Evidence for autosomal dominant inheritance of prostate cancer.

A family-history cancer survey was conducted on 5,486 men who underwent a radical prostatectomy, for clinically localized prostate cancer, in the Department of Urology at the Mayo Clinic during 1966-95; 4,288 men responded to the survey. Complex segregation analysis was performed to assess the genetic basis of age at diagnosis and the familial clustering of prostate cancer. For the total group, no single-gene model of inheritance clearly explained familial clustering of disease, which could be partly explained by lack of Hardy-Weinberg equilibrium, with an excess of homozygotes. After accounting for deviations from Hardy-Weinberg equilibrium, the best-fitting model that explained the familial aggregation and age at diagnosis was a rare autosomal dominant susceptibility gene, and this model fitted best when probands were diagnosed at <60 years of age. The model predicts that the frequency of the susceptibility gene in the population is .006 and that the risk of prostate cancer by age 85 years is 89% among carriers of the gene and 3% among noncarriers. A strength of our study is its large size, such that genetic models could be fitted within strata defined by the age of the proband. Although the autosomal dominant model was consistently the best model, the parameter estimates differed somewhat (P=.03) across the different age groups, suggesting genetic heterogeneity. Additional evidence that the hereditary basis of prostate cancer is likely to be genetically complex was provided by the following: (1) there was a significantly elevated age-adjusted risk of prostate cancer among brothers of probands, compared with their fathers (relative risk 1.5 [95% confidence interval 1.4-1.7]); (2) the autosomal dominant model predicted an excess of homozygotes, over that predicted by Hardy-Weinberg equilibrium; and (3) the model-predicted risk of prostate cancer among relatives was inadequate when probands were diagnosed at age >=70 years.     

Genetic epidemiology of rheumatoid arthritis.

We conducted family studies and segregation analyses of rheumatoid arthritis (RA) that were based on consecutive patients with RA ascertained without regard to family history or known risk factors. First-degree relatives from 135 simplex and 30 multiplex families were included in the analyses. A highly penetrant recessive major gene, with a mutant allele frequency of .005, was identified as the most parsimonious genetic risk factor. Significant evidence for heterogeneity in risk for RA was observed for proband gender but not for proband age at onset. Kaplan-Meier risk analysis demonstrated significant evidence for differences in the distribution of risk among first-degree relatives. These analyses demonstrated that both proband gender and age at onset are important risk factors but that proband gender appears to be the more important determinant of risk, with relatives of male probands having the greatest cumulative risk for RA. In addition, log-linear modeling identified proband gender, familiality (multiplex or simplex), and an interaction term between these two variables as being adequate to define the distribution of risk in families. The pattern of risk for RA among susceptible individuals and its inheritance is thus heterogeneous. For future genetic analyses, families with an excess of affected males having a young age at onset may be the most informative in identifying the putative recessive gene and its modifiers.     

Approaches to familial aggregation: hypothesis testing and estimation when families are selected through parent probands under a variant of single ascertainment

Epidemiologic approaches to testing and estimating familial aggregation of a disease consist of comparing rates of disease in relatives of individuals with the disease (known as case probands) with rates of disease in relatives of individuals without the disease (known as control probands). Gold et al. (J Am Stat Ass 1967;62: 409-420) derived an explicit mathematical model and sampling methods, under which this approach is equivalent to testing the null hypotheses that the disease risk in families is homogenous. A basic assumption of this model is that every family member has the same risk of disease and that disease status is independent among family members, although the disease risk may vary between families. When the disease is suspected of having a genetic component, rather than being purely environmental, this model has been shown to be appropriate for detecting disease aggregation in siblings, when relatives are siblings of probands. This model however is unrealistic for use in nuclear families when the affected status of offspring is not independent of the affected status of parents, and these families are selected through an affected or an unaffected parent, so that a parent is the proband and relatives are offspring of probands. We extend the Gold et al. model to allow for the disease risk in offspring to vary with the affected status of the parent. We assume that families are selected through affected and unaffected parents, under a variation of single ascertainment. Under this study design, we show that the usual test of association between affected status of probands and relatives, performed by comparing sample proportions of affected relatives of affected and unaffected probands, respectively, is no longer equivalent to a test of homogeneity of disease risk in offspring. Instead, it is equivalent to testing that the disease risk in offspring is independent of the number of affected parents. This test reduces to a test of homogeneity if and only if one assumes that the variation in disease risk in offspring, between families, is solely due to the variation in the number of affected parents. As a result, we show that under this study design, the standard chi2 test must be modified in order to obtain a valid test of familial aggregation. In addition the sample proportions of affected relatives of case and control probands, respectively, are shown to provide unbiased estimates of the expected risk of disease in an offspring given an affected/unaffected parent. We apply these results to methods of sample selection and discuss the practical implications of these findings.     

