Epilepsy: Autosomal Dominant Nocturnal Frontal Lobe Epilepsy, Type 4 via the CHRNA2 Gene

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a childhood onset focal epilepsy characterized by seizures that occur during non-REM sleep. Seizures in ADNFLE patients can present as repetitive limb movements, sudden awakening, dystonic posturing, sleep walking, or elevation of the body or head with fear. Seizures are brief, lasting from 5 seconds to 5 minutes, and often patients maintain consciousness throughout the attack. Frontal origin of ADNFLE seizures is revealed by EEG recordings. ADNFLE associated seizures are often managed with low doses of antiepileptic drugs (AEDs). ADNFLE is not generally associated with severe cognitive deficits or psychiatric problems, however, studies suggests that ADNFLE may have wider neurological phenotypes (Aridon et al. 2006. PubMed ID: 16826524; Steinlein et al. 2012. PubMed ID: 22036597; Wood et al. 2010. PubMed ID: 20189461; Bennett et al. 2017. PubMed ID: 28717674).

ADNFLE is inherited in an autosomal dominant manner and can be caused by pathogenic variants in the CHRNA2 gene (Aridon et al. 2006. PubMed ID: 16826524; Trivisano et al. 2015. PubMed ID: 25847220). CHRNA2 encodes neuronally expressed subunit 2 of the nicotinic cholinergic receptor (nAChR) which is a neurotransmitter-gated ion channel that has been fine-tuned through evolution to transduce a chemical signal into an electrical signal. The ADNFLE-associated CHRNA2 pathogenic variants are missense and nonsense. No large deletions or duplications have been reported (Human Gene Mutation Database).

In a cohort of 77 unrelated Autosomal dominant nocturnal frontal lobe epilepsy patients, one had a pathogenic variant in CHRNA2 (Conti et al. 2015. PubMed ID: 25770198).

This test provides full coverage of all coding exons of the CHRNA2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.