Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome

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Excerpt

The congenital myasthenic syndromes (CMSs) are a heterogeneous group of inherited diseases of the neuromuscular junction (NMJ), with fatigable muscle weakness as the clinical hallmark.1 Several molecular causes can be implicated in CMS pathophysiology, including mutations in genes encoding proteins associated with the muscle nicotinic acetylcholine receptor and the synaptic basal lamina, or (more rarely) involved in the NMJ presynaptic transmission.2
We describe 2 families from Kuwait and Israel where 2 of the siblings in each family presented clinical and neurophysiological features typical of a presynaptic CMS. Whole exome sequencing (WES) or whole genome sequencing (WGS) followed by Sanger sequencing unraveled either a homozygous frameshift or missense variants in VAMP1 segregating with the phenotype in the 2 families. Screening a cohort of 63 undiagnosed CMS individuals failed to show any further causative variant in VAMP1.

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