Identification of a novel locus for febrile seizures and epilepsy on chromosome 21q22.
OBJECTIVE
To report results of linkage analysis in a large family with autosomal dominant (AD) febrile seizures (FS) and epilepsy.


BACKGROUND
AD FS and epilepsy is clinically and genetically a heterogeneous group of epilepsies, frequently inherited. The most notable, generalized epilepsy with febrile seizures plus (GEFS+), is characterized by heterogeneous phenotypes including FS persisting beyond the usual age of remission or coexisting with afebrile seizures. Mutations in three subunits of sodium channel genes and one GABA(A)-receptor subunit gene have been identified in some GEFS+ pedigrees. Six genetic loci for FS have been reported so far, but the molecular basis of FS remains unknown.


METHODS
We identified a five-generation family with 13 individuals affected by FS. Evidence was found for coexisting afebrile seizures in some affected individuals. Evaluation included a detailed history and neurologic examination, as well as collection of DNA. After excluding previously identified loci associated with FS and epilepsy, a genome-wide search was performed.


RESULTS
Two affected individuals reported only a single FS, whereas the other affected individuals had a history of repeated FS. Coexisting afebrile seizures developed in three individuals. The mode of inheritance was consistent with AD inheritance with an incomplete penetrance. Tight linkage to a group of markers on chromosome 21q22 was identified with flanking markers D21S1909 and D21S1444, and maximum 2-point lod score 3.35 for markers D21S1910 and D21S1894. We excluded four ion-channel genes within this 6.5-cM locus as a cause of FS and epilepsy in this family.


CONCLUSIONS
We report a novel locus on chromosome 21q22 for AD FS. Identification of the gene causing epilepsy on chromosome 21q22 will advance our understanding of inherited epilepsy and FS, and possibly other types of epilepsies.
Hedera
Peter
P
Department of Neurology, Vanderbilt University, Nashville, Tennessee 37232-8552, USA. peter.hedera@vanderbilt.edu
Ma
Shaochun
S
Blair
Marcia A
MA
Taylor
Kelly A
KA
Hamati
Aline
A
Bradford
Yuki
Y
Abou-Khalil
Bassel
B
Haines
Jonathan L
JL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002675:Child, Preschool; D002874:Chromosome Mapping / Q000706:statistics & numerical data*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D004827:Epilepsy / Q000453:epidemiology / Q000235:genetics*; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D019683:Penetrance; D003294:Seizures, Febrile / Q000453:epidemiology / Q000235:genetics*
D005819:Genetic Markers