A 30-year multicenter retrospective cohort of 321 pediatric hypertrophic cardiomyopathy (HCM) patients reveals that neonatal-onset cases — 75% of the infant cohort — carry a strikingly different genetic architecture than adult HCM. RASopathies (Noonan syndrome spectrum) were the dominant etiology at 41%, far outpacing sarcomeric mutations at just 8%, with mitochondrial/metabolic disorders comprising 18%. Overall 30-year survival reached 88%, but cardiovascular morbidity was substantial: 21% required cardiac surgery, 8% received ICDs, and survival free from ICD implantation fell to just 40% by age 15.
This dataset reframes neonatal HCM as fundamentally distinct from the sarcomere-driven disease familiar in adults and adolescents, where MYH7 and MYBPC3 mutations predominate. The RASopathy predominance has direct clinical implications — these patients require RAS-MAPK pathway-aware management and syndromic surveillance extending well beyond cardiology. The 31% gene-elusive fraction underscores how incomplete current genetic panels remain for this age group.
The practical takeaway for clinicians: first-week-of-life presentation is the strongest risk stratifier identified, demanding immediate multidisciplinary involvement. Limitations include retrospective design, multicenter heterogeneity in genotyping protocols across three decades, and small subgroup sizes that limit etiology-specific survival modeling. As a preprint posted on medRxiv and not yet peer-reviewed, these findings await independent validation before shaping formal guidelines. Still, this represents one of the largest long-term neonatal HCM datasets assembled and offers genuinely paradigm-shifting context for genetic counseling in this rare population.
