Variant interpretation in molecular autopsy: a useful dilemma.
Inherited arrhythmic syndrome
Molecular autopsy
Post-mortem genetic screening
Sudden cardiac death
Sudden death
VUS
Journal
International journal of legal medicine
ISSN: 1437-1596
Titre abrégé: Int J Legal Med
Pays: Germany
ID NLM: 9101456
Informations de publication
Date de publication:
Mar 2022
Mar 2022
Historique:
received:
08
09
2021
accepted:
15
12
2021
pubmed:
30
1
2022
medline:
7
4
2022
entrez:
29
1
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35091851
doi: 10.1007/s00414-021-02764-z
pii: 10.1007/s00414-021-02764-z
pmc: PMC8847204
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
475-482Informations de copyright
© 2021. The Author(s).
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