FRA2A_AFF3
- Gene
- AFF3
- Disease
- FRA2A
- Inheritance
- AD
- Classification
- Definitive
- Total Score
- 12
- Publications Reviewed
- 2
- Publication Span
- 10.59 years
- Last Updated
- 08/12/2025
- Curator(s)
- Macayla Weiner, Laurel Hiatt
Description
A GCC/CGG repeat expansion in an alternative promoter/intronic 5′ region of AFF3 causes the FRA2A folate-sensitive fragile site and is associated with autosomal dominant intellectual disability/developmental delay. The original FRA2A study identified expanded mosaic CGG alleles with promoter hypermethylation and monoallelic AFF3 silencing in carrier families, while a later population-scale study found AFF3 expansions enriched in unsolved ID probands, supported by long-read trio data, methylation, PheWAS associations, and population/control comparisons.
Genetic evidence
Total: 8
| Singular Evidence | Probands | PMID:39313615 | 2 | Two probands with intellectual disability underwent PacBio HiFi trio sequencing, confirming heterozygous expanded AFF3 GCC alleles (157 and 822 copies) inherited from a carrier parent with methylation and size changes on transmission. |
| Collective Evidence | Segregation | PMID:39313615 | 1.5 | Two trios showed transmission of the expanded AFF3 allele from a carrier parent to an affected proband; one maternal allele expanded from 133 to 822 copies and one paternal allele contracted from 424 to 157 copies, consistent with incomplete penetrance. |
| Statistics | Case-control data | PMID:39313615 | 4 | In 100kGP, long AFF3 alleles were enriched in 6,371 unsolved ID probands versus 8,794 ancestry-matched controls, with peak enrichment for alleles ≥61 copies (P=0.002; OR=3.9); 17/6,371 unsolved probands had ≥60-copy alleles versus 0/1,500 ID probands with other pathogenic findings. |
| Collective Evidence | Computational | PMID:39313615 | 0.5 | Computational genotyping and association analyses linked the AFF3 GCC expansion to neurodevelopmental traits: ExpansionHunter identified long alleles, PheWAS associated expansions with reduced educational attainment, and local SNVs tagging the expansion overlapped GWAS signals for intelligence/cognitive ability. |
4 rows
Experimental evidence
Total: 4
| Function | Protein interaction | PMID:24763282 | 0.5 | Gene-level evidence: AFF3 is an AFF-family nuclear transcription-activating factor that forms super elongation complexes with active P-TEFb and AF9/ENL; the cited study did not directly test altered protein interactions caused by the FRA2A repeat. |
| Function | Regulatory impact | PMID:24763282 | 1.5 | The FRA2A CGG expansion lies in a brain-active alternative AFF3 promoter and is associated with local CpG hypermethylation and monoallelic AFF3 expression/silencing in carriers. |
| Functional Alteration | Patient cells | PMID:24763282 | 1 | Patient-derived blood/lymphoblastoid material from FRA2A carriers showed expanded AFF3 CGG alleles with promoter hypermethylation; cSNP analysis in carrier BII.1 demonstrated monoallelic AFF3 expression. |
| Functional Alteration | Non-patient cells | PMID:24763282 | 0.5 | Non-patient controls showed normal-range AFF3 CGG alleles and no methylation above threshold in control family samples, supporting that hypermethylation was specific to expansion carriers; this was comparator/control-cell evidence rather than an engineered expansion model. |
| Models | Non-human model organism | PMID:24763282 | 0.5 | Gene-level model evidence: whole-mount in situ hybridization showed mouse Aff3 expression in developing brain, somites, limb buds and palate; no non-human FRA2A repeat-expansion model was reported. |
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Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.