Mental Retardation, Autosomal Recessive 36

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-36 (MRT36) is caused by homozygous mutation in the ADAT3 gene (615302) on chromosome 19p13.

Clinical Features

Alazami et al. (2013) reported 8 consanguineous Arab families from various geographic regions in which multiple individuals had mental retardation that was often associated with esotropia and failure to thrive. Other more variable features included microcephaly, hypotonia, and mild brain abnormalities on MRI, such as dilated ventricles or delayed myelination.

El-Hattab et al. (2016) reported 15 individuals from 11 apparently unrelated Arab families with features similar to those of the patients reported by Alazami et al. (2013). All of the patients had moderate to severe intellectual disability, and most had strabismus, growth failure, and brain abnormalities on neuroimaging. Previously unreported features included variable dysmorphic facial features (prominent forehead, upslanting palpebral fissures, epicanthus, hypertelorism, telecanthus, depressed nasal bridge) in 10 patients, behavioral problems (aggressiveness, hyperactivity) in 5, and endocrine abnormalities (low IGF1, growth hormone deficiency, hypothyroidism) in 3.

Salehi Chaleshtori et al. (2018) described a 6-year-old girl, born to consanguineous Iranian parents, with mild to moderate cognitive impairment, neurodevelopmental delay, attention-deficit/hyperactivity disorder, asymmetric face, and depressed nasal bridge. She did not have strabismus.

Inheritance

The transmission pattern of MRT36 in the families reported by Alazami et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping of a large consanguineous family with MRT36, Alazami et al. (2013) found linkage to a locus on chromosome 19p13.3 (maximum lod score greater than 4.3 near the proximal telomere).

Molecular Genetics

In affected members of 8 consanguineous Arab families with autosomal recessive mental retardation, Alazami et al. (2013) identified a homozygous mutation in the ADAT3 gene (V128M; 615302.0001). Molecular modeling indicated that the mutation occurs in a hook that protrudes from the surface of the protein and would disrupt this protrusion. The mutation, which was found by homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families and was not found in the 1000 Genomes Project or Exome Variant Server databases or in 580 ethnically matched alleles. Haplotype analysis indicated a founder effect, which was estimated to have occurred between 65 and 111 generations ago. The ADAT3 gene is involved in the regulation of protein translation.

By whole-exome sequencing, El-Hattab et al. (2016) identified homozygosity for the same V128M founder mutation in the ADAT3 gene in affected members of 11 apparently unrelated Arab families with MRT36.

In a 6-year-old Iranian girl, born to consanguineous parents, with MRT36, Salehi Chaleshtori et al. (2018) identified homozygosity for an 8-bp duplication in the ADAT3 gene (615302.0002) that segregated with the phenotype in the family. The mutation was not found in the ExAC, 1000 Genomes Project, or EVS databases.