Mental Retardation, X-Linked, Syndromic 34

A number sign (#) is used with this entry because of evidence that X-linked syndromic mental retardation-34 (MRXS34) is caused by mutation in the NONO gene (300084) on chromosome Xq13.

Description

X-linked syndromic mental retardation-34 is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability with poor speech, dysmorphic facial features, and mild structural brain abnormalities, including thickening of the corpus callosum (summary by Mircsof et al., 2015).

Clinical Features

Mircsof et al. (2015) reported 3 unrelated males, aged 15 to 20 years, with syndromic form of intellectual disability. The patients had delayed psychomotor development with poor nasal speech, and a shy, gentle, and cheerful demeanor. They had a slender build, scoliosis or kyphosis, pes planus, and ankylosis of the metacarpophalangeal joint of P1. Facial features included macrocephaly, long face with upslanting palpebral fissures, malar hypoplasia, thin and high nasal root, small open mouth, and narrow high-arched palate with dental crowding. Additional variable features included strabismus, myopia, and hypotonia with poor sucking in infancy, One patient had seizures and 2 had delayed puberty. Brain imaging showed thickening or dysgenesis of the corpus callosum in 2 patients; 1 patient had a Chiari type I malformation and another had a hypoplastic cerebellum.

Reinstein et al. (2016) reported a 17-year-old Ashkenazi Jewish boy of Libyan origin who had developmental delay, macrocephaly, dysmorphic facies, and left ventricular noncompaction (LVNC). At age 1 month, he presented with macrocephaly, axial hypotonia, and head lag. At 8 months, chest x-ray revealed an enlarged cardiac silhouette, and echocardiography showed LVNC. In addition, he exhibited low muscle tone, and all developmental milestones were delayed. At 4 years of age, he was diagnosed with autism and mild intellectual disability, and at age 12, he developed aggressive behavior. Examination at age 16 showed a shy and anxious patient, with verbal dyspraxia, intention tremor, and mild ataxia. He had mild joint laxity, macrocephaly, and dysmorphic features that included long face, prominent nose, wide mouth, thick lips, and short philtrum. Neurologic examination demonstrated general hypotonia, increased patellar and Achilles reflexes without clonus, kyphoscoliosis, and bilateral hallux valgus. Brain imaging showed a thick calvarium, with a short and hypoplastic corpus callosum, but no cerebellar abnormalities. His parents and 2 sibs were healthy.

Scott et al. (2017) studied 3 unrelated Hispanic boys who all exhibited developmental and intellectual delays, relative macrocephaly, dysmorphic features, and cardiac defects, including LVNC, atrial and ventricular septal defects, patent ductus arteriosus, and patent foramen ovale. MRI of the brain showed corpus callosum defects in 2 of the patients.

Inheritance

The transmission pattern of MRXS34 in one of the families reported by Mircsof et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

Mircsof et al. (2015) reported 3 different hemizygous mutations in the NONO gene (300084.0001-300084.0003) in 3 unrelated males with MRXS34. One patient inherited the mutation from an unaffected mother; another patient had a de novo mutation and also carried a hemizygous deletion of chromosome 15q13, which may have contributed to the phenotype. The mutations were found by whole-exome sequencing; Western blot analysis of patient cells showed loss of NONO protein. Patient fibroblasts showed increased expression of 2 other splicing genes PSPC1 (612408) and SFPQ (605199), as well as a reduced amplitude of circadian oscillations.

In a 17-year-old Ashkenazi Jewish boy of Libyan origin with developmental delay, macrocephaly, dysmorphism, and LVNC, Reinstein et al. (2016) performed exome sequencing and identified hemizygosity for a de novo splice site mutation in the NONO gene (300084.0004). Noting that the cardiac phenotype was not reported in the patients described by Mircsof et al. (2015), Reinstein et al. (2016) suggested that LVNC might be part of MRXS34.

By exome sequencing in 2 unrelated Hispanic boys with global developmental delay, relative macrocephaly, dysmorphic features, and cardiac anomalies including LVNC, Scott et al. (2017) identified mutations in the NONO gene, the previously identified 1-bp duplication (300084.0002) and the R365X substitution (300084.0003), respectively. In a similarly affected Hispanic male infant, the authors identified a maternally inherited Xq13.1 deletion that included the first 3 coding exons of the NONO gene. The authors noted that all 6 reported patients with mutations in the NONO gene exhibited relative macrocephaly and intellectual disability and/or global developmental delay, and 5 of the 6 had abnormalities of the corpus callosum; however, other features showed greater variability. Given that 2 of the patients with LVNC carried the identical mutation as previously reported patients without cardiac defects, Scott et al. (2017) suggested that loss of NONO function might predispose males to the development of congenital heart defects and LVNC, with the penetrance of these cardiac-related problems being influenced by genetic, epigenetic, environmental, or stochastic differences that affect the expression or function of other cardiac genes or compensatory mechanisms.

Animal Model

Mircsof et al. (2015) found that mice with disruption of the Nono gene had a small cerebellum, impaired spatial memory performance, and increased anxiety compared to control mice. Mutant mouse brains and neurons showed decreased levels of Gabra2 (137140) associated with altered postsynaptic clustering of gephyrin (GPHN; 603930). Expression of Gabra2 rescued the defect in gephyrin clustering. The findings suggested that Nono can regulate Gabra2 levels and thus has a role in regulating inhibitory synaptic biology in the brain, which can affect behavior.