A number sign (#) is used with this entry because of evidence that Houge-Janssens syndrome-1 (HJS1) is caused by heterozygous mutation in the PPP2R5D gene (601646) on chromosome 6p21.

Houge-Janssens syndrome-1 (HJS1) is characterized by global developmental delay, hypotonia, variably impaired intellectual development, poor speech, and dysmorphic facial features. Additional more variable features may include macrocephaly and seizures (Houge et al., 2015).

Genetic Heterogeneity of Houge-Janssens Syndrome

Forms of Houge-Janssens syndrome are caused by mutations in the protein phosphatase type 2 family of genes. See also HJS2 (616362), caused by mutation in the PPP2R1A gene (605983) on chromosome 19q13; and HJS3 (618354), caused by mutation in the PPP2CA gene (176915) on chromosome 5q31.

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 an intellectual developmental disorder and mutation in the PPP2R5D gene. 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 an intellectual developmental disorder associated with overgrowth, mainly macrocephaly, and mutation in the PPP2R5D gene. Two patients had increased height.

The heterozygous mutations in the PPP2R5D gene that were identified in patients with HJS1 by the Deciphering Developmental Disorders Study (2015) occurred de novo.

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 Houge-Janssens syndrome, 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 Houge-Janssens syndrome 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.