ADAM23 haploinsufficiency as a putative oligogenic contributor in an individual with focal epilepsy

ADAM23 is involved in neuronal excitability and interacts with LGI1, a known genetic risk factor for focal epilepsy. While ADAM23 has been linked to canine seizures, a recent gene-burden meta-analysis first nominated it as a risk gene for epilepsy in humans. Building on these findings, our study aimed to explore the significance of truncating ADAM23 variants in deeply phenotyped individuals with diverse seizure disorders.

We screened the exome sequencing data from 389 individuals with various seizure phenotypes for truncating variants in ADAM23. This report focuses on one individual harboring a heterozygous frameshift variant in ADAM23, selected for detailed analysis due to intriguing additional genetic findings.

We identified a heterozygous frameshift variant (c.428del, p.Asn143Ilefs*26) in ADAM23 (NM_003812.4) in a patient with drug-resistant, MRI-negative focal epilepsy accompanied by additional neurocognitive and behavioral issues. The ADAM23 variant was inherited from an unaffected parent. Notably, the same individual carried inherited, truncating variants in two other brain-expressed, loss-of-function-intolerant genes: TNRC6A and MAPK8IP3.

These findings suggest that ADAM23 contributes to epilepsy with reduced penetrance, potentially influenced by oligogenic factors. Although descriptive and hypothesis-generating, our data underscore the complexity of currently unexplored genetic contributions to epilepsy.