The Trans-Tasman Response AGAinst sudden Death in the Young team (TRAGADY), the Royal College of Pathologists of Australia, and the National Heart Foundation of New Zealand proposed the first standardized protocol focused on performing an autopsy in young people who died suddenly and without a conclusive cause of decease (named Sudden Unexplained Death, SUD) (www.rcpa.edu.au/getattachment/b72c2a4c-0e36-4656-8704-f2e8a7b7bc20/Guidelines-on-Autopsy-Practice.aspx). In this first guide, properly informing relatives about SUD implications for their survival was strongly emphasized as most cases of SUD in the young population are due to inherited arrhythmogenic syndromes (IAS), including cardiac channelopathies and cardiomyopathies [1, 2]. These entities are caused by pathogenic alterations in gene encoding cardiac ion channels or associated proteins as well as desmosomal, sarcomeric, and cytoskeletal proteins of the myocyte. Current clinical and genetic guidelines recommend performing a post-mortem genetic analysis (called molecular autopsy) in those SUD cases where a highly suspected cause of death is IAS [3, 4]. Owing to the genetic origin of IAS, relatives can be carriers of the same pathogenic alteration, so genetic analysis of family members is highly recommended [5].
A molecular autopsy is a fundamental tool helping to unravel genetic alterations, clarify the cause of SUD, and therefore, facilitate early identification of genetic carriers. The first manifestation of an IAS may be SUD, thus identifying genetic carriers at risk allows for adoption of preventive personalized therapies [3, 4]. Nowadays, use of massive sequencing technologies (called, next generation sequencing) allows wide-ranging genetic analysis [6]. Despite recent advances, genetic diagnosis in some SUD cases remains uncertain mainly because of identifying rare variants classified as variants of unknown significance (VUS) according to the current American College of Medical Genetics and Genomics recommendations [7]. These recommendations include a list of items based on available data at the moment of the analysis. In consequence, modification of data may also alter the previous classification of a genetic variant. In recent years, several studies recommend performing a periodic re-analysis/re-interpretation of rare variants, especially those previously classified as VUS by the American College of Medical Genetics and Genomics [8–10]. This is especially relevant in SUD cases because a large number of variants remains ambiguous [11]. For this reason, molecular autopsy and familial assessment are crucial in unraveling causes of unexpected deaths in young people.
In this issue of the journal, Chmielewski et al. [12], report on clinical and genetic screening in a cohort of 65 young SUD cases from 39 families, including 87 relatives. After a comprehensive analysis of all collected data (situation of death, genetic analysis, familial assessment), definite diagnosis was identified in 44%, mainly cardiomyopathies, followed by cardiac channelopathies. In 18% of cases, a variant with a definite deleterious role was identified and a VUS was identified in 2 SUD cases; the remaining subjects had a negative genetic diagnosis. Familial assessment identified 3 families with a definite diagnosis and affected relatives received guidance on personalized therapeutic preventive measures. Unfortunately, a comprehensive autopsy was not performed in SUD cases, which, from our point of view, is a crucial task to identify any macroscopic and/or microscopic alteration in the heart, especially in cardiomyopathies. The autopsy is a crucial point in disclosing the cause of SUD and may help to interpret genetic variants, especially those classified as VUS. For this reason, the yield of the genetic testing has little effectiveness in families without the disease phenotype. The number of genes with a definitive association with any IAS is limited to no more than 10 in cardiac channelopathies and 25 in cardiomyopathies [3, 4]. Therefore, increasing the knowledge about the number of causative genes in IAS and obtaining forensic data could help to raise the percentage of cases with a definite diagnosis. Despite this limitation, molecular autopsy and familial genotype-phenotype analysis may help to identify relatives at risk and save lives.
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Conflict of interest: None declared.
Funding: This work was supported by Obra Social “La Caixa Foundation” (LCF/PR/GN16/50290001 and LCF/PR/GN19/50320002). Co-funded by Instituto de Salud Carlos III (FIS PI21/00094). CIBERCV is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness. IDIBGI is a “CERCA Programme / Generalitat de Catalunya”. The funders played no role in the study design, data collection, data analysis, interpretation, or writing of the report.
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