Prevalence of Abnormal Heart Weight After Sudden Death in People Younger than 40 Years of Age

Schoppen, Zachary J.; Balmert, Lauren C.; White, Steven M.; Olson, Rachael; Arunkumar, Ponni; Dellefave‐Castillo, Lisa; Puckelwartz, Megan J.; George, Alfred L.; McNally, Elizabeth M.; Webster, Gregory

doi:10.1161/jaha.120.015699

Cited by 9 publications

(8 citation statements)

References 36 publications

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“…A heart weight exceeding the 95% of normal for height, weight, age, and sex (cardiomegaly) 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.…”

Section: Resultsmentioning

confidence: 99%

Genomic Autopsy of Sudden Deaths in Young Individuals

et al. 2021

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IMPORTANCEPostmortem genetic testing of young individuals with sudden death has previously identified pathogenic gene variants. However, prior studies primarily considered highly penetrant monogenic variants, often without detailed decedent and family clinical information.OBJECTIVE To assess genotype and phenotype risk in a diverse cohort of young decedents with sudden death and their families.DESIGN, SETTING, AND PARTICIPANTS Pathological and whole-genome sequence analysis was conducted in a cohort referred from a national network of medical examiners. Cases were accrued prospectively from May 2015 to March 2019 across 24 US states. Analysis began September 2016 and ended November 2020.EXPOSURES Evaluation of autopsy and clinical data integrated with whole-genome sequence data and family member evaluation.RESULTS A total of 103 decedents (mean [SD] age at death, 23.7 [11.9] years; age range, 1-44 years), their surviving family members, and 140 sex-and genetic ancestry-matched controls were analyzed. Among 103 decedents, autopsy and clinical data review categorized 36 decedents with postmortem diagnoses, 23 decedents with findings of uncertain significance, and 44 with sudden unexplained death. Pathogenic/likely pathogenic (P/LP) genetic variants in arrhythmia or cardiomyopathy genes were identified in 13 decedents (12.6%). A multivariable analysis including decedent phenotype, ancestry, and sex demonstrated that younger decedents had a higher burden of P/LP variants and select variants of uncertain significance (effect size, −1.64; P = .001). These select, curated variants of uncertain significance in cardiac genes were more common in decedents than controls (83 of 103 decedents [86%] vs 100 of 140 controls [71%]; P = .005), and decedents harbored more rare cardiac variants than controls (2.3 variants per individual vs 1.8 in controls; P = .006). Genetic testing of 31 parent-decedent trios and 14 parent-decedent dyads revealed 8 transmitted P/LP variants and 1 de novo P/LP variant. Incomplete penetrance was present in 6 of 8 parents who transmitted a P/LP variant.CONCLUSIONS AND RELEVANCE 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.

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Section: Resultsmentioning

confidence: 99%

Genomic Autopsy of Sudden Deaths in Young Individuals

et al. 2021

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“…At autopsy, the heart weighed 90.7 g (upper 95% of normal for age: 45 g) (Schoppen et al, 2020). Grossly, the heart was globoid, with LV hypertrophy (Figure 1(d)).…”

Section: Diagnostic Assessmentmentioning

confidence: 99%

“…Shortly after arrival, he became bradycardic and then developed coarse ventricular fibrillation (VF, Online Supplement, Figure S1). The At autopsy, the heart weighed 90.7 g (upper 95% of normal for age: 45 g) (Schoppen et al, 2020). Grossly, the heart was globoid, with LV hypertrophy (Figure 1…”

Section: Casementioning

confidence: 99%

“…The heart weighed 50 g at autopsy (upper 95% of normal for age: 47 g) (Schoppen et al, 2020). Grossly, there was concentric LV hypertrophy (Figure 1(g)) with a LV wall thickness of 1.1 cm (expected for age: 0.59 cm, SD 0.15 cm) (Schulz et al, 1962).…”

Section: Casementioning

confidence: 99%

“…Whole genome sequencing (WGS) was performed as detailed in the Online Supplement. 4 | DIAGNOSTIC ASSESSMENT 4.1 | Autopsy phenotype 4.1.1 | Case 1At autopsy, the heart weighed 90.7 g (upper 95% of normal for age: 45 g)(Schoppen et al, 2020). Grossly, the heart was globoid, with LV hypertrophy (Figure1(d)).…”

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Mitochondrial cardiomyopathy and ventricular arrhythmias associated with biallelic variants in C1QBP

Webster

Reynolds

Arva

et al. 2021

American J of Med Genetics Pt A

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Patients with biallelic mutations in the nuclear-encoded mitochondrial gene C1QBP/ p32 have been described with syndromic features and autosomal recessive cardiomyopathy. We describe the clinical course in two siblings who developed cardiomyopathy and ventricular fibrillation in infancy. We provide genomic analysis and clinicalpathologic correlation. Both siblings had profound cardiac failure with ventricular arrhythmia. One child died suddenly. The second sibling survived resuscitation but required extracorporeal cardiopulmonary support and died shortly afterward. On cardiac autopsy, the left ventricle was hypertrophied in both children. Histological examination revealed prominent cardiomyocyte cytoplasmic clearing, and electron microscopy confirmed abnormal mitochondrial structure within cardiomyocytes. DNA sequencing revealed compound heterozygous variants in C1QBP (p.Thr40Asnfs*45 and p.Phe204Leu) in both children. Family segregation analysis demonstrated each variant was inherited from an unaffected, heterozygous parent. Inherited loss of C1QBP/p32 is associated with recessive cardiomyopathy, ventricular fibrillation, and sudden death in early life. Ultrastructural mitochondrial evaluation in the second child was similar to findings in engineered C1qbp-deficient mice. Rapid trio analysis can define rare biallelic variants in genes that may be implicated in sudden death and facilitate medical management and family planning. (184/200).

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