Early onset or syndromic epilepsy

Gene: CLCN4

Green List (high evidence)

XLD Raynaud Claes syndrome - X-linked intellectual developmental disorder. Additional features include seizures (variable forms). Some females unaff anf some aff as severe as males. Raynaud et al 1996 - French family (MRX15) - 5 males over 2 generations - none had seizures. Claes et al, 1997 - Family (MRX49) - 5 males spanning 2 generations, 2 obligate female carriers mild symptoms. 1 individual had absence seizure disorder. Veermah et al, 2013 - 14 month old boy who developed refractory complex partial seizures at 4 months - de novo hemizygous missense variant - in vitro functional studies support pathogenicity. Hu et al, 2016 - 13 males from 3 unrelated families (N70, AU27, AU4) - with intellectual disability - some patients had seizures (All males in family AU4 (7) and 1 aff female had a seizure disorder and 1 male in AU27 had complex partial seizures - Palmer et al 2018) In this paper they also found variants reported by In the Raynaud and Claes families - one truncation and rest missense - in vitro functional studies support pathogenicity. Palmer et al 2018 went on to describe 10 previously unreported families and reviewed 6 prev reported famiies - 15/29 had a seizure disorder which was intractable in 8 - mutations identified incl frameshift, missense, splice site and one single exon deletion.

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

Panel Version: 1.188

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Raynaud-Claes syndrome, 300114

Publications

• 27550844

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

Comment on mode of inheritance: Changed MOI from XLR to XLD to match XLD MOI for 'Raynaud-Claes syndrome' (MIM:300114) in OMIM.

Created: 10 Jul 2019, 8:27 p.m. | Last Modified: 10 Jul 2019, 8:27 p.m.

Panel Version: 1.148

Comment when marking as ready: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for INFANTILE EPILEPTIC ENCEPHALOPATHY AND/OR INTELLECTUAL DISABILITY. At least 2 variants reported in 3 unrelated cases in whom seizures are included in their phenotypic features. Supportive functional studies are also reported (PMID 27550844).

Created: 13 Nov 2018, 10:47 a.m.

Green List (high evidence)

Seizures are a reported feature of this intellectual disability syndrome.

Created: 10 Aug 2018, 4:44 a.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Mental retardation, X-linked 49/15, MIM#300114