Submission Details

SLC5A7: autosomal dominant CMT with vocal cord paresis, 09/28/2021

SLC5A7 encodes a presynaptic solute-carrier protein responsible for choline uptake from the synaptic cleft. In 2012, WES revealed a truncating variant in the last exon of SLC5A7 co-segregating in a large family (LOD score: 6.32) with distal motor neuropathy and vocal cord paresis (PMID: 23141292). The authors showed that choline uptake is significantly impaired, demonstrating a dominant negative effect on the wildtype allele. The same variant was recurrently reported again (PMID: 26786006), and so were three more truncating mutations all affecting the last exon of the gene in different populations. All of these changes were predicted to not undergo nonsense-mediated RNA decay (PMIDs: 29582019, 29782645). In addition, the described phenotype was very consistent as well, sparing the sensory system, but commonly involving vocal cord paresis. In parallel, SLC5A7 was first described in the context of autosomal recessive congenital myasthenic syndrome in 2016 (MIM: 617143). Based on the autosomal dominant mode of inheritance with the dominant negative effect, the panel agreed on splitting the neuropathy from the myasthenia phenotype for the present curation. Experimental evidence showed that SLC5A7 is expressed in the neuromuscular junction (PMID: 15173594) and that loss of function results in an impaired choline uptake (PMID: 23132865). An animal model demonstrated that heterozygous KO mice are more vulnerable to choline uptake inhibitors than wildtype animals (PMID: 15173594). In summary, truncating mutations in the last exon of SLC5A7 are linked to a specific molecular mechanism and associated with a distinct phenotype. More reports will solidify the gene-disease relationship in the future. Based on the curated evidence, we classify the gene-disease relationship of SLC5A7 and autosomal dominant motor neuropathy with vocal cord paresis as moderate.