5α-reductase x VGKCs

In case of unexplained sudden death, learned societies recommend performing genetic testing on post-mortem biological specimens to search for a potential hereditary genetic cause and implement, with a multidisciplinary team, screening and prevention measures for the deceased's relatives. The aim of this study was to assess the diagnostic contribution of a rigorous multidisciplinary approach (combining autopsy, toxicology, anatomopathology and genetics) in case of unexplained sudden death.

This was a French, prospective (2008-2020), monocentric cohort study on unexplained sudden death in young subjects (aged 2-50 years). For each case, a rigorous autopsy, and the analysis of anatomopathological, toxicological, and genetic data were performed. Fresh cardiac and brain tissue samples were systematically collected and stored at -80°C. Genetic testing was performed using a targeted panel of 181 genes associated with channelopathies, cardiomyopathies and epilepsy. In negative cases, whole exome sequencing was performed. Exomes analyzed more than two years earlier were also reanalyzed.

One or two pathogenic or likely pathogenic (P/LP) variants were identified in 23.5 % (8/34) of patients, and positive toxicology results as well as notable microscopic cardiac anomalies were identified in 25 % (2/8) of them. One or two variants of uncertain significance (VUS) were identified in 35 % (12/34) of patients, of whom 50 % (6/12) had positive toxicology results and 58.3 % (7/12) showed microscopic cardiac anomalies. In addition, 2.9 % (1/34) of patients carried both a pathogenic variant and a VUS in another gene. The identified variants were associated with cardiac, neurological or metabolic disorders, or found in a gene of uncertain significance. Two patients carried pathogenic variants in genes with an uncertain association with sudden death. A total of 20 different genes carried variants of interest (VUS, P/LP variant): KCNH2, SCN5A, RYR2, SNTA1, PRKAG2, AKAP9, GDP1L, TECRL, TRDN, HCN4, ZFHX3, DEPDC5, TANC2, CHRNA2, DCHS1, DMD, EYA4, ACADM, KLF10, SCN7A.

Our study highlighted the value of extensive genetic testing in case of unexplained sudden death, reinforcing the importance of using a comprehensive, multidisciplinary approach. The presence of multiple genetic variants, minor anatomopathological changes and toxicological factors suggests the complex interplay of contributory mechanisms leading to death. Regular reanalysis of genetic data, combined with close collaboration between forensic pathologists, geneticists and clinicians, is essential to improve diagnostic yield and guide family management.

Intervertebral disk (IVD) degeneration is associated with lower back pain and aging; however, the mechanisms underlying age‐related changes and the changes in macrophage polarization in aging intervertebral disks require further elucidation. The aim of this study was to evaluate changes in macrophages, the differential expression of senescence genes, and their relationship with hub genes in IVDs during aging in mice.

Twenty‐eight male wild C57 mice aged 4 weeks were divided into two groups. Four mice per group were selected for high‐throughput sequencing and 10 for tail IVD immunohistochemical analysis. Adult and aged mouse IVD specimens were stained with hematoxylin–eosin, Fast Green, and Alcian Blue to determine collagen (Col) 1, Col2, proteoglycan, P16, P21, P53, CD11b, CD86, CD206, IL‐1, TGF‐β, and IL‐4 expression. High‐throughput sequencing was performed on adult and aged mouse IVD tissues.

Aged mouse IVDs showed reduced height and marked degeneration, with decreased Col2 and proteoglycan expression and increased Col1 expression. The expression of senescence markers, senescence‐associated IL‐1, TGF‐β, and IL‐4, and macrophage‐related markers, CD11b, CD86, and CD206, increased markedly with age. High‐throughput sequencing revealed 1975 differentially expressed genes in adult and aged mice, with 797 genes showing upregulated expression (top five: Kcna7, Mmp9, Panx3, Myl10, and Bglap) and 1178 showing downregulated expression (top five: Srd5a2, Slc38a5, Gm47283, Npy, and Pcdh8). Gene Ontology and pathway enrichment analyses highlighted aging‐related cellular components, biological processes, and metabolic pathways. The identified hub genes included Cox5a, Ndufs6, and Ndufb9.

Disk senescence and reduced height in aged mice are linked to upregulated expression of senescence‐associated phenotypes and macrophage polarization markers. These findings suggest that macrophages and differential gene expression play key roles in age‐related IVD degeneration, indicating that they can be used as potential targets for therapeutic intervention.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene–disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes.

Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3).

Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.