Mental Retardation, Autosomal Recessive 40

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-40 (MRT40) is caused by homozygous mutation in the TAF2 gene (604912) on chromosome 8q23.

Clinical Features

Najmabadi et al. (2011) reported 2 sibs, born of consanguineous Arab parents, with mental retardation, microcephaly, and foot deformity. Halevy et al. (2012) reported 4 children from a large consanguineous Arab Bedouin kindred with a similar disorder characterized by postnatal microcephaly, delayed psychomotor development, pyramidal signs, and thin corpus callosum. The patients had a normal head circumference at birth, but developed microcephaly (-2 to -5.5 SD) within the first months of life. This was accompanied by poor or no speech, as well as spasticity, hyperreflexia, and extensor plantar responses. Brain imaging showed delayed myelination. One patient had horizontal nystagmus and pigmentary retinal changes, whereas another had a bicuspid aortic valve. Seizures and dysmorphic features were not present. Laboratory studies revealed no abnormalities.

Inheritance

The transmission pattern in the family with MRT40 reported by Halevy et al. (2012) was consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping of an Arab family with autosomal recessive mental retardation, Halevy et al. (2012) found linkage to a locus on chromosome 8q23.2-q24.12 between SNPs rs13265962 and rs9969585 (maximum multipoint lod score of 3.2).

Molecular Genetics

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family M177, they identified a homozygous missense mutation in the TAF2 gene (W649R; 604912.0001) in 2 sibs with autosomal recessive mental retardation, microcephaly, and foot deformity.

In 4 children from a consanguineous Arab Bedouin family with autosomal recessive mental retardation (Halevy et al., 2012), Hellman-Aharony et al. (2013) identified 2 homozygous missense variants in the TAF2 gene (T186R, 604912.0002 and P416H, 604912.0003). The T186R substitution occurred at a more conserved residue than the P416H variant, but it was unclear which of the 2 variants, or whether both together, were responsible for the phenotype. Functional studies of the variants were not performed. The mutations were found by candidate gene sequencing of a region on chromosome 8q previously found by linkage analysis in this family (Halevy et al., 2012). The unaffected parents were heterozygous for both mutations.