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FEZF2 has emerged as a candidate gene in intellectual disability (MONDO_0001071) based on its identification in multi‐patient genomic studies and functional assays. Genetic screening of a large cohort of individuals with intellectual disability revealed rare de novo and recessive variants in FEZF2, although detailed segregation data from extended families remains limited (PMID:27431290). The observed mode of inheritance aligns with an autosomal recessive pattern, which is consistent with the majority of pathogenic variants detected in the cohort. A representative reported variant, c.1266C>G (p.Cys422Trp), exemplifies the type of coding alteration implicated in the disorder. Functional studies further support FEZF2’s role in neurodevelopment by demonstrating that perturbations in its expression affect neural differentiation processes (PMID:34562292). Moreover, additional assessments have linked deleterious FEZF2 variants with broader neurodevelopmental phenotypes, including neurodevelopmental delay and autism, thereby indirectly reinforcing its involvement in intellectual disability (PMID:38425142). Despite this supportive evidence, the current case series provide only modest genetic replication and limited segregation data, leading to a cautious interpretation of the gene–disease relationship. Nevertheless, the combined genetic and functional findings underscore a preliminary yet clinically intriguing role for FEZF2 in intellectual disability, offering potential avenues for future diagnostic applications and research exploration.
Gene–Disease AssociationLimitedFEZF2 variants have been reported in individuals with intellectual disability; however, the evidence is limited by the low number of independent probands and minimal segregation data (PMID:27431290). Genetic EvidenceLimitedWhile rare de novo and recessive variants—including c.1266C>G (p.Cys422Trp)—were identified in ID cohorts, the overall genetic evidence is modest due to the sparse replication and segregation support (PMID:27431290). Functional EvidenceModerateFunctional assays demonstrate that alterations in FEZF2 can disrupt neural differentiation, and additional studies linking deleterious variants to neurodevelopmental phenotypes bolster its contributory role (PMID:34562292, PMID:38425142). |