Human Molecular Genetics, 2000, Vol. 9, No. 1 87-91
© 2000 Oxford University Press
Significant evidence for linkage of febrile seizures to chromosome 5q14–q15
1Department of Medical Genetics, Institute of Basic Medical Sciences and 2Department of Pediatrics, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan, 3Department of Pediatrics, Kitaibaraki Municipal General Hospital, Ibaraki 319-1702, Japan, 4Department of Pediatrics, Kensei General Hospital, Ibaraki 309-1223, Japan, 5Department of Pediatrics, Hitachi General Hospital, Ibaraki 317-0077, Japan and 6Department of Pediatrics, Tsukuba Memorial Hospital, Ibaraki 300-2622, Japan
Received 9 August 1999; Revised and Accepted 28 October 1999.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
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Febrile seizures (FSs) represent the most common form of childhood seizure. In the Japanese population, the incidence rate is as high as 7%. It has been recognized that there is a significant genetic component for susceptibility to this type of seizure. Two putative FS loci, FEB1 (chromosome 8q13–q21) and FEB2 (chromosome 19p), have been mapped. Furthermore, a mutation in the voltage-gated sodium (Na+)-channel ß1 subunit gene (SCN1B) at chromosome 19q13.1 was identified in a family with a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+). These loci are linked to some large families. In this study, we conducted a genome-wide linkage search for FS in one large family with subsequent linkage confirmation in 39 nuclear families. Significant linkage was found at D5S644 by multipoint non-parametric analysis using GENEHUNTER (P = 5.4 x 10–6). Estimated
s at D5S644 was 2.5 according to maximum likelihood analysis. Significant linkage disequilibria with FS were observed at the markers D5S644, D5S652 and D5S2079 in 47 families by transmission disequilibrium tests. These findings indicate that there is a gene on chromosome 5q14–q15 that confers susceptibility to FSs and we call this gene FEB4. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
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Childhood convulsions associated with episodes of fever [febrile seizures (FSs)] are relatively common and represent the majority of childhood seizures. FSs usually occur between 3 months and 5 years of age, and are associated with fever but do not show evidence of intracranial infection or other defined cause (1). Studies in the developed world indicate that 2–5% of all children will experience an FS before the age of 5 (2,3). In Japanese populations, the incidence rate is as high as 7% (4). Approximately 33% of FS patients will experience a second FS (4–8). Of this subpopulation, 50% will have a third. Only 9% of recurrent FS patients have more than three FSs (2,9). Two to seven percent of children who experience FSs go on to develop non-febrile seizure disorders and epilepsy later in life (9,10).
FSs are more likely to occur with a high frequency in families where there is a documented history of FSs (2). Children from such families show a 3-fold or greater risk than the general population of experiencing FSs. The genetics of familial FSs is somewhat ambiguous. Polygenic, autosomal dominant and autosomal recessive models have received support (11–14). Recently, two putative FS loci, FEB1 (chromosome 8q13–q21) and FEB2 (chromosome 19p), were identified by parametric linkage analyses of a large Australian family (15) and a large Midwestern family (16), respectively. Subsequent linkage analyses showed that seizures were linked to FEB2 in one of four large FS families and were not linked to FEB1 in any of these families (17). These data indicate that these loci are not commonly linked to FSs.
A clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond 6 years of age or be associated with afebrile generalized seizures, was described (18). Analysis in one family with GEFS+ identified a mutation in the voltage-gated sodium (Na+)-channel ß1 subunit gene (SCN1B) on chromosome 19q13.1 that was linked to and associated with GEFS+ (19). However, the mutation in SCN1B was not found in 25 other GEFS+ families or 25 FS families indicating that SCN1B mutations are rare as contributors to GEFS+ and FSs.
Loci reportedly linked to FSs have been identified through analysis of large multiplex families where the mode of inheritance was consistent with an autosomal dominant model (15–17,19). In the present study, we tried to identify loci linked to FSs in nuclear families using non-parametric allele sharing methods and found an FS susceptibility locus at chromosome 5q14–q15.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
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Forty-seven families were analyzed in this study (Table 1). All affected children experienced one or more FSs before the age of 5. Of these families, seven consisted of only trios of parents and a child with at least one FS and were used for a transmission disequilibrium test (TDT). Linkage was studied in 40 families. We initially screened for possible linkage loci for FSs in a large multiplex family, KI#1 (Fig. 1), and subsequently confirmed linkage for FSs in nuclear families. A genome-wide scan was performed by semi-automated genotyping of 358 highly polymorphic microsatellite markers (CHKC/Weber Human Screening Set v8) in family KI#1 members, and we evaluated linkage with multipoint non-parametric linkage (NPL) scores by total stat command in GENEHUNTER (20). Through the genome-wide scan, five markers, D1S552, D4S2397, D5S1725, D10S2325 and D15S659 had P values of 0.012, 0.005, 0.012, 0.016 and 0.012, respectively, which were <0.05 for linkage. Genotyping these five markers in 39 nuclear FS families using the single-point command of GENEHUNTER showed that one marker, D5S1725, was possibly a locus linked with FSs and had a P value of 0.048 in the 39 nuclear families and 0.027 in the total families.
