RAPSN-Associated Congenital Myasthenic Syndrome due to Biallelic Single Nucleotide Variants at the Same Position

Biallelic pathogenic variants in RAPSN cause a form of congenital myasthenic syndrome (CMS), which is typically characterized by fatiguable muscle weakness, hypotonia, and feeding difficulties that present in the neonatal period or early childhood. RAPSN-associated CMS can be treated with acetylcholinesterase inhibitors. Here, we present a 4-year-old male with a history of neonatal respiratory distress, hypotonia, and muscle weakness exacerbated by illness who underwent trio genome sequencing and was found to have biallelic single nucleotide variants at the same position in RAPSN, encoding NM_005055.5:c.264C > A p.(N88K) and NM_005055.5:c.264C > G p.(N88K). The paternally inherited c.264C > G variant has not been previously reported. Interestingly, only the maternally inherited c.264C > A variant was reported on the patient's prior clinical exome sequencing, which delayed diagnosis and initiation of treatment for this patient. This case highlights the complexity of identifying multiallelic variants during exome and genome sequencing analysis. Additionally, this case is the first report of facial malformations in a patient with RAPSN-associated CMS due to variants outside of the promoter region. Trial Registration: ClinicalTrials.gov identifier: NCT02450851.