CHRNA2

Inheritance Pattern: AD

Disease ID:MONDO:0000030

Submitter: ClinGen

Variants in the CHRNA2 gene has been reported in 18 affected individuals with autosomal dominant nocturnal frontal lobe epilepsy since 2006 (Aridon et al.). Three unique missense variant proved to affect the protein function by patch clamp analysis (Aridon et al., Conti et al., Vila et al.). The variant in this gene was identified by linkage analysis followed by Sanger sequencing, and segregated with disease in 9 additional family members. In summary, there is limited evidence to support the CHRNA2 and nocturnal frontal lobe epilepsy association. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel by 1/7/2020. Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability between three disease entities: (1) Nocturnal frontal lobe epilepsy (MONDO:0000030), (2) Idiopathic epilepsy (MONDO:0005579) and (3) Benign familial infantile seizure (MONDO:0011140). Therefore, we have split curations for the disease entities, (1) Nocturnal frontal lobe epilepsy (MONDO:0000030), (2) Idiopathic epilepsy (MONDO:0005579) and (3) Benign familial infantile seizure (MONDO:0011140).

Inheritance Pattern: AD

Disease ID:MONDO:0012474

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012474

Submitter: Illumina

The CHRNA2 gene is located on chromosome 8 at 8p21.2 and encodes the cholinergic receptor nicotinic alpha 2 subunit. CHRNA2 is expressed in the brain and is involved with the binding of acetylcholine and the opening of an ion-conducting channel across the plasma membrane (20016990: Steinlein and Bertrand 2010; 25717303: Becchetti et al. 2015). The CHRNA2 gene was first reported in association with autosomal dominant epilepsy, nocturnal frontal lobe, in 2006 (16826524: Aridon et al. 2006). At least four unique variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Heterozygous missense variants in this gene have been reported in at least four probands from four publications (16826524: Aridon et al. 2006; 25770198: Conti et al. 2015; 25847220: Trivisano et al. 2015; 30809122: Villa et al. 2019). All reported variants were inherited, and variants in this gene segregated with disease in approximately 20 additional family members. A disease mechanism has not been established; two of the identified variants resulted in a loss of receptor function, while a third resulted in increased receptor sensitivity. This association is also supported by expression data, in vitro functional assays, and a shared biochemical function other nicotinic acetylcholine receptor subunit genes (20016990: Steinlein and Bertrand 2010; 16826524: Aridon et al. 2006). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

Inheritance Pattern: AD

Disease ID:MONDO:0020300

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012474

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0017615

Submitter: ClinGen

Variant in the CHRNA2 gene has been reported in 1 proband with autosomal dominant benign familial infantile seizure since 2015 (Klassen et al.). One unique missense variant has been reported. There is no evidence of gene impact of the missense variant and the variant was also observed in general population database (gnomAD). The variant in this gene was identified by NGS panel testing and segregated with disease in 2 additional family members. In summary, there is no scored evidence to support the CHRNA2 and benign familial infantile seizure association. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel by 1/7/2020. As of 11/9/2022, this record underwent administrative updates to change the obsolete MONDO disease term, benign familial neonatal-infantile seizures (MONDO:0011140), to benign familial epilepsy (MONDO:0017615). Additionally, the record's scoring has been updated to be consistent with SOP Version 9. No new evidence has been reviewed or added. Original Lumping and Splitting comments, saved for historical reference: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability between three disease entities: (1) Nocturnal frontal lobe epilepsy (MONDO:0000030), (2) Idiopathic epilepsy (MONDO:0005579) and (3) Benign familial infantile seizure (MONDO:0011140). Therefore, we have split curations for the disease entities, (1) Nocturnal frontal lobe epilepsy (MONDO:0000030), (2) Idiopathic epilepsy (MONDO:0005579) and (3) Benign familial infantile seizure (MONDO:0011140).