The KDM5C gene has been associated with X-linked syndromic intellectual disability using the ClinGen Clinical Validity Framework as of 9/17/2018. This association was made using case-level and experimental data. At least 9 variants (missense, frameshift, splice-site variants) have been reported in humans. KDM5C was first associated with this disease in humans as early as 2005 (Jensen et al.). Association is seen in at least 9 probands in 2 publications (PMID:15586325,18697827). Variants in this gene segregated with disease in 30 additional family members. More evidence is available in the literature. The mechanism for disease is loss of function. This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. In summary, KDM5C is definitively associated with X-linked syndromic intellectual disability. This curation was approved by the Autism and Intellectual Disability Gene Curation Expert Panel on September 28, 2018.
KDM5C was first reported in relation to X-linked syndromic intellectual disability in 2005 (Jensen et al., PMID: 15586325). Six variants (nonsense, frameshift, splice, missense) that have been reported in six probands in two publications (PMIDs: 15586325, 18697827) are included in this curation. Variants in this gene segregated with disease in 30 additional family members. More evidence is available in the literature. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by animal models and in vitro functional assays.
In summary, there is definitive evidence supporting the relationship between KDM5C and X-linked syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 19, 2018 (SOP Version 6).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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