ZC4H2 was first reported in relation to X-linked syndromic intellectual disability in 2013 (Hirata et al., PMID: 23623388). ZC4H2-associated disorders include Wieacker-Wolff syndrome and Miles-Carpenter syndrome. Individuals with ZC4H2 variants present with developmental delay, intellectual disability, arthrogryposis multiplex congenita, hypo-/akinesia, facial dysmorphism, and skeletal abnormalities (Frints et al., 2019, PMID: 31206972).
Variants in this gene have been reported in at least 33 probands in 3 publications (PMIDs: 23623388, 26056227, 31206972). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Variants in affected males are mostly inherited missense and are likely hypomorphic alleles, whereas female patients have de novo loss-of-function variants, which are likely lethal in males (PMID: 31206972). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by phenotype characterization and rescue experiments in a zebrafish model.
In summary, there is definitive evidence supporting the relationship between ZC4H2 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 classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 7, 2020 (SOP Version 7).
Variants in ZC4H2 were first reported in relation to X-linked syndromic intellectual disability as early as 2013 (Hirata et al., PMID: 23623388). ZC4H2-associated disorders include Wieacker-Wolff syndrome and Miles-Carpenter syndrome. Individuals with ZC4H2 variants present with developmental delay, intellectual disability, arthrogryposis multiplex congenita, hypo-/akinesia, facial dysmorphism, and skeletal abnormalities (Frints et al., 2019, PMID: 31206972). Numerous unique variants in ZC4H2 have been reported in humans. Of note, variants in affected males are mostly inherited missense and are likely hypomorphic alleles, whereas female patients have de novo loss-of-function variants, which are likely lethal in males (Frints et al., PMID: 31206972). The mechanism for disease is haploinsufficiency. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 33 probands in 3 publications (PMIDs: 23623388, 26056227, 31206972). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is further supported by phenotype characterization and rescue experiments in a zebrafish model (2 points). In summary, In summary, there is definitive evidence to support the association between ZC4H2 and X-linked syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 10/20/2020 (SOP Version 7).
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