Cancer in relatives of leukemic patients with chromosomal rearrangements at rare (heritable) fragile-site locations in their malignant cells.

The cancer occurrence in relatives (N = 407) of 40 case probands (who had leukemia and rearrangements at the same chromosomal location as at least one of 23 recognized rare [heritable] autosomal fragile sites [Sutherland and Mattei 1987]) was compared both to cancer occurrence in relatives (N = 390) of 40 control probands (who had leukemia or other hematologic illness but no recognized chromosomal rearrangements) and to cancer incidence in the general population of the United States. Fragile-site carrier status was not determined in case or control probands. No significant excess of cancer in case relatives, compared with either control relatives or to general (SEER) population expectancies, was found. Furthermore, there was neither evidence of cancer at younger ages, when cases were compared with control relatives, nor an excess of cancer at multiple sites. Male relatives of cases did, however, show a small excess of cancer, especially in older age groups. There was a slight, but not statistically significant, excess of lung cancer in case relatives, with this deviation occurring almost exclusively in relatives of probands having rearrangements at 11q23 and having lymphoid leukemia. It is possible that heritable tendency to chromosomal rearrangement--and thus to cancer--is expressed in such a small proportion of family members that cancer excess in these families could not be detected with the numbers of relatives analyzed in this study, although there was no significant evidence for a hereditary predisposition to cancer in the families of probands with leukemia and with chromosomal rearrangements at the same apparent chromosomal location as rare fragile sites.     

Patterns of maternal transmission in bipolar affective disorder.

The mode of inheritance of bipolar affective disorder (BPAD) appears complex, and non-Mendelian models of inheritance have been postulated. Two non-Mendelian phenomena, genomic imprinting and mitochondrial inheritance, may contribute to the complex inheritance pattern seen in BPAD. Both imprinting and mitochondrial inheritance share the feature of differential expression of the phenotype, depending on the parent of origin. In this study we tested the hypothesis of a parent-of-origin effect on the transmission of BPAD. We examined the frequency and risk of affective disorder among relatives in a sample of 31 families ascertained through treated probands with BPAD and selected for the presence of affected phenotypes in only one parental lineage. Three specific comparisons were performed: (1) the observed frequency of transmitting mothers versus transmitting fathers; (2) the observed frequency and lifetime risk of BPAD among the maternal versus the paternal relatives of probands; and (3) the observed frequency and lifetime risk of BPAD for the offspring of affected mothers compared with the offspring of affected fathers. We observed a higher than expected frequency of affected mothers (P < .04), a 2.3-2.8-fold increased risk of illness for maternal relatives (P < .006), and a 1.3- 2.5-fold increased risk of illness for the offspring of affected mothers (P < .017).In seven enlarged pedigrees, fathers repeatedly failed to transmit the affected phenotype to daughters or sons. Taken together, these findings indicate a maternal effect in the transmission of BPAD susceptibility and suggest that molecular studies of mtDNA and imprinted DNA are warranted in patients with BPAD.     

BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer

Ovarian cancer is a component of the autosomal-dominant hereditary breast-ovarian cancer syndrome and may be due to a mutation in either the BRCA1 or BRCA2 genes. Two mutations in BRCA1 (185delAG and 5382insC) and one mutation in BRCA2 (6174delT) are common in the Ashkenazi Jewish population. One of these three mutations is present in approximately 2% of the Jewish population. Each mutation is associated with an increased risk of ovarian cancer, and it is expected that a significant proportion of Jewish women with ovarian cancer will carry one of these mutations. To estimate the proportion of ovarian cancers attributable to founding mutations in BRCA1 and BRCA2 in the Jewish population and the familial cancer risks associated with each, we interviewed 213 Jewish women with ovarian cancer at 11 medical centers in North America and Israel and offered these women genetic testing for the three founder mutations. To establish the presence of nonfounder mutations in this population, we also completed the protein-truncation test on exon 11 of BRCA1 and exons 10 and 11 of BRCA2. We obtained a detailed family history on all women we studied who had cancer and on a control population of 386 Ashkenazi Jewish women without ovarian or breast cancer. A founder mutation was present in 41.3% of the women we studied. The cumulative incidence of ovarian cancer to age 75 years was found to be 6.3% for female first-degree relatives of the patients with ovarian cancer, compared with 2.0% for the female relatives of healthy controls (relative risk 3.2; 95% CI 1.5-6.8; P=.002). The relative risk to age 75 years for breast cancer among the female first-degree relatives was 2.0 (95% CI 1.4-3.0; P=.0001). Only one nonfounder mutation was identified (in this instance, in a woman of mixed ancestry), and the three founding mutations accounted for most of the observed excess risk of ovarian and breast cancer in relatives.     

