Findings show that NaV1.5_p.Leu96Pro causes severe loss of sodium channel function and support the value of combining molecular autopsy, family evaluation, and functional studies for variant interpretation in SUD.
Abstract
Molecular autopsy can identify candidate variants in unexplained sudden cardiac death (SUD), but functional evidence is often required to support pathogenic interpretation and family risk assessment. Here, we investigated the functional consequences of the SCN5A c.287 T > C (NaV1.5_p.Leu96Pro) variant, identified in a 29-year-old man who died of SUD. Cascade screening identified additional relatives carrying the variant, with variable clinical expression. Sodium current (INa) was analyzed in heterologously transfected human embryonic kidney (HEK) tsA201 cells and in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from two variant carriers and two non-carrier relatives. SCN5A transcript levels, NaV1.5 membrane expression, and additional arrhythmia-associated genetic variation were also assessed. In HEK tsA201 cells, NaV1.5_p.Leu96Pro produced no measurable INa when expressed alone, whereas co-expression with wild-type SCN5A caused an approximately 50% reduction in peak INa density. Cell-surface biotinylation showed preserved total and membrane NaV1.5 expression, indicating that loss of current was not explained by impaired trafficking. hiPSC-CMs from both carriers showed reduced INa density compared with non-carrier relatives, despite no reduction in SCN5A transcript levels. Targeted sequencing did not identify variants explaining the differences between the two hiPSC-CM carriers, but revealed an additional SCN5A splice-site deletion in family members with more severe clinical manifestations. These findings show that NaV1.5_p.Leu96Pro causes severe loss of sodium channel function and support the value of combining molecular autopsy, family evaluation, and functional studies for variant interpretation in SUD.
The first functional characterization of the cardiomyopathy-associated SMYD1 N101S variant identified in a child with severe infantile cardiomyopathy is provided, establishing a mechanistic link between SMYD1 dysfunction and infantile cardiomyopathy and highlighting the importance of integrating genomic and functional approaches in rare cardiovascular disease.
Marta W. Szulik, Clint Gwynn, Magnus Creed et al.· bioRxiv· 0 citations
Background Genetic evaluation has become a routine component of clinical practice for dilated cardiomyopathy (DCM). However, a substantial proportion of test results return as variants of uncertain significance (VUS), posing considerable challenges for clinical decision-making and genetic counseling. The MYH6 gene encodes the cardiac α-myosin heavy chain, and although its association with DCM has been established, related case reports remain scarce, and the genotype–phenotype correlation is poorly defined. Case report We report a 41-year-old Han Chinese male carrying a heterozygous MYH6 variant (c.2894A > C, p.K965 T), classified as VUS in ClinVar, who presented with a progressive DCM phenotype. Despite 13 years of guideline-directed medical therapy, the patient demonstrated relentless left ventricular enlargement (left ventricular end-diastolic diameter increasing from 71 mm to 98 mm), persistent severe systolic dysfunction (left ventricular ejection fraction consistently ≤17%), and suffered an out-of-hospital cardiac arrest in the 12th year of his disease course. Cardiac magnetic resonance (CMR) revealed extensive transmural septal fibrosis. Sanger sequencing of family members showed that his healthy mother carried the identical variant, whereas his affected father and elder brother did not, forming a classic “genotype–phenotype non-segregation” paradox. Following the cardiac arrest, the patient received a cardiac resynchronization therapy defibrillator (CRT-D), but exhibited no left ventricular reverse remodeling at 12 months post-implantation and is currently undergoing pre-transplant evaluation for heart transplantation. Conclusion This case suggests that a MYH6 VUS may be associated with a severe and rapidly progressive DCM phenotype in specific clinical contexts. However, the non-segregation within the family implies that this variant may act merely as a disease modifier or may require synergistic genetic or environmental co-factors to manifest pathogenicity. Long-term multimodality imaging follow-up and assessment of device therapy response are critical for individualized management of VUS carriers.
Jing-Wen Deng, Xiaoting Li, Taihao Wang et al.· Frontiers in Cardiovascular...· 0 citations
A Chinese pediatric patient with epilepsy and congenital heart disease who carries a novel CACNA1E variant that lies in a highly conserved and intolerant region provides a potential treatment clue for ACTH responsiveness in CACNA1E-related spasms.
Juan Pan, Mei-Fang Zhao, Zhaochuan Liu et al.· Frontiers in Medicine· 0 citations
Sudden unexplained nocturnal death syndrome (SUNDS), a subtype of sudden unexplained death, predominantly affects young, otherwise healthy individuals, with a higher prevalence in males and a geographic concentration in Southeast Asia, particularly Thailand. Despite extensive investigation, the genetic basis of SUNDS remains incompletely understood. Sarcomeric and non-sarcomeric gene variants were investigated in 98 SUNDS cases using whole-exome sequencing (WES). Postmortem cardiac examination and molecular modeling were performed to assess myocardial abnormalities and the structural impact of selected sarcomeric variants. Eleven missense variants in five sarcomeric genes (MYBPC3, MYH7, TNNI3, TNNT2, and TPM1) were identified in 12 cases (12.2%), whereas 37 variants across 18 non-sarcomeric genes were detected in 29 cases (29.6%). The MYH7 variant c.1562T>C (p.Ile521Thr) was identified as likely pathogenic. Cardiac histopathology revealed heterogeneous myocardial remodeling, including myocyte hypertrophy and interstitial fibrosis; some MYH7 variant carriers showed increased left ventricular wall thickness (>1.5 cm). Molecular modeling of the TPM1 variant c.641A>G (p.Tyr214Cys), located in the hinge region of the tropomyosin-troponin regulatory complex, suggested disruption of a native π-π stacking interaction, potentially affecting thin-filament stability. Sarcomeric variants were associated with heterogeneous myocardial remodeling in SUNDS. These findings highlight the genetic and pathological heterogeneity of SUNDS and suggest that sarcomeric gene variants represent a previously underrecognized contributor to myocardial remodeling and arrhythmogenic risk.
