Mental Retardation, X-Linked, Syndromic, Bain Type

A number sign (#) is used with this entry because of evidence that the Bain type of X-linked syndromic mental retardation (MRXSB) is caused by heterozygous mutation in the HNRNPH2 gene (300610) on chromosome Xq22.

Description

MRXSB is an X-linked dominant neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability with behavioral abnormalities, and dysmorphic facial features. Additional variable features include musculoskeletal abnormalities, seizures, acquired microcephaly, and feeding problems with poor overall growth. Only females are affected (summary by Bain et al., 2016).

Clinical Features

Bain et al. (2016) reported 6 unrelated females, ranging in age from 2 to 34 years, with a complex neurodevelopmental disorder. All had delayed psychomotor development, intellectual disability, and poor or absent speech. Three patients showed developmental regression, suggesting an underlying neurodegenerative process. Most had behavioral or psychiatric abnormalities, including autism spectrum disorder, aggression, attention deficit-hyperactivity disorder, and self-injurious behavior. Additional neurologic features included hypotonia, hypertonia, and ataxic gait. Three had seizures and 2 had acquired microcephaly. Dysmorphic facial features included almond-shaped eyes, short palpebral fissures, short philtrum, full lower lip, long columella, hypoplastic alae nasi, and micrognathia. Musculoskeletal abnormalities included short stature, scoliosis, lordosis, pectus carinatum, pes planus, and joint laxity. More variable features included feeding difficulties, gastroesophageal reflux disease, and constipation.

Molecular Genetics

In 5 unrelated female patients with MRXSB, Bain et al. (2016) identified 3 different de novo heterozygous missense mutations in the HNRNPH2 gene: 3 patients carried the same variant (R206W; 300610.0001), 1 carried a different mutation at the same residue (R206Q; 300610.0002), and 1 carried a mutation that was 3 amino acids away (P209L; 300610.0003). All mutations affected conserved residues in the nuclear localization sequence. The patients were from a large cohort of 2,030 females and 2,486 males with developmental delay and/or intellectual disability who underwent whole-exome sequencing. Bain et al. (2016) noted that a sixth female patient with the R206W mutation and a similar phenotype was identified by another laboratory. Functional studies of the variants and studies of patient cells were not performed; however, Bain et al. (2016) noted that all mutations affected highly conserved residues in the nuclear localization sequence, and postulated a toxic gain-of-function effect. The authors suggested that these variants may be lethal in males.