Early onset or syndromic epilepsy

Gene: CHRNA2

Green List (high evidence)

Comment on list classification: As there are three unrelated cases reported with familial sleep-related hypermotor epilepsy phenotype despite limited rating in ClinGen, this gene can remain green on this panel.

Created: 16 Oct 2025, 1:26 p.m. | Last Modified: 17 Oct 2025, 3:52 p.m.

Panel Version: 8.45

Monoallelic variants in CHRNA2 gene have been associated with relevant phenotype in OMIM (MIM #610353, record accessed on 16 October 2025) and Gene2Phenotype (with strong rating on the DD panel).

Monoallelic variants in this gene have been associated with two different phenotypes by the Epilepsy GCEP expert panel in ClinGen:
- familial sleep-related hypermotor epilepsy (MONDO:0000030) - 'Limited' rating. There are three unrelated probands reported with monoallelic CHRNA2 variants and this phenotype.
- benign familial infantile epilepsy (MONDO:0017615) - 'Disputed' rating. There is only one proband reported with CHRNA2 variant and this phenotype.

This gene is also present with monoallelic MOI and green rating in Genetic Epilepsy panel of PanelApp Australia (https://panelapp-aus.org/panels/202/gene/CHRNA2/)

Created: 16 Oct 2025, 1:21 p.m. | Last Modified: 16 Oct 2025, 1:25 p.m.

Panel Version: 8.44

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epilepsy, nocturnal frontal lobe, type 4, OMIM:610353; autosomal dominant nocturnal frontal lobe epilepsy 4, MONDO:0012474

Publications

• 16826524
• 25770198
• 25847220
• 30809122

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)

Missense mutations have been reported to cause ADNFLE, however, the aetiology of disease could be variants specific (both GOF and LOF mechanisms have been suggested). AD Nocturnal frontal lobe epilepsy 4. Aridion et al, 2006 - in all 10 aff members of a Sardinian family - het missense variant, 1 unaff family member carried the variant - suggest incomplete penetrance. Conti et al, 2015 - 7 aff members of a large family (6 with seizures) - het missense variant. In vitro functional expression studies in HEK293 cells showed that the het mutation resulted in a reduction in current denisty to ~40%. Trivisano et al, 2015 - het missense variant - segregated with disorder in the family (father and 2 daughters).

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
Epilepsy, nocturnal frontal lobe, type 4,610353

Publications

• 16826524
• 25770198

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments

Green List (high evidence)

Comment on list classification: It is appropriate for CHRNA2 to be green on this merged epileptic panel.

Created: 9 Apr 2018, 9:14 a.m.

Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 3 variants reported in unrelated cases. CHRNA2 had previously been reviewed as red because the particular phenotype was not relevant to the individual epileptic panel, however, it is appropriate for it to be green on this merged epileptic panel.

Created: 9 Apr 2018, 9:01 a.m.

Variants in CHRNA2 do not appear to be associated with autosomal dominant nocturnal frontal lobe epilepsy in Chinese population.

Created: 11 Dec 2017, 3:06 p.m.

Publications

• 26309560
• 25847220
• 25770198

Green List (high evidence)

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

Phenotypes
Epilepsy, nocturnal frontal lobe, type 4

Publications

• Aridon et al (2006) Am J Hum Genet 79: 342-350

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

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

Phenotypes
Epilepsy, nocturnal frontal lobe, type 4

Publications

• Aridon et al (2006) Am J Hum Genet 79: 342-350

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

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

Phenotypes
Epilepsy, nocturnal frontal lobe, type 4

Publications

• Aridon et al (2006) Am J Hum Genet 79: 342-350

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

Insufficient data currently

Created: 8 Feb 2016, 2:48 a.m.

Comment on list classification: Discussion amoungst reviewers by email concluded that this should be rated red. In gene2phenotype it is a possible DD gene, associated with autosomal dominant nocturnal frontal lobe epilepsy.

Created: 17 Dec 2015, 3:19 p.m.

Comment on mode of inheritance: Checked the imprinted gene list.

Created: 17 Dec 2015, 3:14 p.m.

Red List (low evidence)

Causes a different seizure phenotype

Created: 16 Dec 2015, 10:24 a.m.

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

Phenotypes
Epilepsy, nocturnal frontal lobe, type 4

Publications

• Aridon et al (2006) Am J Hum Genet 79: 342-350

Variants in this GENE are reported as part of current diagnostic practice