SHROOM4

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

The relationship between *SHROOM4* and X-linked complex neurodevelopmental disorder has been evaluated by ClinGen three times: an initial curation in 2019, a re-evaluation in 2021, and a subsequent review in 2026. Across these reviews, the evidence has remained insufficient to establish a gene-disease relationship. The relationship was first proposed in 2006 by Hagens et al. (PMID: 16249884), who reported three families with intellectual disability and variants involving *SHROOM4*. Two cases involved balanced translocations affecting multiple genes and were not considered informative. The third was a multigenerational family with intellectual disability, bilateral congenital hip luxation, and short stature, previously described as "Stocco dos Santos X-linked Mental Retardation Syndrome." Although a *SHROOM4* missense variant was identified, it lacked functional support, no additional genetic testing was performed to exclude alternate etiologies, and *SHROOM4* is not constrained for missense variation in gnomAD (v4.1; Z = 1.86). Therefore, this variant was not scored. Additional reported variants have also failed to provide convincing support. A missense variant associated with intellectual disability, Rett-like features, and autistic traits (PMID: 26740508) was later found to occur at a relatively high frequency in gnomAD. A nonsense variant reported in an individual with intellectual disability was also present in two unaffected brothers (PMID: 25167861). Reported microdeletions involving *SHROOM4* affected additional genes and were not considered supportive evidence. The 2026 review, prompted by a report of an individual with a *SHROOM4* variant and spastic cerebral palsy with intellectual disability (PMID: 42632887), also considered several publications that had appeared since the 2021 review (PMIDs: 35663265, 35937050, 36379543, 40642607). Both the ID/Autism and Cerebral Palsy GCEPs concluded that these new data did not change the Disputed classification. Most newly reported variants were missense changes without functional evidence, putative loss-of-function variants have been observed in both affected and unaffected individuals, several variants are present in gnomAD, and reported phenotypes are highly variable, including cerebral palsy, epilepsy, infantile spasms, and VACTERL-like anomalies with or without neurodevelopmental involvement. Although *Shroom4* knockdown in rat hippocampus results in increased anxiety-like behavior, reduced sociability, and seizure susceptibility (PMID: 28262662), this model was not scored because of the lack of convincing human genetic evidence. In summary, this gene-disease relationship has been reviewed three times by ClinGen expert panels: initially in December 2019, re-evaluated in January 2021, and reviewed again in 2026. The 2019 curation received a Limited classification, but application of updated scoring practices during the 2021 review resulted in reclassification to Disputed. Following review of additional publications in 2026, both the ID/Autism and Cerebral Palsy GCEPs concluded that the available evidence remains insufficient to support a causal relationship between *SHROOM4* and X-linked complex neurodevelopmental disorder, and the classification remains Disputed.

Inheritance Pattern: XL

Disease ID:MONDO:0010325

Submitter: Orphanet

Inheritance Pattern: XL

Disease ID:MONDO:0005579

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0010325

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0019719

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0100038

Submitter: Ambry Genetics