A new locus for familial temporal lobe epilepsy on chromosome 3q

• We performed linkage analysis in a family with autosomal dominant inheritance of seizures originating in the temporal lobe.
• Seizures were infrequent and generally responded well to treatment. The proband had no hippocampal sclerosis.
• Epilepsy was not preceded by febrile seizures, however four subjects with no epilepsy had febrile seizures in childhood.
• We established linkage in a region on chromosome 3q25-q26 not corresponding to any known locus for familial epilepsy.
• We found no disease causing mutations in two candidate genes in the linked region, KCNAB1 and NLGN1.

SummaryBackgroundTemporal lobe epilepsy (TLE) is a common and heterogeneous focal epilepsy syndrome with a complex etiology, involving both environmental and genetic factors. Several familial forms of TLE have been described, including familial lateral TLE (FLTLE), familial mesial TLE (FMTLE) without hippocampal sclerosis, and FMTLE with hippocampal sclerosis. Mutations have been identified only in the leucine-rich, glioma-inactivated 1 (LGI1) gene on chromosome 10q22-q24 in FLTLE. Several loci have been mapped in families with FMTLE, but responsible genes have not been found. We report clinical evaluation in a large family with FMTLE and a new genetic locus.MethodsWe conducted a genome-wide scan using 10 cM-spaced microsatellite markers on a family with TLE. Seven individuals had TLE without antecedent FS; four other individuals had FS during childhood, but no subsequent epilepsy. Patients with TLE had infrequent simple partial, complex partial and secondarily generalized seizures that generally responded well to treatment. The proband had no hippocampal sclerosis. The mode of inheritance appeared to be autosomal dominant with incomplete penetrance. Linkage analysis was performed using the Genehunter software. Regions with LOD score > 1 and those that were poorly informative in the first-pass scan were further genotyped.ResultsLinkage was identified on chromosome 3q25-q26 in a 13 cM region flanked by markers D3S1584 and D3S3520, with a peak LOD score of 3.23. This interval does not correspond to any previously known locus for familial epilepsy or FS. KCNAB1, encoding a voltage-gated, shaker-related potassium channel, and NLGN1, encoding a member of a family of neuronal cell surface protein were excluded as disease causing mutations.ConclusionWe identified a novel locus for familial TLE with FS, providing additional evidence of the complexity and genetic heterogeneity of familial focal epilepsy.