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As a next step, we examined linkage using 19 additional microsatellite markers (D5S2029, D5S617, D5S618, D5S815, D5S2100, D5S2498, D5S644, D5S652, D5S1462, D5S484, D5S1393, D5S1496, D5S495, D5S2079, D5S1503, D5S1373, D5S409, D5S1453, D5S2501) spanning 26 cM located near D5S1725 in 40 families. The locations of these markers were based on those in the Genome Data Base (GDB; http://gdb.org ). Multipoint-linkage analysis showed an NPL Zall score of 4.59 (P = 5.4 x 10–6) at D5S644 (Fig. 2). The NPL Zpairs scores were lower than the NPL Zall scores between D5S617 and D5S2498. An NPL Zpairs score of 3.84 (P = 5.7 x 10–5) at D5S644. The Zlr scores by the asm program were almost the same as the NPL Z scores (Fig. 2). Information contents were >0.8 through the 26 cM area. Although the 39 nuclear families contributed little for the marker D5S1725, they contributed considerably for D5S644: the P value at D5S644 for the KI#1 family was 0.006 and that for the 39 nuclear families was 0.0004. The maximum likelihood of the proportion of zero-sharing sib-pairs (weighted) was 0.10 at D5S644, allowing us to estimate
s of 2.5 at the locus.
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TDT of the 20 markers was performed in 47 families using the SIB-PAIR program. Because we tested 20 markers, global TDT was considered significant at markers where P < 0.0025. Because we tested a total of 182 alleles, allele-by-allele TDT was considered significant where P < 0.00028. Significant transmission disequilibrium was observed for D5S644, D5S652 and D5S2079 (Table 2). Allele-by-allele TDT showed that the 97 bp allele of D5S644, the 202 bp allele of D5S652 and the 226 bp allele of D5S2079 were significantly preferentially transmitted to affected children. Marginal genotypic TDT showed that homozygosity for the 97 bp allele at D5S644 was transmitted to affected children 18 times and not transmitted 5 times (uncorrected P = 0.007), and the genotype homozygous for the 202 bp allele at D5S652 was transmitted to affected children 37 times and not transmitted 10 times (uncorrected P = 0.00008).
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In our children with FSs, five also had afebrile seizures, suggesting some heterogeneity. Therefore, we re-analyzed the data by those with afebrile seizures as unknown phenotype. Slightly decreased NPL scores were obtained between D5S1725 and D5S2501. An NPL Zall score decreased to 3.68 (P = 7.8 x 10–5) at D5S644. TDT also resulted in slightly less deviated transmissions of alleles listed in Table 2 to affected children (data not shown). Therefore, both individuals with FS only and those with FS and afebrile seizures commonly contributed for the linkage and transmission disequilibrium at this region.
The most likely haplotypes of the individuals in family KI#1 were generated by GENEHUNTER (Fig. 1). The same haplotype of the region from D5S1725 to D5S652 was transmitted to all affected children. The 97 bp allele at D5S644 and the 202 bp allele at D5S652 of this haplotype were the commonly transmitted alleles found in the TDT. The 224 bp allele at D5S2079 transmitted to all but one affected children in family KI#1 was not preferentially transmitted to affected children in the 39 nuclear families.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
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The present study suggests a susceptibility locus for FSs near the marker D5S644 at chromosome 5q14–q15. We propose calling this locus FEB4. In contrast to FEB1 and FEB2, linkage to FEB4 was suggested in nuclear FS families, indicating that FEB4 may be the linkage locus common in FS families. Based on the almost 3-fold risk for FSs (21–24) in sibs of FS probands and the estimated locus-specific
s of 2.5 at D5S644, FEB4 may represent nearly 70% of the total FS genetic susceptibility. This large contribution either suggests that this is a major or submajor gene locus for FSs in the general population or it may indicate a Japanese-specific effect. The higher incidence rate of FS in Japanese than in Caucasian populations may support the latter possibility (4).
Most of the FS families that we analyzed in this study were nuclear families. The mode of inheritance of FSs in nuclear families is not known. Therefore, we analyzed linkage by non-parametric methods. One shortcoming of non-parametric methods is that the linkage region is not narrowed. The NPL scores were >3.0 in the region between D5S1725 and D5S2501, which spans ~20 cM. To narrow the linkage region, TDT was performed. Significant transmission disequilibrium was observed at D5S644 and D5S652 where the most significant linkage was observed. Haplotypes in family KI#1, in which one recombination was observed between D5S652 and D5S1462 in individual III-7, favor the supposition that susceptibility gene(s) exist proximal to D5S1462. These data suggest that the gene that contributes to FSs is located near D5S644 and D5S652. Maximum likelihood of proportion of two identical-by-descent-shared affected sib-pairs was 0.5, and the homozygous states for the 97 bp allele of D5S644 and the 202 bp allele of D5S652 were transmitted preferentially to the affected children suggesting that the gene for susceptibility is inherited in a recessive or additive fashion rather than in a dominant fashion. Some genes mapped to this region of chromosome 5, including calpastatin, polysialtransferase and peptidylglycine 
-amidating monooxygenase (25–27), are expressed in human and/or rat brain (28–30) and may be candidate genes for FSs.
