Submission Details

The USP27X gene encodes a deubiquitinase highly expressed in the brain. To date, three variants in USP27X have been published in two large exome sequencing studies of families with X-linked intellectual disability. In 2016, Hu et al. (PMID: 25644381) reported a frameshift variant in a multigenerational family with three affected males with borderline to moderate ID, variable absent or poor speech, and behavioral problems. They also reported a missense variant in a family with four affected males, but only one was genotyped. This variant was not scored as there is insufficient evidence to support its pathogenicity. In 2019, Sanchis-Juan et al. (PMID: 31316545) reported a different frameshift variant in two half-siblings with developmental delay and intellectual disability, as well as dysmorphic facial features in one individual.

ClinVar contains one record of a likely pathogenic nonsense variant related to a neurodevelopmental disorder (Variation ID: 1321965). In the absence of additional information about the phenotype and the presence of other pathogenic variants, this variant was not scored. Additionally, DECIPHER has a de novo missense variant in an individual with global developmental delay and mild intellectual disability who also carries a pathogenic frameshift variant in SHANK3, implicated in Phelan-McDermid syndrome (DECIPHER Patient ID: 482675). Therefore, the role of the variant in USP27X cannot be determined and was not scored. USP27X is constrained for both loss-of-function and missense variants (pLI 0.92 and missense Z score 3.18, gnomAD V2.1.1). No experimental evidence supporting this gene-disease relationship was identified. In summary, there is limited evidence at this time to support the relationship between USP27X and X-linked intellectual disability. Additional studies are required to verify this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 1, 2023 (SOP Version 9).