Case Report: Lethal neonatal hypertrophic cardiomyopathy from compound heterozygous MYBPC3 variants

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.

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.

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.

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.