Penetrance of LGI1 mutations in autosomal dominant partial epilepsy with auditory features

BACKGROUND: Assessment of the penetrance of disease-causing mutations is extremely important for developing clinical applications of gene discovery, such as genetic testing and counseling. Mutations in the leucine-rich, glioma inactivated 1 gene (LGI1) have been identified in about 50% of families with autosomal dominant partial epilepsy with auditory features (ADPEAF), but estimates of LGI1 mutation penetrance have ranged widely, from 50 to 85%. The current study aimed to provide a more precise estimate of LGI1 mutation penetrance. METHODS: We analyzed data from all 24 previously published ADPEAF families with mutations in LGI1. To estimate penetrance, we used the information from the published pedigree figures to determine the proportion of obligate carriers who were affected. We assessed whether penetrance was associated with the total number of affected individuals in each family, or mutation type (truncating or missense) or location within the gene. We also compared penetrance in males and females, and among different generations within the families. RESULTS: Overall penetrance was 67% (95% CI 55-77%), and did not vary according to mutation type or location within the gene. Penetrance was greater in families with more affected individuals, but this trend was not significant. Penetrance did not differ by gender but increased with advancing generation, probably because of limited information about early generations. CONCLUSIONS: Our results suggest that about two-thirds of individuals who inherit a mutation in LGI1 will develop epilepsy. This probably overestimates the true penetrance in the population because it is based on data from families containing multiple affected individuals.