Case Report: Lethal Neonatal Hypertrophic Cardiomyopathy from Compound Heterozygous MYBPC3 Variants

Jianying Wang¹Lingye Hong²Yao Li¹Zhengrong Mao¹Yuefeng Zhu³Ming Qi³REN ZHOU³Xutao Hong^3*

• ¹Zhejiang University, Hangzhou, China
• ²Wenzhou Medical University, Wenzhou, China
• ³Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China

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.