Early onset or syndromic epilepsy

Gene: CLTC

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AD mental retardation 56 - DeMari et al, 2016 - 3.5 year old girl - dev delay no seizures reported and brain imaging and EEG normal. Hamdan et al, 2017 - 12 unrelated patients - 4 patients has seizures with onset in first years of life and a fifth patient had a seizure without recurrence - de novo het variants identified - 5 truncating, 2 inframe dels, 1 splice site and 3 missense (1 of these recurrent and seen in 3 unrelated patients). No functional studies performed.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Mental retardation 56,617854

Publications

• 29100083
• 26822784

Green List (high evidence)

Comment on list classification: Added new Green gene to Epileptic encephalopathy panel, there is enough evidence to support the epilepsy phenotype.

Created: 26 Feb 2018, 5:25 p.m.

Added from the Intellectual Disability review. There are more than three unrelated cases with autosomal dominant mental retardation-56 (MRD56). De Mari et al., 2016 (PMID:26822784) identified a de novo heterozygous frameshift mutation in the CLTC gene in a young patient, the authors postulated haploinsufficiency of CLTC as the pathogenetic mechanism. Hamdan et al., 2017 (PMID:29100083) identified de novo heterozygous missense mutations in the CLTC gene in 12 unrelated patients with MRD56 in 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. In both studies by De Mari et al. and Hamdan et al. functional studies of the variant and studies of patient cells were not performed. This is a probable DD gene in Gene2Phenotype for Epilepsy and intellectual disability and a possible DD gene in Gene2Phenotype for Overgrowth intellectual disability.

Created: 26 Feb 2018, 5:24 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Mental retardation, autosomal dominant 56, 617854; Autosomal dominant non-syndromic intellectual disability; Epilepsy and intellectual disability

Publications

• 26822784
• 29100083