Early onset or syndromic epilepsy

Gene: CSNK2A1

Red List (low evidence)

AD OCNDS. Owen et al, 2018 (29383814) - 11 individuals with 8 diff de novo CSNK2A1 varants - 1 had had 3x febrile seizures and 1 had ? absence seizures. Chiu et al, 2017 (29240241) - 8 subjects with de novo CSNK2A1 variants - looking at the clinical features of 14 subjects with CSNK2A1 variants (there patients, patient from Trinh et al and DDD cases) 2/8 of there cases had epilepsy (case 6 - febrile seizures - resolved after 5 years of age and subject 8 had a history of myoclonic seizures) and 2/5 of the DDD cases - probably the same two mentioned in the Owens et al paper as this is a DDD paper. Okur et al, 2016 (27048600) - 5 patients with a neurodevelopmental disorder with de novo CSNK2A1 variants - 1 patient had daily atonic seizures with abnormal EEG. Are a few cases where epilepsy has been seen; however it seems to have a very specific phenotype which would likely be covered by a different panel, therefore as epilepsy is not a major feature keep as red.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

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

I don't know

PMID 27048600 associates this gene with neurodevelopmental abnormalities and dysmorphic features. Of the five patients with de novo CSNK2A1 variants, one was reported to have atonic seizures. Based on this and the review below, I have rated as Amber.

Created: 23 Aug 2019, 10:27 a.m. | Last Modified: 23 Aug 2019, 10:27 a.m.

Panel Version: 1.256

Phenotypes
Neurodevelopmental abnormalities and dysmorphic features

Publications

• 27048600

I don't know

Kept rating as Red based on post-Webex reviews from Helen Lord and Alison Callaway: Although there is an argument to upgrade to Amber, epilepsy is not a major part of the overall phenotype so on balance kept rating as Red.

Created: 9 Sep 2019, 9:36 a.m. | Last Modified: 9 Sep 2019, 9:36 a.m.

Panel Version: 1.304

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Comment on list classification: Rated CSNK2A1 as Red based on 1 paper (PMID:30655572) with 2 unrelated Japanese patients and de novo variants. Functional studies were not performed, and the seizures (and other features) were variable between the patients.

Created: 27 Jun 2019, 4:26 p.m. | Last Modified: 27 Jun 2019, 4:26 p.m.

Panel Version: 1.81

Added CSNK2A1 to the epilepsy panel based on PMID:30655572. Nakashima et al, 2019 describe 4 patients with DD and seizures. Two of the patients (both Japanese) had de novo variants in CSNK2A1: c.593A>G, p.Lys198Arg in Patient 1, c.571C>T, p.Arg191* in Patient 2. Although both shared global DD and seizures, patient 1 showed later onset (4 yrs old) seizures which were less frequent. Additional features in Patient 1 include facial dysmorphisms, short stature and muscle weakness. Patient 2 had a more severe phenotype with seizures starting in the early infantile stage (5 months) with acute encephalopathy and death age 1 yr, 7 months. Note that Patient 1 had 3 candidate de novo deleterious variants (ATAD2B, TOPORS, CSNK2A1): ACMG variant guidelines were used to evaluate the pathogenicity of the variants. ATAD2B and TOPORS variants were likely pathogenic, and CSNK2A1 variant was pathogenic. In Patient 2, no further likely de novo variants were found.
Sources: Literature

Created: 27 Jun 2019, 4:23 p.m.

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

Phenotypes
seizures; Okur-Chung neurodevelopmental syndrome, 617062; CSNK2A1 syndrome

Publications

• 30655572