FRA12A_DIP2B
- Gene
- DIP2B
- Disease
- FRA12A
- Inheritance
- AD
- Classification
- Disputed
- Total Score
- 10.5
- Publications Reviewed
- 6
- Publication Span
- 19.32 years
- Last Updated
- 05/20/2026
- Curator(s)
- Gabriel Zinser, Macayla Weiner, Harriet Dashnow
Description
FRA12A is a rare, folate-sensitive chromosomal fragile site on chromosome 12 associated with intellectual developmental disorder, FRA12A type. The DIP2B CGG repeat expansion causes this folate-sensitive site and is associated with a broad phenotypic range, including intellectual disability, ataxia/movement disorder, and epilepsy; cardiovascular associations have also been reported but were not scored and are noted for completeness. For this curation, the neurodevelopmental and neurologic presentations (intellectual disability, ataxia/movement disorder, and epilepsy) were lumped as a single phenotypic spectrum, which supports the current score. If these phenotypes are treated as distinct entities, the evidence strength and resulting score may differ. Patients across multiple independent families and cohorts provide inheritance and functional support. Mechanistically, repeat expansions are associated with promoter hypermethylation, altered regulatory activity, and changes in DIP2B expression. Case-control studies report enrichment of DIP2B expansions in ataxia cohorts (OR = 2.8) and cardiovascular disease populations (OR = 2.7), and computational analyses support biological relevance through conservation and a predicted interaction with the DMAP1 methylation complex.
Genetic evidence
Total: 9.5
| Singular Evidence | Probands | PMID:39854091 PMID:17236128 PMID:34622207 | 6 | PMID 39854091: Two male siblings with a DIP2B CGG repeat expansion presented with neurodevelopmental disability, dysmorphic traits, and a severe progressive movement disorder (chorea, dystonia, and ataxia). Inheritance and functional evidence are provided for this family; 5 additional independent ataxia probands were identified in a replication cohort with no prior genetic diagnosis, with DIP2B alleles varying from 65 to 102 CGG repeats. PMID 17236128 associates the DIP2B CGG repeat expansion with fragile site FRA12A and intellectual disability; two families are described, both with inheritance and functional evidence. In PMID 34622207, one proband with Lennox-Gastaut syndrome (seizures and intellectual disability) had a DIP2B expansion and supporting functional evidence. |
| Collective Evidence | Allele | PMID:42205056 | 0 | In a cohort of 14 individuals with DIP2B CGG expansions ranging from 90 to 677 repeats, no common phenotypic pattern was identified. Individuals with long expansions included healthy individuals with 152 and 616 repeats, and an individual with breast carcinoma with 677 repeats. Other reported phenotypes included neurological and non-neurological presentations such as rod-cone dystrophy, heterogeneous neurological disorders, cerebellar ataxia, epilepsy/epileptic encephalopathy, ALS, FTD, Parkinson's disease, developmental delay, and metabolic disease. The presence of highly expanded alleles in unaffected and phenotypically diverse individuals is evidence against a consistent relationship between allele size and phenotype. |
| Collective Evidence | Computational | PMID:17236128 | 0.5 | Comparative conservation and predicted domain structure support biological relevance. Protein structure suggests involvement in methylation/transcriptional regulation pathways. DIP2B is predicted to interact with the DMAP1 methylation complex. |
| Statistics | Case-control data | PMID:39854091 PMID:38418263 | 3 | In 39854091: moderate statistical power limited by the small number of affected cases (5/788), bias may be introduced by the use of aggregate gnomAD population controls rather than closely matched controls, and borderline statistical significance demonstrating enrichment of large DIP2B CGG repeats in the ataxia cohort compared to controls (OR = 2.8, P = 0.04). In 38418263: Moderate-quality association evidence: cardiovascular disease enrichment among DIP2B expansion carriers (OR = 2.7, p = 1.6 × 10⁻²), but controls are aggregate disease cohorts. This phenotype is not clearly related to the primary neurological phenotype so is not scored. |
Experimental evidence
Total: 1
| Function | Regulatory impact | PMID:37248219 PMID:42205056 | 0.5 | Repeat expansion associated with loss of regulatory activity, and predicted allelic silencing. Expanded CGG repeat associated with reduced DIP2B expression. Unmethylated expansion associated with overexpression. Hypermethylation has been detected in expanded alleles [@pmid:37248219], however another correlation analysis of long-read genomes shows no strong association between DIP2B CGG repeat length and promoter hypermethylation [@pmid:42205056]. |
| Functional Alteration | Patient cells | PMID:38418263 PMID:17236128 | 0.5 | Patient cells show hypermethylation and reduced gene expression in cardiac tissue. A lower score is given for this evidence as the phenotype is not clearly related to the primary neurological phenotype. |
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.