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From the Division of Epilepsy and Clinical Neurophysiology (A.P., V.C.), Department of Neurology, Children’s Hospital Boston, MA; Department of Biostatistics (Y.W.), Mailman School of Public Health, Columbia University, New York, NY; Department of Genetics (D.G.), Rutgers University, Piscataway, NJ; Gertrude H. Sergievsky Center (S.B.-R., C.B.-C., A.U., W.A.H., R.O.), Columbia University, New York; Division of Genetics (R.S.H., C.A.W.), Children’s Hospital Boston and Harvard Medical School, Boston; Department of Neurology and Howard Hughes Medical Institute (R.S.H., C.A.W.), Beth Israel Deaconess Medical Center, Boston; Institute for Human Genetics (N.R.), University of California at San Francisco; Department of Neurology (W.A.H., T.A.P., R.O.), College of Physicians and Surgeons, Columbia University, New York; Department of Epidemiology (C.B.-C., W.A.H., R.O.), Mailman School of Public Health, Columbia University, New York; and New York State Psychiatric Institute (R.O.), New York-C. is currently with Social & Scientific Systems, Inc., Durham, NC.
Address correspondence and reprint requests to Dr. Ruth Ottman, G.H. Sergievsky Center, Columbia University, 630 W. 168th St., P&S Box 16, New York, NY 10032
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.
Abbreviations: CIDR = Center for Inherited Disease Research; EFSCU = Epilepsy Family Study of Columbia University; FS = febrile seizures; FS+ = febrile seizures plus; GBP = gabapentin; GEFS+ = genetic epilepsy with febrile seizures plus; GTC = generalized tonic-clonic seizure without aura or lateralizing postictal symptoms or signs; Mb = megabase; MGR = minimal genetic region; PPL = posterior probability of linkage; SMEB = borderline severe myoclonic epilepsy of infancy; STRP = short tandem repeat polymorphism; UCSC = University of California Santa Cruz.
Supported by NIH grants R01 NS020656 and R37 NS35129.
Disclosure: Author disclosures are provided at the end of the article.
Received January 13, 2009. Accepted in final form July 16, 2009.
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