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AFF3 – Intellectual Disability

The association between AFF3 and Intellectual Disability is based on the characterization of the FRA2A folate-sensitive fragile site. In three unrelated families, affected individuals exhibited mosaic expansions of a CGG repeat in an alternative, brain-active promoter of AFF3, leading to local CpG hypermethylation, transcriptional silencing, and monoallelic expression consistent with functional haploinsufficiency. These carriers presented a spectrum of neurodevelopmental phenotypes, including delayed motor and language acquisition (PMID:24763282).

Concordant functional data include bisulfite and pyrosequencing assays demonstrating AFF3 promoter hypermethylation and loss of expression, and whole-mount in situ hybridization in mouse embryos showing strong regional expression in developing brain. However, evidence is limited to a single case series of three families, and replication in additional unrelated cohorts is required to conclusively establish a causal relationship.

References

  • PLoS genetics • 2014 • FRA2A is a CGG repeat expansion associated with silencing of AFF3. PMID:24763282

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

One study of three unrelated families (three probands) identified FRA2A CGG repeat expansions in AFF3 with promoter silencing and monoallelic expression ([PMID:24763282]).

Genetic Evidence

Limited

CGG repeat expansions detected in three probands across three families causing AFF3 silencing and predicted haploinsufficiency ([PMID:24763282]).

Functional Evidence

Limited

Bisulfite and pyrosequencing assays show promoter hypermethylation and loss of AFF3 expression; in situ hybridization confirms brain‐active expression but lacks in vivo phenotypic modeling ([PMID:24763282]).