The marker D5S2079 is not linked to the KI#1 family and is 3.3 cM telomeric to D5S644 and D5S652, yet significant transmission disequilibrium was found. Significant trans- mission disequilibrium was not found for the markers between D5S652 and D5S2079. Disequilibrium is usually only found over very small map distances. Although the NPL Zall score of 3.67 (P = 0.0002) at D5S2079 was not approaching significant linkage, the possibility of an FS locus in the region including D5S2079 remains, warranting further studies.
Although all offspring of the families examined in this study had evidence of FSs, some also had afebrile seizures, suggesting some heterogeneity. Data on linkage and linkage disequilibrium at D5S644, D5S652 and D5S2079 do not suggest different contribution between presence and absence of afebrile seizures. Scheffer et al. (18) defined GEFS+ families as those in which many family members have seizures with fever that may persist beyond 6 years of age or are associated with afebrile generalized seizures. Wallace et al. (19) reported linkage to chromosome 19q13.1 in a large GEFS+ family and identified a mutation in SCN1B. According to Scheffer et al. (18), family KI#1 in which we screened the entire genome for linkage is regarded as GEFS+. The GEFS+ family members with the SCN1B mutation showed a broad spectrum of different seizure phenotypes even though they had the same mutation. Based on Wallace et al.’s (19) observations, we hypothesized that FSs in family KI#1 and our nuclear families had a common susceptibility locus for FSs and we tried to find a locus commonly associated with FSs and GEFS+. Although our data support the hypothesis that FEB4 confers susceptibility to FSs and GEFS+, the small number of GEFS+ cases in this study warrants further investigation.
Management and prophylaxis of FSs remain controversial. Although there is still controversy over whether FS patients go on to develop an increased incidence of mesial temporal sclerosis, which is the primary cause of temporal lobe epilepsy, a prolonged FS is considered the most important determinant of the association between FSs and mesial temporal sclerosis (9). The establishment of a linkage marker, and eventual identification of a specific gene, will have direct implications for accurate counseling of parents and for planning appropriate trials of prophylactic therapies.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
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Subjects
The families analyzed in this study were recruited through FS patients visiting the Pediatric Neurology Clinic of Tsukuba University Hospital. Diagnosis of FSs was performed by analyzing medical records and collecting detailed information about convulsive disorders in family members interviewed by trained pediatricians. A full verbal and written explanation of the study was given to all family members interviewed, and 47 families (185 members including 95 affected children) gave informed consent and participated in this study. Fathers’ samples were not available in six nuclear families. Informed consent for subjects under school age was given by their parents. This study was approved by the Ethics Committee of University of Tsukuba, Japan. The characteristics of subjects are shown in Table 1.
Molecular methods
DNA was extracted from peripheral blood leukocytes of the subjects. Genotypes were determined by the sizes of the fragments amplified by polymerase chain reaction with fluorescently labeled primers. Electrophoresis was carried out using the ABI PRISM model 377 sequencer. Genescan Analysis 3.1 and Genotyper 2.5 (Perkin-Elmer, Foster City, CA) were used for semi-automatic ‘allele calling’ as described in the manufacturer’s manual.
Statistical analyses
Linkage analyses were performed using the computer program GENEHUNTER 2 (20) for the multipoint and single-point non-parametric analysis. Equal marker allele frequencies were used for the initial genome-wide screen (CHKC/Weber Human Screening Set v8; Research Genetics, Huntsville, AL) for FS loci in family KI#1. Allele frequencies estimated from the parental chromosomes were used for the dense markers at 5q14–q15 to evaluate linkage in our total families. We used the NPL Zall statistic and the results were repeated using the Zpairs statistic and the asm program as per GENEHUNTER-PLUS software (31) to obtain the Zlr. P-values are computed by GENEHUNTER assuming the NPL Zall scores follow a standard normal distribution. TDT was performed using the SIB-PAIR program (http://www.qimr.edu.au/davidD/davidd.html ).
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ACKNOWLEDGEMENT |
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This work was supported in part by a grant from the University of Tsukuba Research Project.
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NOTE ADDED IN PROOF |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
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Whilst this paper was under review, a paper was published by Peiffer et al. [A locus for febrile seizures (FEB3) maps to chromosome 2q23–24, Ann. Neurol., 46, 671–678, 1999]: there now appear to be at least four loci for febrile seizures.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +81 298 53 3352; Fax: +81 298 53 3177; Email: tarinami@md.tsukuba.ac.jp
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
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T. Sugawara, Y. Tsurubuchi, K. L. Agarwala, M. Ito, G. Fukuma, E. Mazaki-Miyazaki, H. Nagafuji, M. Noda, K. Imoto, K. Wada, et al. A missense mutation of the Na+ channel alpha II subunit gene Nav1.2 in a patient with febrile and afebrile seizures causes channel dysfunction PNAS, May 22, 2001; 98(11): 6384 - 6389. [Abstract] [Full Text] [PDF]
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