Mental Retardation, Autosomal Dominant 18

A number sign (#) is used with this entry because autosomal dominant mental retardation-18 (MRD18) is caused by heterozygous mutation in the GATAD2B gene (614998) on chromosome 1q21.

Description

Autosomal dominant mental retardation-18 is characterized by severe intellectual disability, limited language development, motor delay, and dysmorphic features, including hypertelorism and narrow palpebral fissures (summary by Luo et al., 2017).

Clinical Features

De Ligt et al. (2012) reported a girl (patient 69) with global developmental delay who learned to walk at 3 years and had a few single words at age 8. She had tics, high pain threshold, and hypoplasia of the optic nerve. At 34 years of age, she had severe intellectual disability and strabismus and made grimaces. Height and head circumference were normal. Facial characteristics included thin blonde hair, deeply set eyes, tubular nose with a broad nasal tip, and a large mouth with a thin upper lip. The woman was found to have a mutation in the GATAD2B gene. De Ligt et al. (2012) screened a second cohort of 765 individuals with intellectual disability and identified a second mutation in GATAD2B in a patient with severe developmental delay with delayed motor milestones, limited speech, and overlapping facial features.

Willemsen et al. (2013) reported a girl with developmental delay and similar dysmorphic features as the patients reported by de Ligt et al. (2012). The patient was hypotonic in the neonatal period and thereafter showed delayed psychomotor development. She learned to walk at age 2 years and started to speak during the third year, but only spoke 6 words at age 12 years. Her behavior was characterized by hyperactivity, inappropriate laughter, obsession for shiny objects, and mild self-mutilation. She also had strabismus and hypermetropic astigmatism. Facial dysmorphism included a broad forehead, a broad nasal bridge with full nose tip, a broad mouth with wide-spaced central incisors, short philtrum, and long palpebral fissures. She had thin, blond hair. Her fingers were long and she had fleshy hands.

Luo et al. (2017) reported 2 unrelated Chinese children with severe mental retardation. One child had hypertelorism, downward slanting palpebral fissures, and flat nasal bridge. At age 4 years, he could not walk stably. At age 11, he could speak only a few words and could walk but not run normally. The other child, born full-term to nonconsanguineous parents, had small palpebral fissures, hypertelorism, a flat, low nasal bridge, and dental misalignment. She sat at age 10 months, stood at age 1 year, and walked at age 2. At age 9, she had hyperactivity. At age 12, she could not speak any words; she could run and play alone and eat independently, but could not wash her face.

Cytogenetics

Willemsen et al. (2013) reported a girl with intellectual disability associated with a de novo heterozygous 249-kb deletion of chromosome 1q21.3 encompassing 10 genes and disrupting GATAD2B. No other known disease-related genes were in the deleted region. The girl had hypotonia and feeding difficulties in the neonatal period, followed by delayed psychomotor development and poor speech. Medical problems included hypermetropia and strabismus, and she had 1 episode of absence epilepsy. Facial dysmorphism included hypertelorism, a broad forehead, a broad and flat nasal bridge, and a full square tip of the nose. She had thin, blond hair.

Molecular Genetics

In 2 patients with severe intellectual disability and similar dysmorphic features, de Ligt et al. (2012) identified heterozygous de novo mutations in the GATAD2B gene: a nonsense mutation (Q470X; 614998.0001) and a frameshift mutation (614998.0002).

In a patient with intellectual disability and dysmorphic features, Willemsen et al. (2013) identified a heterozygous truncating mutation in the GATAD2B gene (614998.0003). Her unaffected mother carried the mutation in mosaic state (10% in peripheral blood leukocytes). The patient was identified from a larger cohort of 80 patients with similar features who were screened for mutations in the GATAD2B gene.

In 2 patients with severe intellectual disability, limited language development, and dysmorphic features, Luo et al. (2017) identified heterozygous de novo frameshift mutations in the GATAD2B gene (614998.0004-614998.0005). The mutations were identified by a next-generation sequencing panel targeting genes associated with intellectual disability. Western blot analysis revealed a reduction in the GATAD2B protein in lymphoblasts from both individuals compared with normal controls.