Submission Details

TSPAN7 was initially reported in relation to X-linked intellectual disability in 2000 (PMID: 10655063). A female with mild intellectual disability was found to carry a balanced translocation [46,X,t(X;2)(p11.4;p21.3)] with a breakpoint within TSPAN7 that disrupted its expression. Though this case was not scored, it ultimately led to further investigation of this gene as a potential cause for X-linked intellectual disability (PMID: 10655063). One family with multiple affected males was found to have a nonsense variant. Another family was found to have a missense variant (NM_004615.3:c.515C>A, p.Pro172His); this variant was also reported in other manuscripts as being observed in individuals with intellectual disability or autism spectrum disorder (PMIDs: 14735593, 20479760). This variant was subsequently found to be observed at frequencies too high in the general population to be consistent with disease (205 total alleles across various populations in gnomAD v.2.1.1, including 66 hemizygotes), and was therefore not scored as evidence to support this gene disease relationship. Since the initial report, only two other frameshift variants have been reported: one in four affected males in a family with X-linked intellectual disability (PMID: 12070254), and the other in a male with intellectual disability (PMID: 26350204). Other articles reported individuals with intellectual disability or autism spectrum disorder with a partial duplication of TSPAN7 spanning exons 2-8 (PMID: 22511893, 19339915, 24768552, 25661985). This recurrent duplication is of uncertain significance and was therefore not scored. There is experimental evidence to support this gene-disease relationship, including functional alteration in hippocampal neurons (PMID:22445342) and a mouse model (PMID:28968657). In summary, there is moderate evidence supporting a relationship between TSPAN7 and X-linked intellectual disability. This curation was approved by the ClinGen ID/Autism GCEP on December 2, 2020 (SOP v8).