Phenotypic variations in carriers of predicted protein-truncating genetic variants in MYBPC3: an autopsy-based case series

Williams, Nori; Marion, Robert W.; McDonald, Thomas V.; Wang, Dawei; Zhou, Bo; Eng, Lucy S.; Um, Sung Yon; Ying, Lin; Ruiter, Kevin; Rojas, Lisa; Sampson, Barbara A.; Tang, Yingying

doi:10.1016/j.carpath.2018.09.001

Cited by 10 publications

(20 citation statements)

References 8 publications

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“…86 Postmortem genetic testing (the so-called molecular autopsy) is now scientifically feasible, although the financing of these studies is problematic. 87 –89 Blood or fresh tissue samples for DNA and RNA analysis are still preferable. But technological progress is making it increasingly feasible to perform genetic analyses on FFPET.…”

Section: Ongoing Risks and Opportunities For The Autopsymentioning

confidence: 99%

The Importance of the Autopsy in Medicine: Perspectives of Pathology Colleagues

et al. 2019

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This article presents a perspective on the importance of the autopsy in medical practice and science based on experiences of the authors as physician-scientists involved in autopsy practice. Our perspectives are presented on the seminal contributions of the autopsy in the areas of cardiovascular disease, including congenital heart disease, atherosclerosis, coronary artery disease, and myocardial infarction, and infectious disease, including tuberculosis and viral infections. On the positive side of the future of the autopsy, we discuss the tremendous opportunities for important research to be done by application of advanced molecular biological techniques to formalin-fixed, paraffin-embedded tissue blocks obtained at autopsy. We also note with concern the countervailing forces impacting the influence of pathology in education and clinical practice at our academic medical centers, which also present impediments to increasing autopsy rates. Our challenge as academic pathologists, whose careers have been molded by involvement in the autopsy, is to counter these trends. The challenges are great but the benefits for medicine and society are enormous.

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Section: Ongoing Risks and Opportunities For The Autopsymentioning

confidence: 99%

The Importance of the Autopsy in Medicine: Perspectives of Pathology Colleagues

et al. 2019

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“…Many reports considered sudden unknown deaths in which autopsy findings revealed a normal heart . Fewer studies have included hearts with cardiomyopathy phenotypes . Therefore, genetic evaluation often centered on arrhythmia genes, with limited phenotyping in the decedent or the family.…”

Section: Introductionmentioning

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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“…Williams et al conducted a postmortem analysis on two males with HOCM in whom heart weight was found to be 890 g and 980 g, respectively [ 16 ]. When converted into a ratio of heart weight to BMI, which is thought to be a strong predictor of heart weight, the ratios were 34.9 (890/25.5) and 23.6 (980/41.6) [ 16 ]. The latter ratio is comparable to the present donor’s ratio at 22.5 (510.1/22.7), suggesting that this case is consistent with prior reports.…”

Section: Discussionmentioning

confidence: 99%

A Cadaveric Evaluation of Hypertrophic Obstructive Cardiomyopathy

Murtha,

Dobson,

Olinger

2023

Cureus

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Hypertrophic obstructive cardiomyopathy (HOCM) describes a pathologic state in which the subaortic region of the interventricular septum undergoes significant hypertrophy and fibrosis, resulting in septal bowing into the left ventricle. The reduced left ventricular chamber size and altered cardiac function impair diastolic filling, stroke volume, and cardiac output. This case report evaluates the cardiac tissue of a 36-year-old, formalin-embalmed cadaver affected by HOCM, with the goal of providing a comprehensive overview of the gross and pathologic findings associated with the condition. This donor’s heart was found to be larger than average, weighing 510.1 g, which is 52% heavier than the predicted value of 335.6 g for a male of similar stature. The thickness of the interventricular septum, right ventricular free wall, and left ventricular free wall was comparable to other reports of HOCM. However, asymmetrical thickening of the left ventricular walls, which is characteristic of HOCM, was less prominent than expected. Histologic staining of the cadaveric tissue, with hematoxylin and eosin, trichrome, and desmin, further bolstered the diagnosis. Importantly, this also showed that histologic examination of embalmed tissue is effective and diagnostic, even 11 months after embalming. The report herein demonstrates that morphologic and histologic analysis of cadaveric cardiac tissue is sufficient to support a diagnosis of HOCM. To the researchers' knowledge, this is the first case report evaluating HOCM in a cadaver donated for medical education.

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Phenotypic variations in carriers of predicted protein-truncating genetic variants in MYBPC3: an autopsy-based case series

Cited by 10 publications

References 8 publications

The Importance of the Autopsy in Medicine: Perspectives of Pathology Colleagues

The Importance of the Autopsy in Medicine: Perspectives of Pathology Colleagues

Genomic Autopsy of Sudden Deaths in Young Individuals

A Cadaveric Evaluation of Hypertrophic Obstructive Cardiomyopathy

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