New recessive mutations in causing severe presynaptic congenital myasthenic syndromes.

Objective: To report the identification of 2 new homozygous recessive mutations in the synaptotagmin 2 () gene as the genetic cause of severe and early presynaptic forms of congenital myasthenic syndromes (CMSs).

Methods: Next-generation sequencing identified new homozygous intronic and frameshift mutations in the gene as a likely cause of presynaptic CMS. We describe the clinical and electromyographic patient phenotypes, perform ex vivo splicing analyses to characterize the effect of the intronic mutation on exon splicing, and analyze the functional impact of this variation at the neuromuscular junction (NMJ).