Mental Retardation, Fra12a Type

A number sign (#) is used with this entry because of evidence that the FRA12A type of mental retardation is caused by a heterozygous expanded CGG repeat in the 5-prime untranslated region of the DIP2B gene (611379) on chromosome 12q13.

Description

FRA12A is a folate-sensitive chromosomal fragile site prone to breakage. No consistent phenotype has been observed with FRA12A, and it can be inherited without phenotypic effect (Berg et al., 2000). However, mental retardation with or without other anomalies has been described in patients with over 40% of cells expressing FRA12A (Winnepenninckx et al., 2007).

Clinical Features

Giraud et al. (1976) identified a chromosomal breakage point of chromosome 12q13 in a male patient with mental retardation and multiple congenital anomalies. An unaffected woman with the 12q13 fragile site had a baby with lethal arthrogryposis, but the baby did not have the 12q13 fragile site, leaving the phenotypic association undetermined.

Sutherland and Hinton (1981) reported a family in which 6 persons spanning 3 generations had a fragile site at chromosome 12q13. The fragile site was suppressed by folic acid and thymidine in lymphocyte culture. Although epidermolysis bullosa simplex (131900) also segregated in this family, the authors concluded that it was probably coincidence because at least 3 persons had one or the other disorder, but not both.

Smeets et al. (1985) reported a 15-year-old boy with mental retardation associated with a fragile site at 12q13 detected in 40% of metaphyses from peripheral lymphocytes. He also had seizures and behavioral problems. The unaffected mother and sister showed the same chromosomal fragility, at 26% and 22%, respectively. Kumar et al. (1986) reported a family in which heritable fragile 12q13 was an incidental finding in 3 women with cellular levels of 20 to 30%.

Berg et al. (2000) reported an 11-year-old girl with mental retardation, pulmonary stenosis, and bullous ichthyosiform erythroderma (BIE; 113800) associated with fragile 12q13 in 40% of lymphocytes. Her unaffected mother and maternal grandmother had 20 and 2%, respectively. In a review of reports of fragile 12q13 from the literature, Berg et al. (2000) concluded that individuals with greater than 40% of cells showing the fragile site have mental handicap, whereas those with lesser levels of fragile 12q13 may be unaffected, suggesting a dosage phenomenon.

Molecular Genetics

From an overview of FRA12A cytogenetic expression in 41 individuals from 16 published families, Winnepenninckx et al. (2007) concluded that a high level of cytogenetic expression of this rare folate-sensitive fragile site was significantly associated with mental retardation. The patients included those reported by Smeets et al. (1985) and Berg et al. (2000). In patients with FRA12A, the authors identified an elongated polymorphic CGG repeat in the 5-prime untranslated region of the DIP2B gene (611379.0001), which encodes a protein with a DMAP1 (605077) binding domain, suggesting a role in DNA methylation machinery. DIP2B mRNA levels were halved in 2 subjects with FRA12A with mental retardation in whom the repeat expansion was methylated. In 2 individuals without mental retardation but with an expanded and methylated repeat, DIP2B expression was reduced to approximately two-thirds of the values observed in controls. A carrier of an unmethylated CGG repeat expansion showed increased levels of DIP2B mRNA, which suggested that the repeat elongation increases gene expression, as previously described for the fragile X-associated tremor/ataxia syndrome (300623). The data suggested that deficiency of DIP2B, a brain-expressed gene, may mediate the neurocognitive problems associated with FRA12A.