Abstracts

Rationale: Mutations in the LIS1 gene are known to cause lissencephaly and posterior subcortical band heterotopia, with associated developmental delay, intellectual disability and epilepsy. To date, mutations within LIS1 have only been reported in severely affected sporadic subjects. Here we report the first family with epilepsy caused by a segregating LIS1 point mutation. Methods: Multigenerational family study with extensive electroclinical and imaging phenotyping incorporating interictal and ictal EEG, MRI, SPECT, PET, EEG-fMRI and molecular genetic analyses. Results: A three generation family was studied. The proband, her sister and mother had childhood onset, refractory epilepsy with a mixture of focal and generalized seizures and electrographic features. They had mild intellectual disability but all lived independently as adults. The cause of their familial epilepsy had remained obscure despite meticulous clinical study over two decades. Interictal and ictal EEG, ictal SPECT, PET and 1.5 and 3T MRI did not enable localisation of epileptogenic regions. EEG-fMRI of the proband showed increased BOLD signal in posterior brain regions, prompting repeat brain MRI, revealing subtle, posterior-dominant band heterotopia. Sequence analysis of the LIS1 gene demonstrated a missense mutation (c.484G>A (p.Gly162Ser)) in the proband, her mother and her sister. Pathogenicity was corroborated by Polyphen-2 (score: 1.00, probably damaging). Further support came from a report of the same mutation in an unrelated individual with subtle posterior pachygyria and a mild phenotype (Cardoso, C., Leventer, R. J. et al. (2000) Human Molecular Genetics 9, 3019-3028). Sanger sequencing of DNA from the proband's deceased maternal grandfather, who had suffered 4 convulsions during life, did not demonstrate the mutation. Allele-specific PCR optimised to demonstrate <1% mosaicism did not reveal mosaicism in this individual. Conclusions: This is the first report of a familial intragenic LIS1 mutation. Mutations in LIS1 should be considered among the causes of familial epilepsies and MRI scans in such patients scrutinized for subtle posterior-predominant malformations. Genetic counseling for individuals with milder LIS1 mutations is crucial.