Submission Details

The relationship between variants in SHROOM4 and X-linked complex neurodevelopmental disorder was first suggested in 2006 when Hagens et al. reported 3 families with intellectual disability and variants involving SHROOM4 (PMID: 16249884). Two unrelated females were found to have balanced translocations disrupting SHROOM4; because other genes were involved and their roles in the phenotype cannot be ruled out, these cases were not used as evidence. The third family reported in Hagens et al. was a multigenerational pedigree with 4 males presenting with intellectual disability, bilateral congenital hip luxation, and short stature. As the family was originally described by Stocco dos Santos et al. in 1991, this presentation became known as “Stocco dos Santos X-linked Mental Retardation Syndrome”. The missense variant identified had no supportive functional evidence, and no additional testing was performed on this family to rule out other possible genetic etiologies. According to gnomAD (v2.1.1), SHROOM4 is not constrained for missense variation (Z score = 0.92). Given the lack of evidence supporting the role of this variant in this disease, the limited genetic investigation performed on this family, and the fact that no other plausible disease-causing variants in SHROOM4 have been reported, the ID/Autism GCEP decided not to score this variant. Additionally, because there are so few reports of individuals with possible disease-causing variants in this gene, it is unclear whether or not this represents a true, unique, syndromic presentation, and we have opted to curate this gene in relation to the more generic term X-linked complex neurodevelopmental disorder.

While other variants have been reported, these have been ruled out. A missense variant reported in a boy with intellectual disability, Rett-like features, and “autistic traits” (PMID: 26740508) was later found to have a high population frequency in gnomAD 2.1.1. Additionally, a nonsense variant in SHROOM4 reported in a proband with intellectual disability was also seen in his 2 unaffected brothers (PMID: 25167861). As of January 2021, these are the only single-gene variants in SHROOM4 reported in the literature. Microdeletions involving SHROOM4 have been reported, but they all affected other genes, and therefore were not used as supportive evidence. Knockdown of Shroom4 in the rat hippocampus leads to increased anxiety-like behavior, reduced sociability, and susceptibility to seizures; learning and memory were not assessed (PMID: