Our 2-point LOD score of 1.85 and multipoint LOD score of 2.93 in these three additional families with ADPEAF provide strong confirmatory evidence for link age of a gene causing this syndrome to chromosome 10q24. Because replication involves testing an established hypothesis, a lower LOD score is needed to establish statistical significance in a replication study than in a genome-wide scan used to search for linkage. Lander and Kruglyak (46
) recommended a nominal p value of 0.01 for confirmation
of linkage, corresponding to a LOD score of ~1.2 (i.e., lower than their recommended LOD score of 3.3 for detection
of linkage). Unfortunately, there were no key recombinants in any of these three families that allowed us to narrow the minimal genetic region further. However, if it can be assumed that the Basque family described by Poza et al. (33
) harbors the same gene, the region of interest can be narrowed to the 3-cM overlap zone.
Phenotype definition poses a significant problem in the investigation of the genetic basis of epilepsy. We focused on auditory auras as the characteristic symptom to define the ADPEAF phenotype and direct the search for additional families. Our linkage results in these families confirm that this cardinal clinical manifestation has genetic relevance, and merits its place in definition of the ADPEAF phenotype. Although other symptoms are reported in these families, they may not be so specific an indicator of this genetic syndrome. One reason auditory auras are useful for defining a characteristic phenotype is the infrequency with which they are reported. In most studies, elementary auditory auras occur in <3% of patients (35
). In addition, auditory auras can give insight into an anatomic site of the abnormality produced by mutations in the ADPEAF gene, because they have been shown to be particularly useful in localization to the lateral temporal lobe (35
Based on our haplotype analysis, it appears that febrile seizures are not part of the ADPEAF phenotype. However, individuals whose epilepsy was attributed to severe head trauma were found to carry the haplotype, suggesting that their epilepsy may have been caused either by the gene or a gene–environment interaction.
ADPEAF appears to be quite rare. The original family in which we found linkage was identified from our database of 1,957 families collected for epidemiologic purposes without regard to family history. Very few of the other families in this database had family histories consistent with autosomal dominant inheritance, and only one other small family (family C, ) appeared to have auditory symptoms consistent with ADPEAF. We also solicited referrals of patients with the syndrome in a mailing to the membership of the American Epilepsy Society, and many members said that none had been seen in their practices.
Despite the probable rarity of this syndrome, identification of the causative gene on chromosome 10q would have broad, important implications. Discovery of the gene, its product, and its pathophysiologic mechanism would elucidate the way in which a genetic defect can produce abnormalities that differentially affect the lateral temporal lobe, and may give insight into the pathophysiology of focal epilepsy, or epilepsy overall.
We have been performing molecular studies aimed at identification of the causative gene, focusing on the 3-cM overlap region between our original linkage family and that described by Poza et al. (33
). These studies indicate that the overlap region (between markers D10S185 and D10S577) is approximately four megabases in size. The region does not appear to contain any obviousion channels, but several genes contain membrane-spanning regions and may be reasonable candidates. Recently mutation screening for one of these has produced promising results, which we will describe separately.