Autosomal Dominant Nocturnal Frontal Lobe Epilepsy via the CHRNB2 Gene

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE, OMIM:600513) is a partial seizure disorder characterized by seizures that occur during non-REM sleep. Seizures in ADNFLE patients can present as repetitive limb movements, dystonic posturing, sleep walking, or sudden elevation of the body or head (Kurahashi and Hirose, GeneReviews, 2012). 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 ictal EEG recordings; interictal EEGs are normal. ADNFLE associated seizures are often managed with low doses of antieplieptic drugs (AEDs). ADNFLE is not generally associated with cognitive deficits or psychiatric problems, however, recent evidence suggests that a subset of ADNFLE-causing mutations may have wider neurological phenotypes (Steinlein et al. Seizure 21(2):118-123, 2012). ADNFLE can be difficult to clinically distinguish from other non-epileptic paroxysmal sleep disorders, therefore a video-polysomnography recording brain/eye/muscle activity during sleep is considered essential for diagnosis.

ADNFLE is inherited in an autosomal dominant manner. ADNFLE is a genetically heterogeneous disorder. Mutations in the CHRNB2 gene have been reported in ~5% of individuals with a family history of ADNFLE (Ottman et al. Epilepsia 51(4):655-670, 2010). The penetrance of CHRNB2 mutations is incomplete (~70%), thus ADNFLE presentation can be variable in families (Kurahashi and Hirose, 2012).

CHRNB2 encodes a neuronally expressed beta-subunit of the nicotinic acetylcholine receptor (nAChR). The nAChRs belong to a super-family of ligand-gated ion channels. All of the reported ADNFLE-associated CHRNB2 variants are missense mutations and most are located within the transmembrane domain of the receptor. Highly conserved residues within the transmembrane domain dictate the ligand-specificity and activity of the receptor. Reported mutations in CHRNB2 are gain of function mutations, resulting in an increased sensitivity of neuronal nAChRs to the agonist acetylcholine (Phillips et al. Am J Hum Genet. 68(1):225-231, 2001). It is hypothesized that increased nAchR activity underlies the epilepsy phenotype associated with CHRNB2 mutations.

Mutations in CHRNB2 account for ~5% of familial ADNFLE cases (Ottman et al. Epilepsia 51(4):655-670, 2010).

This test provides full coverage of all coding exons of the CHRNB2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.