Suggestive evidence for a new locus for epilepsy with heterogeneous phenotypes on chromosome 17q

Abstract

Purpose: To characterize the clinical features and molecular genetic background in a family with various epilepsy phenotypes including febrile seizures, childhood absence epilepsy, and possible temporal lobe epilepsy.

Methods: Clinical data were collected. DNA and RNA were extracted from peripheral blood. A genome-wide microsatellite marker scan was performed and regions with a multipoint location score > or =1.5 were fine mapped. Functional candidate genes identified from databases and by comparing gene expression profiles of genes between affected and unaffected individuals were sequenced. Copy number variation was evaluated with array-based comparative genomic hybridization.

Results: The seizure phenotype was benign. Inheritance was consistent with an autosomal dominant model and reduced penetrance. The highest two-point LOD score of 2.8 was identified at marker D17S1606 in a 37cM interval on chromosome 17q12-q24. Loci on 5q11.2 and on 18p11-q11, showed LOD scores > or =1.5 after fine mapping. Sequencing of nine ion-channel genes and two (RPIP8 and SLC25A39) differentially expressed genes from 17q12-q24, as well as IMPA2 from 18p11-q11 did not reveal a pathogenic alteration. No clinically relevant copy number variation was identified.

Conclusions: Our findings suggest complex inheritance of seizure susceptibility in the family with contribution from three loci, including a possible new locus on chromosome 17q. The underlying molecular defects remain unknown.