The AFF2 gene encodes a protein involved in transcriptional regulation and alternative splicing. AFF2 was first reported in relation to X-linked non-syndromic intellectual disability in 1996 (Gecz et al., PMID: 8673085). AFF2, previously referred to as FMR2, is associated with the folate-sensitive fragile X E (FRAXE) locus on chromosome Xq28. FRAXE intellectual disability syndrome can result from the silencing of the AFF2 gene due to a CCG expansion in the 5' UTR of the gene, or from deletions or loss-of-function variants. Affected males commonly present with developmental delay, mild to moderate intellectual disability, communication deficits, and behavioral abnormalities, including autism or autistic behavior, attention deficit, and hyperactivity. Some individuals may exhibit mild dysmorphic facial features. Carrier females are unaffected.
Five variants (the 5' UTR repeat expansion and four intragenic deletions) that have been reported in eight probands in five publications (PMIDs: 7783162, 8023854, 8334699, 21739600, 22065534) are included in this curation. Variants in this gene segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. AFF2 is highly constrained for loss-of-function variants (gnomAD v2.1.1). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by a mouse model and functional alterations in patient cells.
In summary, there is definitive evidence supporting the relationship between AFF2 and X-linked non-syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2017. It was reevaluated on August 11, 2025 (SOP Version 11). Although new cases were added, the classification did not change.
The AFF2 gene encodes a protein involved in transcriptional regulation and alternative splicing. AFF2 was first reported in relation to X-linked non-syndromic intellectual disability in 1996 (Gecz et al., PMID: 8673085). AFF2, previously referred to as FMR2, is associated with the folate-sensitive fragile X E (FRAXE) locus on chromosome Xq28. FRAXE intellectual disability syndrome can result from the silencing of theAFF2 gene due to a CCG expansion in the 5' UTR of the gene, or from deletions or loss-of-function variants. Affected males commonly present with developmental delay, mild to moderate intellectual disability, communication deficits, and behavioral abnormalities, including autism or autistic behavior, attention deficit, and hyperactivity. Some individuals may exhibit mild dysmorphic facial features. Carrier females are unaffected.
Five variants (the 5' UTR repeat expansion and four exonic deletions) that have been reported in eight probands in five publications (PMIDs: 7783162, 8023854, 8334699, 21739600, 22065534) are included in this curation. Variants in this gene segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. AFF2 is highly constrained for loss-of-function variants (gnomAD v2.1.1). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by a mouse model and functional alterations in patient cells.
In summary, there is definitive evidence supporting the relationship between AFF2 and X-linked non-syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2017. It was reevaluated on August 11, 2025 (SOP Version 11). Although new cases were added, the classification did not change.
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