Submission Details

SH3TC2 was first reported in relation to autosomal recessive hereditary demyelinating motor and sensory neuropathy in 2003 (Senderek et al., PMID:14574644). It is mainly characterized by a sensory-motor demyelinating neuropathy with onset typically in childhood. Early-onset scoliosis is present in a large number of patients. SH3TC2 has been noted to be associated with the following disease entities: Charcot-Marie-Tooth disease, type 4C (OMIM: 601596) and Mononeuropathy of the median nerve, mild (OMIM: 613353). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern AND phenotypic variability. Therefore, the disease entities have been Split. About 80 variants have been reported, including missense and nonsense variants. The maximum score for genetics evidence has been reached (12 points). Evidence supporting the gene-disease relationship includes case-level variant evidence and experimental data. Hela cells transfected with SH3TC2 mutants fail to co-localize with RAB11 at recycling endosomes and co-immunoprecipitation assay confirmed loss of protein-protein interaction with RAB11 in the mutants. SH3TC2 mutants fail to induce membrane receptor internalization in transfected cells compared to wild-type (Gouttenoire et al., PMID: 23553667). Therefore, the mechanism for pathogenicity appears to be loss-of-function. A knockout mouse model for SH3TC2 developed progressive peripheral neuropathy, mimicking the human phenotype (Arnaud et a., PMID: 19805030). Nerve biopsy shows severe hypomyelination in the knockout mice. The mice phenotype was rescued with a lentivirus expressing the human SH3TC2 cDNA, which was delivered intrathecally (Schiza et al., PMID: 30907403). In summary, SH3TC2 is definitively associated with autosomal recessive hereditary demyelinating motor and sensory neuropathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.