Abstracts

Benign familial infantile seizures (BFIS) and paroxysmal dyskinesias (PD) are clinically and genetically heterogeneous, autosomal dominant disorders. In some families BFIS occurs together with PD. We have identified and clinically characterized two large Finnish families with BFIS and PD linked to chromosome 16p12.1-16p11.2. Here we have used linkage and candidate gene analysis with the aim of further narrowing the disease gene region and of identifying the underlying mutation(s). Medical records of 18 consenting patients were examined. Microsatellite markers were tested to evaluate the disease gene locus on chromosome 16. Haplotypes spanning the candidate region were constructed and LOD scores were calculated with MLINK and GENEHUNTER 2.1 programs. The gene content of the region of interest was examined with the NCBI genome browser. The coding regions and exon-intron boundaries of three candidate genes were amplified from genomic DNA by PCR and sequenced in 2 patients and 1 control. The affected individuals had variable phenotypes including infantile convulsions with favorable outcome and paroxysmal dyskinesia with onset later in life. The infantile convulsions started at the age of 3 to 8 months and subsided later. The onset of PD was at the age of 5 to 17 years and the PD symptoms had features of both kinesigenic and non-kinesigenic dyskinesia. The psychomotor development of all patients was normal. Significant linkage was detected to markers on chromosome 16p12.1-16p11.2. A maximum two-point LOD score of 4.95 (at [theta]=0.000) and multipoint LOD score of 4.80 were obtained at marker D16S3022 using a penetrance of 80% and a phenocopy rate of 2%. Meiotic recombinations defined a candidate region of 4.76 cM, where patients in the two families shared a common haplotype suggesting a common ancestor. This 4.60 Mbp region contains 140 known or predicted genes in NCBI sequence map. Three genes were considered as potential candidates due to their position, known or predicted function, and expression in the central nervous system. The genes were sequenced exon by exon from PCR-amplified genomic DNA. No disease-associated mutations were identified in the coding or immediate flanking intronic regions. Some previously described exonic polymorphisms were found. The candidate locus on chromosome 16 contains 140 already known or predicted genes. By sequence analysis we were not able to identify a disease-associated mutation in three positional and functional candidates making these genes unlikely to underlie the BFIS-PD phenotype in our families. (Supported by Finnish State Grant TYH3239, The Folkhalsan Research Foundation, University of Helsinki)