Mental Retardation, Autosomal Dominant 56

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-56 (MRD56) is caused by heterozygous mutation in the CLTC gene (118955) on chromosome 17q23.

Clinical Features

DeMari et al. (2016) reported a 3.5-year-old girl, conceived through in vitro fertilization, with global developmental delay, intellectual disability, absent language, hypotonia, and inability to walk. Her neonatal period was notable for hypoglycemia, apnea, bradycardia, hyperbilirubinemia, subdural hematoma, laryngomalacia, and feeding difficulties requiring admission to the NICU for a month. She also had hydrocephalus, hypothyroidism, and vitamin K-dependent clotting factor deficiency, and she developed a mediastinal ganglioneuroblastoma. Dysmorphic features included low-set ears, depressed nasal bridge, anteverted nares, and widely spaced and inverted nipples. She did not have seizures; brain imaging and EEG were normal. At age 3.5 years, she was socially alert and interactive and was making some developmental progress.

Hamdan et al. (2017) reported 12 unrelated patients with MRD56. The patients ranged in age from 3 to 30 years. All had global developmental delay of varying degree and intellectual disability that ranged from borderline to severe. Most had hypotonia, delayed walking, poor fine motor skills, clumsiness, and poor or absent speech. Several patients were able to attend special schools, whereas a few patients had more significant disability, never achieving ambulation or speech. Several patients had nonspecific and variable dysmorphic features, such as upslanting palpebral fissures, long philtrum, thin upper lip, open mouth, high-arched palate, and prominent ears. Four patients had seizures with onset in the first years of life, and a fifth patient had 1 seizure at age 14 years without recurrence. Two patients had had pharmacoresistant epilepsy with a preponderance of myoclonic and generalized tonic-clonic seizures, whereas 2 had seizures that could be controlled. Other more variable features included ataxia, spasticity, paraparesis, acquired microcephaly, oral and motor apraxia, and behavioral abnormalities, such as impulsivity and attention deficits. Brain imaging was normal in most patients, but showed nonspecific abnormalities in others, including pontocerebellar atrophy, thin corpus callosum, delayed myelination, and abnormal T2-weighed signals.

Molecular Genetics

In a 3.5-year-old girl, conceived by in vitro fertilization, with MRD56, DeMari et al. (2016) identified a de novo heterozygous frameshift mutation in the CLTC gene (118955.0001). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated haploinsufficiency of CLTC as the pathogenetic mechanism. DeMari et al. (2016) noted that CLTC is highly expressed in the brain and plays a role in neuronal transmission by facilitating the recycling and/or release of vesicles at the presynaptic termini of neurons.

In 12 unrelated patients with MRD56, Hamdan et al. (2017) identified de novo heterozygous missense mutations in the CLTC gene (see, e.g., 118955.0002-118955.0006). The mutations were found by whole-exome or whole-genome sequencing of several cohorts of patients with developmental delay and epilepsy. There were 5 truncating mutations, 2 small in-frame deletions, 1 splice site mutation, and 3 missense mutations, 1 of which was recurrent and found in 3 unrelated patients. Individuals with refractory epilepsy were found to carry variants in the first section of the clathrin light chain-binding domain, whereas truncating mutations affecting the C terminus tended to be associated with hypotonia, global developmental delay, and intellectual disability. Studies of patient cells and functional studies of the variants were not performed. Hamdan et al. (2017) noted that CLTC is involved in endocytosis, intracellular trafficking, and synaptic recycling.