschild, Markus A.
Verhoff, Marcel A.
Kauferstein, Silke
Variant interpretation in molecular autopsy: a useful dilemma
title Variant interpretation in molecular autopsy: a useful dilemma
title_full Variant interpretation in molecular autopsy: a useful dilemma
title_fullStr Variant interpretation in molecular autopsy: a useful dilemma
title_full_unstemmed Variant interpretation in molecular autopsy: a useful dilemma
title_short Variant interpretation in molecular autopsy: a useful dilemma
title_sort variant interpretation in molecular autopsy: a useful dilemma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847204/
https://www.ncbi.nlm.nih.gov/pubmed/35091851
http://dx.doi.org/10.1007/s00414-021-02764-z
work_keys_str_mv AT scheiperwellingstefanie variantinterpretationinmolecularautopsyausefuldilemma
AT tabunscikmonika variantinterpretationinmolecularautopsyausefuldilemma
AT grosstheresae variantinterpretationinmolecularautopsyausefuldilemma
AT jeneweintina variantinterpretationinmolecularautopsyausefuldilemma
AT beckmannbrittm variantinterpretationinmolecularautopsyausefuldilemma
AT niessconstanze variantinterpretationinmolecularautopsyausefuldilemma
AT gradhandelise variantinterpretationinmolecularautopsyausefuldilemma
AT wundercora variantinterpretationinmolecularautopsyausefuldilemma
AT schneiderpeterm variantinterpretationinmolecularautopsyausefuldilemma
AT rothschildmarkusa variantinterpretationinmolecularautopsyausefuldilemma
AT verhoffmarcela variantinterpretationinmolecularautopsyausefuldilemma
AT kaufersteinsilke variantinterpretationinmolecularautopsyausefuldilemma