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

Abstract

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 (Finsterer 2019; Prior et al. 2021; Engel et al. 2015). The SNAP25-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 novo SNAP25 c.529C>T; p.Gln177Ter variant. In this report, we present a novel case of CMS18 related to a variant affecting both SNAP25A and SNAP25B isoforms with complex neonatal consequence. This discovery offers unique insight into the extent of phenotypic severity in CMS18, expands the reported SNAP25 variant phenotype and paves a foundation for personalized management for CMS18.

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

“…Autosomal dominant inheritance or hemiallelic pathogenic variants are observed in SCCMS, SNAP25 -CMS [ 15 , 54 ], PURA -CMS [ 55 ], and some [ 9 , 56 , 57 ] but not the other [ 58 , 59 , 60 ] patients of SYT2 -CMS. In contrast, other groups of CMS show autosomal recessive inheritance or require pathogenic loss-of-function variants in two alleles.…”

“…Some patients with SYT2 -CMS [ 9 , 56 , 57 , 60 ] and all the two patients with SNAP25 -CMS [ 15 , 54 ] are caused by hemiallelic pathogenic variants, whereas the other LEMS-like CMS requires biallelic pathogenic variants.…”

“…SNAP25 -CMS was reported in a single patient in 2014 [ 15 ] and another in 2022 [ 54 ]. Both were caused by hemiallelic pathogenic variants.…”

“…In a case in 2014, low-frequency RNS caused a decremental CMAP, but high-frequency RNS was not performed [ 15 ]. In a case in 2022, no RNS studies were performed [ 54 ]. ChEI was ineffective, but amifampridine was effective [ 15 ].…”

“…ChEI was ineffective, but amifampridine was effective [ 15 ]. A case in 2022 died at age 6 days due to respiratory distress [ 54 ].…”