Clinico-genetical studies of colonic cancer. III. Primary multiple malignant neoplasms

The results of clinico-genealogic analysis of 46 patients with primary-multiple malignant neoplasms are given (among them 16 patients with primary-multiple malignant neoplasms of colon cancer and 30 patients with one or more neoplasms in combination with different malignant tumors of other organs). The values of segregation rates obtained for primary-multiple malignant neoplasms are lower than theoretically expected for simple monogeneous types of inheritance. The relation analysis of primary-multiple malignant neoplasms and colon cancer revealed that these tumors are likely to appear among relatives of probands under the influence of the same genetic system of determination. Risk of the colon cancer development for relatives of the patients with primary-multiple malignant neoplasms is higher than for relatives of the patients with colon cancer.     

Familial Aggregation of Morbid Obesity

Recent studies have shown major gene effects for obesity in randomly ascertained families. To investigate the familial aggregation of a specific subset of obesity, which is particularly prone to medical complications, families with morbid obesity were studied. This condition occurs in 1%-2%of the population and is defined as 45.5 kg (100 pounds) or more over ideal weight. First-degree relatives of 221 morbidly obese probands (1560 adults) were identified, and height and weight (current and greatest) were obtained from each family member. Morbid obesity occurred in the family members of the probands 8 times more often than in the general population. Of the morbidly obese probands, 48% had one or more first-degree relatives who were also morbidly obese compared to a 6% population estimate. By the ages of 20–24, 12% of the morbidly obese probands were already 45.5 kg or more overweight, and 45% were 22.7 kg (50 pounds) or more overweight. There was little difference in the prevalence of familial morbid obesity by the gender of the probands: 47% of the male probands and 48% of the female probands had another morbidly obese relative, while 67% and 53% of the early onset (before age 25) male and female probands, respectively, had one or more first-degree relatives who were also morbidly obese. In addition to the extreme degree of familial aggregation, the prevalence of morbid obesity in parent-offspring sets was calculated within the morbidly obese families. Morbidly obese families who have one or two morbidly obese parents have a 2.6 times increased risk (p<0.002) of having one or more morbidly obese adult offspring, compared to families who have neither parent morbidly obese. Evidence for trimodality of the body mass index distribution was found for each gender (p = 0.0006 for male relatives and p = 0.075 for female relatives). The strong familial aggregation of morbid obesity indicates the need for further understanding of the genetic determinants of this extreme clinical disorder and how environmental factors affect the genetic expression of the trait. (OBESITY RESEARCH 1993;1:261–270)     

A familial association between twinning and upper-neural tube defects.

An increased twinning rate has been observed in the near relatives (sibs, parents, and aunts and uncles) of probands with neural tube defects (NTDs) occurring at the level of the 11th thoracic vertebra and above (upper NTDs). The twin rate was more than double that of the near relatives of probands with lower NTDs and of those of probands with Mendelian disorders (the controls). The excess twinning was same sex and can therefore consist of either MZ or same-sex DZ twins. Furthermore, upper-NTD families with twins had a higher NTD-sibling occurrence rate than did families without twins. These findings, if corroborated, may imply an etiology common to twinning and NTDs and can perhaps be applied in counseling NTD families.     

Familial predisposition to cancer and age at onset of disease in randomly selected cancer patients

Incidence of malignancy among close relatives was used to evaluate the relationship of early age at diagnosis and familial cancer predisposition in a general population of cancer patients. The occurrence of cancer and other conditions in families of more than 1,350 randomly selected patients with a wide variety of malignancies was ascertained. Each patient was assigned to one of four study groups based on comparison of his age at diagnosis with the distribution of ages at diagnosis for his cancer site compiled by the Third National Cancer Survey. These groups consisted of patients whose ages at diagnosis were in: (1) the lowest decile, (2) the median decile, (3) above the median decile, and (4) between the lowest and median deciles. Person-years and calendar time at risk were calculated for first-degree relatives in each group. The numbers of cancers expected among these relatives were calculated using age- and time-specific incidence rates of a standard population. Statistical analysis of (1) the numbers of reported vs. expected cancers in relatives and (2) the numbers of families reporting cancer in parents or siblings of patients showed that a familial tendency to develop cancer exists in this randomly selected population of cancer patients, regardless of age at onset of malignancy in the proband. Conversely, early age at diagnosis of cancer may indicate genetic predisposition to malignancy only in exceptional cases.     

