Webster G, Puckelwartz MJ, Pesce LL, Dellefave-Castillo LM, Vanoye CG, Potet F, Page P, Kearns SD, Pottinger T, White S, Arunkumar P, Olson R, Kofman A, Ibrahim N, Ing A, Brew C, Yap KL, Kadri S, George AL Jr, McNally EM. JAMA Cardiol. 2021 Nov 1;6(11):1247-1256. doi: 10.1001/jamacardio.2021.2789. PMID: 34379075
Take Home Points:
- Whole genome sequencing effectively identified P/LP variants in cases of sudden death in young individuals, implicating both arrhythmia and cardiomyopathy genes.
- Genomic analyses and familial phenotype association suggest potentially additive, oligogenic risk mechanisms for sudden death in this cohort.
- In multivariate analysis, rare variants in cardiac genes (pathogenic/likely pathogenic/uncertain significance) were associated with younger age at death, and with potentially additive effect.
Commentary from Dr. Manoj Gupta (New York City, NY, USA), chief section editor of Pediatric & Fetal Cardiology Journal Watch.
Postmortem genetic testing discovers pathogenic or likely pathogenic (P/LP) variants in genes affecting heart rhythm and function among 10% to 25% of people who have sudden unexplained death (SUD) before age 40 years. Family screening for P/LP monogenic variants can identify and reduce risk in relatives. The authors considered a model associating rare variants in a small number of genes with phenotypes (an oligogenic approach).
A prospective study. Recruited from May 2015 to March 2019. Decedents aged between 1 and 45 years at death were included.
Genomic Analysis: Whole-genome sequencing was completed and analyzed. We constructed a consensus arrhythmia and cardiomyopathy gene panel.
In total, 103 individuals with sudden death were included for analysis. The mean (SD) age at death was 23.7 (11.9) years, and 33 individuals (32%) were 18 years or younger (Table 1). Most decedents were male (77 of 103 [75%]). Activity at time of death included sleep (42 [41%]), awake but at rest (27 [26%]), strenuous activity (15 [15%]), light activity (11 [11%]), and other or not documented (8 [8%]). A heart weight exceeding the 95% of normal for height, weight, age, and sex (cardiomegaly)30 was present in 21 of 103 decedents (20%). Cardiomegaly was present in 8 of 10 decedents with hypertrophic cardiomyopathy, 2 of 6 with dilated cardiomyopathy, and 2 of 10 with arrhythmogenic ventricular cardiomyopathy. Isolated cardiomegaly was present in 4 of 23 decedents (17%) with an FUS and in 1 with SUD (1 of 44 [2%]).
Abbreviations: FUS, findings of uncertain significance; NA, not applicable; SUD, sudden unexplained death. Hispanic and Asian decedents were clustered along the Euro-Asian line of the genetic principal component analysis
P/LP Genetic Variants:
We assembled a cardiac panel of 118 genes implicated in inherited cardiomyopathy and arrhythmia conditions. Using this cardiac panel, we identified P/LP variants in 13 of 103 decedents (12.6%). A P/LP variant was present in 6 of 36 decedents (17%) with a postmortem clinical diagnosis, 2 of 23 (9%) with an FUS, and 5 of 44 (11%) classified as SUD. P/LP variants were distributed uniformly across the ages in this cohort.
VUS in Cardiac Genes
For initial VUS analysis, we considered the 118 genes on the cardiac panel. We identified 292 variants from 80 of these genes. At least 1 P/LP/VUS variant was present in 93 of 103 individuals (90%), with a mean (SD) of 3.0 (1.7) variants per decedent. We identified 205 VUSs among 89 decedents (86%; mean [SD], 2.3 [1.4] VUS per decedent). Almost all variants were heterozygous (204 of 205 [99.5%]). There was 1 hemizygous variant in DMD.
We identified 41 rare variants of interest in 30 preliminary evidence genes, present within 32 of 103 decedents (31.1%) (e-Table 2)
Transmitted P/LP Variants Associated with a Range of Clinical Findings
We obtained DNA from 31 parent-decedent trios and 14 parent decedent dyads. From these data, 9 P/LP variants were captured; 8 were inherited and 1 was de novo.
Genotype-Phenotype Analysis Suggests Oligogenic Risks:
P/LP genotypes did not fully predict phenotype; therefore, we assessed genetic features across all decedents that may promote risk of death, as manifested by an association between variant burden and age at death. For this analysis, we examined all P/LP/VUS variants in the 118 gene cardiac panel and the 41 rare variants of interest in 30 preliminary evidence genes. We found that having more variants was associated with a younger age at death. For decedents older than 2 years at death, a younger age was associated with a greater number of rare cardiac variants.
Multiple Genetic Variants May Contribute to Sudden Death Risk:
We identified a quantitative association between risk of sudden death and a multiple-gene model of cardiac disease, in which each variant provides a small contribution to sudden cardiac death risk (an oligogenic approach).
In current practice, P/LP variants are clinically actionable and VUSs are not. The demonstration of oligogenic effects does not elevate any individual VUS to a clinically actionable status. However, the refinement of oligogenic models may complement the efforts of ClinGen and others to adjudicate highly penetrant cardio-rhythm gene variants, leading to improved classification and improved clinical care.
Both genotype and phenotype analyses implicated additional, oligogenic risk factors in sudden death in young individuals.