Mental Retardation, X-Linked 102

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-102 (MRX102) is caused by mutation in the DDX3X gene (300160) on Xp11.

Clinical Features

Snijders Blok et al. (2015) reported 38 females with mild to severe intellectual disability and variable neurologic features, including hypotonia in 12 (76%), movement disorders comprising dyskinesia, spasticity, and stiff-legged or wide-based gait in 17 (45%), microcephaly in 12 (32%), behavioral problems such as autism spectrum disorder, hyperactivity, and aggression in 20 (53%), and epilepsy in 6 (16%). Additional variable nonneurologic features included joint hyperlaxity, skin pigmentary abnormalities, cleft lip and/or palate, hearing and visual impairment, and precocious puberty. Some patients had abnormal brain imaging findings, such as corpus callosum hypoplasia (35%), ventricular enlargement (35%), and evidence of cortical dysplasia (4 patients). Although common dysmorphic facial features were noted, there was no consistent recognizable phenotype. Five males from 3 additional, unrelated families also had MRX102. Features included mild to severe intellectual disability, movement disorders, such as spasticity, behavioral problems, and variable dysmorphic features. Carrier females in these 3 families were unaffected.

Inheritance

The transmission pattern of mental retardation in 38 females from 35 families reported by Snijders Blok et al. (2015) was consistent with X-linked dominant inheritance.

The transmission pattern of mental retardation in males in 3 families reported by Snijders Blok et al. (2015) was consistent with X-linked recessive inheritance. Carrier females in these families were unaffected.

Molecular Genetics

Snijders Blok et al. (2015) identified 35 different de novo heterozygous mutations in the DDX3X gene (see, e.g., 300160.0001-300160.0004) in 38 girls with X-linked dominant mental retardation-102. The mutations were found by whole-exome sequencing of 3 large cohorts of patients referred for testing (including the Deciphering Developmental Disorders Study, 2015); DDX3X mutations were found in 1 to 3% of these patient cohorts, rendering it one of the most common causes of intellectual disability in females. Nineteen of the mutations were predicted to cause complete loss of function, resulting in haploinsufficiency in the female patients. In vitro cellular functional expression studies and in vivo studies in zebrafish of some of the identified missense mutations showed that they caused a loss of function in the canonical WNT signaling pathway with a disruption of beta-catenin signaling. There was no evidence for a dominant-negative effect; Snijders Blok et al. (2015) postulated haploinsufficiency as the disease mechanism. De novo variants were not found in any male patients who were part of the cohorts, but affected males in 3 families were found to carry hemizygous missense mutations in the DDX3X gene (see, e.g., 300160.0005) that were inherited from an unaffected mother. Functional studies revealed no differences of the male mutant alleles from wildtype, but Snijders Blok et al. (2015) speculated that they were pathogenic and that the effect of the mutant alleles was beyond the detection range of the assays. The results were consistent with the hypothesis that DDX3X is dosage sensitive and may have differential activity in females than in males.