Etiologic heterogeneity in the familial aggregation of congenital cardiovascular malformations.

Recent data indicate that there is increased risk of congenital cardiovascular malformations (CCVM) within families of probands diagnosed with congenital cardiovascular malformations that are due to altered embryonic blood flow (flow lesions). In the present study, regressive models recently developed by Bonney were used to compare specific models of inheritance and to test for etiologic heterogeneity among three subgroups of 375 flow-lesion families identified by the Baltimore-Washington Infant Study. When all families were analyzed as a single group, the best-fitting model was a simple recessive model with Mendelian transmission; race did not have a significant effect on estimated risk. Separate analyses of families of probands with left heart defects, right heart defects, and ventricular septal defects (VSD) confirmed this simple Mendelian recessive model as the model of choice. However, when race was included as a covariate in these genetic models, there was evidence for significant heterogeneity among the three subgroups. There was an increased risk to relatives of white probands with right heart defects and to relatives of black probands with VSD, while there was no effect of race among relatives of probands with left heart defects. These results strongly suggest that there is etiologic heterogeneity in the control of CCVM among flow-lesion families and that the patterns of familial aggregation differ among the races.     

Type II diabetes of early onset: a distinct clinical and genetic syndrome?

The inheritance of non-insulin-dependent (type II) diabetes was studied by a continuous infusion of glucose test in all available first degree relatives of 48 diabetic probands of various ages and with differing severity of disease. In an initial study of 38 type II diabetic subjects and their first degree relatives six islet cell antibody negative patients with early onset disease (aged 25-40 at diagnosis) were found to have a particularly high familial prevalence of diabetes or glucose intolerance. Nine of 10 parents available for study either had type II diabetes or were glucose intolerant. A high prevalence of diabetes or glucose intolerance was also found in their siblings (11/16;69%). In a second study of the families of a further 10 young diabetic probands (presenting age 25-40) whose islet cell antibody state was unknown a similar high prevalence of diabetes or glucose intolerance was found among parents of the five islet cell antibody negative probands (8/9; 89%) but not among parents of the five islet cell antibody positive probands (3/8;38%). Islet cell antibody negative diabetics with early onset type II disease may have inherited a diabetogenic gene or genes from both parents. They commonly need insulin to maintain adequate glycaemic control and may develop severe diabetic complications. Early onset type II diabetes may represent a syndrome in which characteristic pedigrees, clinical severity, and absence of islet autoimmunity make it distinct from either type I diabetes, maturity onset diabetes of the young, or late onset type II diabetes.     

Segregation analysis of cryptogenic epilepsy and an empirical test of the validity of the results.

We used POINTER to perform segregation analysis of cryptogenic epilepsy in 1,557 three-generation families (probands and their parents, siblings, and offspring) ascertained from voluntary organizations. Analysis of the full data set indicated that the data were most consistent with an autosomal dominant (AD) model with 61% penetrance of the susceptibility gene. However, subsequent analyses revealed that the patterns of familial aggregation differed markedly between siblings and offspring of the probands. Risks in siblings were consistent with an autosomal recessive (AR) model and inconsistent with an AD model, whereas risks in offspring were inconsistent with an AR model and more consistent with an AD model. As a further test of the validity of the AD model, we used sequential ascertainment to extend the family history information in the subset of families judged likely to carry the putative susceptibility gene because they contained at least three affected individuals. Prevalence of idiopathic/cryptogenic epilepsy was only 3.7% in newly identified relatives expected to have a 50% probability of carrying the susceptibility gene under an AD model. Approximately 30% (i.e., 50% x 61%) were expected to be affected under the AD model resulting from the segregation analysis. These results suggest that the familial distribution of cryptogenic epilepsy is inconsistent with any conventional genetic model. The differences between siblings and offspring in the patterns of familial risk are intriguing and should be investigated further.     

