STEEP1 and Intellectual Disability

This summary compiles evidence linking STEEP1 (HGNC:26239) to intellectual disability (MONDO_0001071). Multiple independent studies have identified rare, likely loss‑of‑function variants in STEEP1 that segregate with the phenotype in families with an X‑linked pattern of inheritance (PMID:29374277, PMID:31822863).

Clinical findings include a three‑generation family with five affected males and one affected female, along with additional unrelated cases that reinforce a consistent pattern of intellectual disability and neurological abnormalities. The observation of skewed X‑inactivation in unaffected carrier females further supports the X‑linked contribution of STEEP1 variants to the disorder (PMID:29374277).

Genetic evidence is robust, with reported mutations such as c.593G>A (p.Arg198Gln) contributing to the variant spectrum. In total, three distinct STEEP1 mutations have been documented, and the presence of these variants in affected individuals from different families underscores a strong gene‑disease association. The reported variants primarily include missense and frameshift changes that are concordant with a loss‑of‑function mechanism (PMID:29374277, PMID:31822863).

Functional studies, although limited in scope, indicate that these variants result in nonsense‑mediated decay and reduced STEEP1 mRNA expression in patients. The experimental data support a haploinsufficiency model where decreased protein levels disrupt normal neuronal development and function, contributing to the intellectual disability phenotype.

No significant conflicting evidence has been reported; while some studies have included deletions affecting multiple genes, the segregation analysis and consistent phenotype across cases strongly implicate STEEP1. Further research may expand on these findings and delineate additional aspects of the molecular pathology.

In summary, the collective clinical, genetic, and preliminary functional data provide strong evidence for the role of STEEP1 in intellectual disability. This association is of clinical utility for diagnostic decision‑making and suggests that STEEP1 should be considered in molecular testing panels aimed at X‑linked intellectual disability.

References

• European journal of human genetics : EJHG • 2018 • CXorf56, a dendritic neuronal protein, identified as a new candidate gene for X‑linked intellectual disability PMID:29374277
• European journal of human genetics : EJHG • 2020 • Novel clinical and genetic insight into CXorf56-associated intellectual disability PMID:31822863

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