Mental Retardation, Autosomal Dominant 35

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-35 (MRD35) is caused by heterozygous mutation in the PPP2R5D gene (601646) on chromosome 6p21.

Clinical Features

The Deciphering Developmental Disorders Study (2015) identified 4 patients with intellectual disability and mutation in the PPP2R5D gene. The first patient was a girl with severe intellectual disability, hydrocephalus, chronic diarrhea, and hypoglycemia. The second was a boy with global developmental delay, seizures, ventriculomegaly, narrow forehead, downslanted palpebral fissures, pyloric stenosis, and macrocephaly. The third patient was a boy with global developmental delay, deeply set eyes, myopia, strabismus, and generalized hypotonia. The fourth was a girl with global developmental delay, congenital muscular torticollis, and congenital hip dislocation.

Houge et al. (2015) reported 7 additional children with MRD35 confirmed by genetic analysis. All had neonatal and persistent hypotonia and delayed psychomotor development with poor speech. Most had increased head circumference, which was associated with hydrocephalus in at least 1 case. Dysmorphic facial features included hypotonic face with tented upper lip, mild hypertelorism with downslanting palpebral fissures, and frontal bossing.

Loveday et al. (2015) reported 3 unrelated patients with MRD35 associated with overgrowth, mainly macrocephaly. Two patients had increased height.

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 PPP2R5D gene was implicated in a gene-specific analysis (p = 6.01 x 10(-12)). The Deciphering Developmental Disorders Study (2015) identified 4 patients with intellectual disability who had heterozygous de novo missense mutations in the PPP2R5D gene. Three patients carried the same mutation (E198K; 601646.0001), and the fourth carried a different mutation (P201R; 601646.0002).

In 7 unrelated patients with MRD35, Houge et al. (2015) identified 5 different de novo heterozygous missense mutations in the PPP2R5D gene (601646.0001-601646.0005). Three of the patients carried the same E198K mutation. The mutations were found by parent-child trio exome sequencing and confirmed by Sanger sequencing. All mutations clustered in a highly conserved acidic loop that faces the A and C subunits of the PP2A complex, except one (P52S; 601646.0003). In vitro functional expression studies in HEK293 cells showed that all mutations, except P53S, showed deficient holoenzyme formation of PP2A with decreased association of the mutant PPP2R5D subunit to the A or C subunits, consistent with a dominant-negative effect. Houge et al. (2015) suggested that disruption of normal phosphorylation in the brain may result in brain dysfunction, perhaps by having far-reaching consequences for regulation of localized signaling.

Loveday et al. (2015) identified 2 different heterozygous missense mutations in the PPP2R5D gene (601646.0001 and 601646.0004) in 3 unrelated patients with MRD35 associated with overgrowth, including macrocephaly. Functional studies of the variants were not performed, but Loveday et al. (2015) postulated that they could plausibly alter the ability of PP2A to dephosphorylate target substrates. The first 2 patients were ascertained from a larger cohort of 111 parent-child trios with overgrowth syndrome, often associated with intellectual disability, who underwent exome sequencing. The third patient was ascertained from a cohort of 152 individuals with overgrowth phenotypes for whom parental DNA was not available. Loveday et al. (2015) postulated that the mutations may disrupt the PI3K (see 171834)/AKT1 (164730) growth regulatory cascade.