From weeks to hours: rapid whole-genome sequencing reduces diagnostic odyssey in Menke-Hennekam syndrome-a case report.

backgroundMenke-Hennekam syndrome (MKHK) is a rare autosomal dominant disorder caused by mutations in the CREBBP and EP300 genes. The absence of established diagnostic criteria and non-specific clinical manifestations complicate timely diagnosis and management. This report presents a case of MKHK in which early diagnosis and intervention were achieved through the application of rapid whole-genome sequencing (rWGS), a tool that offers superior speed and genomic coverage compared to whole-exome sequencing (WES). CASE PRESENTATION: This case report describes a male Han Chinese neonate who presented at birth (0 days) with intrauterine growth restriction, respiratory distress, and feeding difficulties. During follow-up, he developed hearing loss and demonstrated global developmental delay. Clinical examination revealed craniofacial dysmorphism. Trio rWGS was performed in the neonatal period, with results returned within 72 h of sample submission at 23 days of age. Trio rWGS identified a de novo missense variant in the CREBBP gene (c.5570A > C, p.His1857Pro). Sanger sequencing confirmed its absence in both parents, and the variant was classified as likely pathogenic despite no prior documented cases. Based on integrated genetic and clinical findings, a neonatal diagnosis of MKHK-ID4 was established. Following this diagnosis, early targeted interventions were initiated, including hearing aid fitting, enrollment in a comprehensive rehabilitation program, and planning for necessary surgical corrections. Significant developmental improvement was observed at the 15-month follow-up assessment.

conclusionIn this case, rWGS facilitated a neonatal diagnosis of MKHK-ID4 and enabled early multidisciplinary intervention during a critical neurodevelopmental window. This experience suggests that such an approach may contribute to improved developmental outcomes in this rare disorder, though further studies are required to confirm its broader applicability and long-term benefits.