Mental Retardation, Autosomal Dominant 36

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-36 (MRD36) is caused by heterozygous mutation in the PPP2R1A gene (605983) on chromosome 19q13.

Clinical Features

The Deciphering Developmental Disorders Study (2015) identified 3 patients with intellectual disability who carried heterozygous mutations in the PPP2R1A gene. All 3 patients had hypoplasia of the corpus callosum. The first patient also had joint hypermobility, deviation of the fifth finger, pectus excavatum, and seizures. The second patient had plagiocephaly, anteverted nares, muscular hypotonia, broad hallux, abnormal hair whorl, ocular abnormalities, hydrocephalus, and seizures. The third patient had plagiocephaly, delayed gross motor development, congenital visual impairment, facial asymmetry, and prominent metopic ridge.

Houge et al. (2015) reported 2 additional unrelated patients with MRD36. Common features included hypotonia, severely delayed psychomotor development with absent or very poor speech, agenesis of the corpus callosum, enlarged ventricles, hypotonic facies with open mouth, and mild hypertelorism.

Molecular Genetics

The Deciphering Developmental Disorders Study (2015) examined 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements. The authors discovered 12 novel genes associated with developmental disorders. The PPP2R1A gene was implicated in a gene-specific analysis (p = 2.03 x 10(-8)). The Deciphering Developmental Disorders Study (2015) identified 3 patients with intellectual disability who had heterozygous de novo missense mutations in the PPP2R1A gene. Two patients carried the same mutation (R182W; 605983.0001), and the third carried a different mutation (P179L; 605983.0002).

In 2 unrelated patients with MRD36, Houge et al. (2015) identified 2 different de novo heterozygous missense mutations in the PPP2R1A gene (605983.0001 and 605983.0003). The mutations were found by parent-child trio exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that all 3 reported PPP2R1A mutations affected PP2A holoenzyme formation by variably interfering with interaction of the A-alpha subunit with the C subunit. All mutations resulted in decreased phosphatase activity, consistent with a dominant-negative effect.