Curation FRA12A DIP2B

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.

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.

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.

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.

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 alleles¹ , however another correlation analysis of long-read genomes shows no strong association between DIP2B CGG repeat length and promoter hypermethylation² .

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.