Analysis of 5382insC (BRCA1) and 6174delT (BRCA2) mutations in 382 healthy Chilean women with a family history of breast cancer

Breast cancer is the most common malignancy among women. Chilean studies reveal that this cancer presents the third highest mortality rate. A family history of breast cancer is one of the major risk factors for the development of this disease. BRCA1 and BRCA2 are the two main hereditary breast cancer susceptibility genes, and mutations in these genes are related to inherited breast cancer. In specific populations only some mutations have been found to be associated with susceptibility. The purpose of this study was to establish the frequency of 5382insC (BRCA1) and 6174delT (BRCA2) germline mutations in 382 healthy Chilean women with at least two relatives affected with breast cancer and in probands and their relatives from 8 high risk families for breast cancer, using mismatch PCR assay. The results obtained showed that 5382insC and 6174delT mutations were not found in either of the groups studied. The ethnic origin of the contemporary Chilean population and the data reported in the literature suggest that these mutations may be absent or have a very low frequency in this population.. This genetic study is part of a breast cancer screening program that also includes annual mammography and clinical breast examination over a five-year period. Strategies to reduce morbidity and mortality associated with breast cancer lie in early detection in women with genetic risk.     

Genotype-specific recurrence risks as indicators of the genetic architecture of complex diseases

A statistic is introduced that relates discoveries made in genome-wide association (GWA) studies to patterns of disease risks among relatives. The genotype-specific recurrence risk (GSR) is the genotype-specific risk to relatives of known relationship to affected probands. The GSRs can be used for three purposes. (1) They can provide an independent test of whether an allele identified in a GWA study is associated with the disease. (2) They can provide a test of whether interactions among loci affecting the disease are multiplicative. (3) They can be used by genetic counselors to incorporate information from GWA studies for predicting the risk to relatives of known genotype. Under a multiplicative model of disease causation, the GSRs for a locus are the genotypic risks in probands for that locus multiplied by lambda(R)/lambda(jR), where lambda(R) is Risch's recurrence risk ratio and lambda(jR) is the contribution to lambda(R) from the locus of interest. If there is saturation of risk with increasing numbers of causative alleles, then observed GSRs for individuals with high-risk genotypes will be lower than predicted by the multiplicative model.     

Identifying families with likely genetic protective factors against Alzheimer disease

Elderly individuals who lived beyond the age of 90 years without dementia were hypothesized to have increased concentrations of genetic protective factors against Alzheimer disease (AD), conferring a reduced liability for this disease relative to less-aged nondemented elderly. However, testing this hypothesis is complicated by having to distinguish such a group from those who may lack genetic risk factors for AD, have had protective environmental exposures, or have escaped dementia for other reasons. Probands carrying genetic protective factors, however, should have relatives with lower illness rates not only for earlier-onset disease, when genetic risk factors are a strong contributing factor to the incidence of AD, but also for later-onset disease, when the role of these factors appears to be markedly diminished. AD dementia was assessed through family informants in 6,660 first-degree relatives of 1,049 nondemented probands aged 60-102 years. The probands were grouped by age (60-74, 75-89, and 90-102 years), and the cumulative survival from AD and 10-year-age-interval hazard rates of AD were calculated in their first-degree relatives. Cumulative survival from AD was significantly greater in the relatives of the oldest proband group (aged 90-102 years) than it was in the two younger groups. In addition, the reduction in the rate of illness for this group was relatively constant across the entire late life span. The results suggest that genetic factors conferring a lifelong reduced liability of AD may be more highly concentrated among nondemented probands aged >/=90 years and their relatives. Efforts to identify protective allele-bearing genes that are associated with very late-onset AD should target the families of nonagenarians and centenarians.     

Magnified Risks From Cigarette Smoking for Coronary Prone Families in Utah

The contribution of currently accepted risk factors to the familiality of early coronary heart disease (CHD) is poorly understood. In a telephone and mail survey, risk factor and disease morbidity and mortality data were collected from 100 proband and 185 control families encompassing about 40,000 person-years of experience. Probands were white married men who had died of CHD by age 45. There was a threefold increase in CHD incidence among first-degree relatives of probands compared with control families. In all, 67% of probands had at least one first-degree relative with early CHD, and 29% had two or more first-degree relatives with early CHD compared with 8% of the control families with two or more cases of early CHD.The most striking new finding of this study is the apparently magnified liability of cigarette smoking in families prone to have early coronary heart disease. This effect was seen strongly at younger ages (under 50). Furthermore, in about a third of all families with a history of early CHD, smoking seemed to be the only risk factor contributing to the familial occurrence of the disease. The findings show a large excess absolute risk for CHD among smoking members of proband families and further suggest a possibly heritable susceptibility to the deleterious effects of smoking in many families prone to early coronary disease. Modification of coronary risk factors, especially cigarette smoking, would be of greatest benefit among members of high-risk families.     

