Novel susceptibility locus at chromosome 6q16.3-22.31 in a family with GEFS+.

BACKGROUND: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with extremely variable expressivity. Mutations in 5 genes that raise susceptibility to GEFS+ have been discovered, but they account for only a small proportion of families. METHODS: We identified a 4-generation family containing 15 affected individuals with a range of phenotypes in the GEFS+ spectrum, including febrile seizures, febrile seizures plus, epilepsy, and severe epilepsy with developmental delay. We performed a genome-wide linkage analysis using microsatellite markers and then saturated the potential linkage region identified by this screen with more markers. We evaluated the evidence for linkage using both model-based and model-free (posterior probability of linkage [PPL]) analyses. We sequenced 16 candidate genes and screened for copy number abnormalities in the minimal genetic region. RESULTS: All 15 affected subjects and 1 obligate carrier shared a haplotype of markers at chromosome 6q16.3-22.31, an 18.1-megabase region flanked by markers D6S962 and D6S287. The maximum multipoint lod score in this region was 4.68. PPL analysis indicated an 89% probability of linkage. Sequencing of 16 candidate genes did not reveal a causative mutation. No deletions or duplications were identified. CONCLUSIONS: We report a novel susceptibility locus for genetic epilepsy with febrile seizures plus at 6q16.3-22.31, in which there are no known genes associated with ion channels or neurotransmitter receptors. The identification of the responsible gene in this region is likely to lead to the discovery of novel mechanisms of febrile seizures and epilepsy.

MHC fine mapping of human type 1 diabetes using the T1DGC data.

AIM: The human Major Histocompatibility Complex (MHC) is a highly polymorphic genomic region occupying approximately 4 Mb on chromosome 6p21.3. The relationship between human MHC and type 1 diabetes (T1D) has been previously investigated. To fine map the disease locus in this region, we carried out both linkage and association analyses using the Type 1 Diabetes Genetics Consortium data. METHODS: Two-point linkage analysis was performed with a set of microsatellite markers assuming a fully recessive inheritance model, where we found clustering of high LOD (logarithm of the odds) scores across the MHC region. To narrow down the linkage region, we performed association analyses using both microsatellite and two sets of single nucleotide polymorphism (SNP) markers. We focused on the nuclear families containing a discordant sib-pair (an affected and unaffected sib). For the microsatellite markers, we computed the average repeat length for each individual and carried out a paired t-test. RESULTS: Microsatellite marker D6S2884 showed the highest association in a sharp peak with a p value of 3.15E-24. We confirmed this finding when using also SNP markers performing a McNemar's test for association. The SNPs that showed the most significant evidence of association mapped to almost the same location as the microsatellite markers. CONCLUSIONS: Besides the main goal of fine mapping of T1D genes, our results also illustrated the differences and the advantage of using both linkage and association analyses. After the identification of a wide peak with linkage analysis, we were able to dramatically narrow down the region by performing association analysis.