Rapid genome sequencing identifies a novel de novoSNAP25variant for neonatal congenital myasthenic syndrome

Congenital myasthenic syndrome (CMS) is a group of 32 disorders involving genetic dysfunction at the neuromuscular junction resulting in skeletal muscle weakness that worsens with physical activity. Precise diagnosis and molecular subtype identification are critical for treatment as medication for one subtype may exacerbate disease in another (Engel et al.,Lancet Neurol14: 420 [2015]; Finsterer,Orphanet J Rare Dis14: 57 [2019]; Prior and Ghosh,J Child Neurol36: 610 [2021]). TheSNAP25-related CMS subtype (congenital myasthenic syndrome 18, CMS18; MIM #616330) is a rare disorder characterized by muscle fatigability, delayed psychomotor development, and ataxia. Herein, we performed rapid whole-genome sequencing (rWGS) on a critically ill newborn leading to the discovery of an unreported pathogenic de novoSNAP25c.529C > T; p.Gln177Ter variant. In this report, we present a novel case of CMS18 with complex neonatal consequence. This discovery offers unique insight into the extent of phenotypic severity in CMS18, expands the reportedSNAP25variant phenotype, and paves a foundation for personalized management for CMS18.