RESUMEN
We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 x 10(-8)). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 15 , Epilepsia Generalizada/genética , Predisposición Genética a la Enfermedad , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Humanos , Masculino , Receptores Nicotínicos/genética , Factores de Riesgo , Adulto Joven , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
PURPOSE: We observed three apparently unrelated and geographically separate Arab families with Lafora disease in Israel and the Palestinian territories. METHODS: We clinically evaluated the families and analyzed their DNA for EPM2A mutations. RESULTS: Of seven individuals with Lafora disease, the clinical onset varied from 13 to 20 years. All three families shared the same novel homozygous deletion in EPM2A. Haplotype analysis around the deletion showed that the families shared a common homozygous haplotype. The boundaries of this haplotype varied between families and even within one family. CONCLUSIONS: We conclude that considerable variability in the age at onset of Lafora disease can occur within families. Identical mutations can be associated with the classic adolescent presentation, as well as late-onset cases. Haplotype analysis suggests that this EPM2A mutation arose many generations previously, so it may be of importance for cases distributed more widely in the Middle East.
Asunto(s)
Árabes/etnología , Árabes/genética , Proteínas Portadoras/genética , Deleción Cromosómica , Familia , Efecto Fundador , Enfermedad de Lafora/diagnóstico , Enfermedad de Lafora/genética , Mutación/genética , Adolescente , Adulto , Edad de Inicio , Femenino , Frecuencia de los Genes/genética , Pool de Genes , Genotipo , Haplotipos/genética , Homocigoto , Humanos , Israel/epidemiología , Enfermedad de Lafora/epidemiología , Masculino , Medio Oriente/epidemiología , Linaje , FenotipoRESUMEN
PURPOSE: Idiopathic generalized epilepsy (IGE) accounts for approximately 20% of all epilepsies and affects about 0.2% of the general population. The etiology of IGE is genetically determined, but the complex pattern of inheritance suggests an involvement of a large number of susceptibility genes. The objective of the present study was to explore the genetic architecture of common IGE syndromes and to dissect out susceptibility loci predisposing to absence or myoclonic seizures. METHODS: Genome-wide linkage scans were performed in 126 IGE-multiplex families of European origin ascertained through a proband with idiopathic absence epilepsy or juvenile myoclonic epilepsy. Each family had at least two siblings affected by IGE. To search for seizure type-related susceptibility loci, linkage analyses were carried out in family subgroups segregating either typical absence seizures or myoclonic and generalized tonic-clonic seizures on awakening. RESULTS: Nonparametric linkage scans revealed evidence for complex and heterogeneous genetic architectures involving linkage signals at 5q34, 6p12, 11q13, 13q22-q31, and 19q13. The signal patterns differed in their composition, depending on the predominant seizure type in the families. CONCLUSIONS: Our results are consistent with heterogeneous configurations of susceptibility loci associated with different IGE subtypes. Genetic determinants on 11q13 and 13q22-q31 seem to predispose preferentially to absence seizures, whereas loci on 5q34, 6p12, and 19q13 confer susceptibility to myoclonic and generalized tonic-clonic seizures on awakening.