Aummarin Chaloemthanetphong, B. Nutho, Rachtipan Pitiwararom et al.· Journal of Molecular Diagnos...· 0 citations
Cardiomyopathies are a leading cause of heart failure, arrhythmia and sudden cardiac death, yet patients sharing a diagnosis, and even a causal variant, follow markedly different clinical courses. This thesis argues that disease expression depends on the biological context in which genetic susceptibility acts, and that studying this requires experimental models containing the relevant context. Each chapter adds a layer.
The starting point is genetic. Among nearly 470,000 UK Biobank participants, carriers of TNNT2 p.Arg288Cys showed no excess hypertrophic cardiomyopathy after correction for multiple testing and cumulative penetrance below 1% by age 80, while displaying subtle functional differences on cardiac MRI. Dutch probands presented with more severe disease, consistent with ascertainment bias and enrichment for modifiers. The variant is therefore intermediate in effect, insufficient alone but capable of contributing in a permissive context. The question shifts from whether a variant is pathogenic to under which conditions it becomes so.
Cellular identity is the first layer. Endothelial and smooth muscle cells from nine canine macrovessels retained location-associated transcriptional programmes through at least three passages, with embryonic positional transcription factors providing the strongest discrimination. An epigenetic mechanism is plausible. Cell source is thus a design decision rather than a practical detail.
Local tissue context was added in a fibrin-based co-culture, where endothelial cells self-assembled into lumenised networks alongside hiPSC-derived cardiomyocytes and remained stable for at least three weeks in a commercially available microfluidic device. The positional identity findings simultaneously define its main limitation, since umbilical vein endothelial cells were used.
Environmental context was introduced as lipid overload in an isogenic MYH7 p.Arg403Leu pair. A model providing context is of limited value if the readout averages that context away. Across 44,403 single-cell measurements of calcium handling and contraction, within-well variability accounted for 76 to 96% of total variance, and clustering identified a lipid-enriched subpopulation invisible in well averages. Model complexity and measurement resolution are two sides of the same problem.
Some layers cannot be engineered. Lifelong exposure, genetic diversity and spontaneous progression are inherent to naturally occurring disease in companion animals. Canine dilated cardiomyopathy returns genetic susceptibility to the foreground with full context attached, with breed-level uniformity supporting bidirectional discovery. In 37 cats with hypertrophic cardiomyopathy, digital pathology combined with Nanopore sequencing revealed structure only after outcome-based reclassification, distinguishing arterial thromboembolism from congestive heart failure.
The same morphometric approach across 46 vertebrate species established a physiological reference frame, since a tenfold increase in body mass corresponded to roughly 8% greater cardiomyocyte diameter and no species approached dimensions reported in hypertrophic cardiomyopathy.
The contribution is both methodological, favouring continuous measurement analysed with models matched to nested data structures, and conceptual, in showing that genetic findings acquire meaning only within their spatial, metabolic and species-specific context. No single model suffices, but complementary models each supply a different layer.
Cardiomyopathies in children associate with significant morbidity and mortality. PPA2 deficiency is a rare mitochondrial disorder linked to sudden cardiac death in children and adolescents. Most reported cases are post-mortem, with limited data on surviving individuals. To expand the phenotypic understanding of
PPA2
-related disease, we describe the cardiac features of nine previously unreported homozygous carriers of the
PPA2
c.380G > T, p.(Arg127Leu) variant.
This study included 23 individuals (22 living, one deceased) from a large Finnish family. All participants underwent genetic testing. Twenty individuals were interviewed by telephone, 16 underwent cardiac evaluation, and hospital records were reviewed for six participants.
Nine individuals homozygous for the
PPA2
p.(Arg127Leu) variant were identified. Two 15-year-old males experienced severe cardiac events following alcohol exposure: one suffered sudden cardiac death, while the other developed fulminant myocarditis. In the deceased male, a recent respiratory infection also preceded the fatal event. The remaining seven homozygotes, aged 24 to 81 years, reported no cardiac symptoms, had limited alcohol exposure restricted to communion, and showed no pathological findings on cardiac evaluation. No participants displayed neurological symptoms attributable to
PPA2
-related disease. All 14 heterozygous carriers were asymptomatic.
PPA2 deficiency represents a rare but potentially fatal cause of sudden cardiac death or fulminant myocarditis, particularly in the setting of alcohol exposure. Our findings indicate that individuals homozygous for the
PPA2
c.380G > T, p.(Arg127Leu) variant may remain asymptomatic into adulthood.
K. Heliö, Aurelia Ahokas, Sonja Sulkava et al.· Orphanet Journal of Rare Dis...· 0 citations
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