Frontiers in cardiovascular medicine · 2025
Case Report: Lethal neonatal hypertrophic cardiomyopathy from compound heterozygous MYBPC3 variants.
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Wang Jianying, Hong Lingye, Li Yao, Mao Zhengrong, Zhu Yuefeng, Qi Ming, Zhou Ren, Hong Xutao
Аннотация
INTRODUCTION: Bi-allelic pathogenic variants in MYBPC3 cause a rare and lethal neonatal form of hypertrophic cardiomyopathy (HCM) that often evades detection during routine prenatal screening. We report a comprehensive investigation of such a case to highlight the clinical utility of postmortem molecular diagnosis.
METHODS: A two-month-old infant died from sudden-onset acute heart failure. We performed a full forensic autopsy with detailed histological examination and conducted trio-based whole-exome sequencing (WES) on the proband and parents to identify the genetic etiology.
RESULTS: Postmortem examination revealed severe HCM, an atrial septal defect (ASD), and extensive myocardial necrosis and fibrosis. WES identified compound heterozygous pathogenic variants in MYBPC3: a known paternal splice-site variant (c.2905+1G>A) and a novel maternal truncating frameshift variant (c.836del; p.Gly279Valfs*21). Both variants are predicted to result in a complete loss of protein function.
DISCUSSION: This "molecular autopsy" established a definitive cause for the infant's death, linking a novel variant to a severe pathological phenotype. Crucially, the diagnosis guided the clinical management of the asymptomatic carrier parents, prompting long-term cardiac surveillance and enabling preimplantation genetic testing (PGT) for future family planning. This case demonstrates how integrating molecular diagnostics with forensic pathology facilitates a systems medicine approach, transforming a fatal index case into actionable preventive care for the entire family.
METHODS: A two-month-old infant died from sudden-onset acute heart failure. We performed a full forensic autopsy with detailed histological examination and conducted trio-based whole-exome sequencing (WES) on the proband and parents to identify the genetic etiology.
RESULTS: Postmortem examination revealed severe HCM, an atrial septal defect (ASD), and extensive myocardial necrosis and fibrosis. WES identified compound heterozygous pathogenic variants in MYBPC3: a known paternal splice-site variant (c.2905+1G>A) and a novel maternal truncating frameshift variant (c.836del; p.Gly279Valfs*21). Both variants are predicted to result in a complete loss of protein function.
DISCUSSION: This "molecular autopsy" established a definitive cause for the infant's death, linking a novel variant to a severe pathological phenotype. Crucially, the diagnosis guided the clinical management of the asymptomatic carrier parents, prompting long-term cardiac surveillance and enabling preimplantation genetic testing (PGT) for future family planning. This case demonstrates how integrating molecular diagnostics with forensic pathology facilitates a systems medicine approach, transforming a fatal index case into actionable preventive care for the entire family.