Evaluating genetic association among ovarian, breast, and endometrial cancer: evidence for a breast/ovarian cancer relationship

The possibility of a genetic relationship between ovarian, breast, and endometrial cancer was investigated in data from a large multicenter, population-based, case-control study, the Cancer and Steroid Hormone Study conducted by the Centers for Disease Control (CDC). Age-adjusted relative risks (RRs) for mothers and sisters of 493 ovarian cancer cases, 895 breast cancer cases, and 143 endometrial cancer cases versus 4,754 controls were calculated. Significantly elevated age-adjusted RRs were found for ovarian cancer (RR = 2.8; 95% confidence interval [CI] = 1.6-4.9) and breast cancer (RR = 1.6; 95% CI = 1.1-2.1) among relatives of ovarian cancer probands and for breast cancer (RR = 2.1; 95% CI = 1.7-2.5) and ovarian cancer (RR = 1.7; 95% CI = 1.0-2.0) among relatives of breast cancer probands. Relatives of endometrial cancer probands had an elevated RR for endometrial cancer only (RR = 2.7; 95% CI = 1.6-4.8). The genetic relationship between ovarian, breast, and endometrial cancer was tested using a multivariate polygenic threshold model developed by Smith (1976), which was modified to accommodate three classes of probands. Estimates of heritability for ovarian, breast, and endometrial cancer were 40%, 56%, and 52%, respectively. There was a significant genetic correlation between ovarian and breast cancer (R12 = .484). Evidence for significant genetic overlap between endometrial cancer and either ovarian or breast cancer was not found. These results suggest the existence of a familial breast/ovarian cancer syndrome. Endometrial cancer, while heritable, appears to be genetically unrelated.     

Genotype–phenotype correlation in long QT syndrome families

Heterogeneity in clinical manifestations is a well-known feature in Long QT Syndrome (LQTS). The extent of this phenomenon became evident in families wherein both symptomatic and asymptomatic family members are reported. The study hence warrants genetic testing and/or screening of family members of LQTS probands for risk stratification and prediction.Of the 46 families screened, 18 probands revealed novel variations/compound heterozygosity in the gene/s screened. Families 1–4 revealed probands carrying novel variations in KCNQ1 gene along with compound heterozygosity of risk genotypes of the SCN5A, KCNE1 and NPPA gene/s polymorphisms screened. It was also observed that families- 5, 6 and 7 were typical cases of “anticipation” in which both mother and child were diagnosed with congenital LQTS (cLQTS). Families- 16 and 17 represented aLQTS probands with variations in IKs and INa encoding genes. First degree relatives (FDRs) carrying the same haplotype as the proband were also identified which may help in predictive testing and management of LQTS. Most of the probands exhibiting a family history were found to be genetic compounds which clearly points to the role of cardiac genes and their modifiers in a recessive fashion in LQTS manifestation.     

Genetic analysis of kifafa, a complex familial seizure disorder.

Kifafa is the Swahili name for an epileptic seizure disorder, first reported in the early 1960s, that is prevalent in the Wapogoro tribe of the Mahenge region of Tanzania in eastern Africa. A 1990 epidemiological survey of seizure disorders in this region reported a prevalence in the range of 19/1,000-36/1,000, with a mean age at onset of 11.6 years; 80% of those affected had onset prior to 20 years of age. A team of investigators returned to Tanzania in 1992 and collected data on > 1,600 relatives of 26 probands in 20 kifafa families. We have undertaken a genetic analysis of these data in order to detect the presence of familial clustering and whether such aggregation could be attributed to genetic factors. Of the 127 affected individuals in these pedigrees, 23 are first-degree relatives (parent, full sibling, or offspring) of the 26 probands; 20 are second-degree relatives (half-sibling, grandparent, uncle, or aunt). When corrected for age, the risk to first-degree relatives is .15; the risk to second-degree relatives is .063. These risks are significantly higher than would be expected if there were no familial clustering. Segregation analysis, using PAP (rev.4.0), was undertaken to clarify the mode of inheritance. Among the Mendelian single-locus models, an additive model was favored over either a dominant, recessive, or codominant model. The single-locus model could be rejected when compared with the mixed Mendelian model (inclusion of a polygenic background), although the major-gene component tends to be recessive.(ABSTRACT TRUNCATED AT 250 WORDS)