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Objective: To identify Essential Tremor (ET) genes, WGS was performed in 8 ET families to test whether rare variants contribute to complex disease etiology. Background: ET is one of the most common causes of tremor in humans. However, few susceptibility genes for ET have been identified, and the mode of inheritance and transmission of variants in familial and sporadic ET is largely unknown. To date, studies have not assessed the burden of rare variants to complex disease etiology in ET families. Design/Methods: The pedigrees for 8 ET families (n=40 individuals) were whole genome sequenced. Paired end sequencing was performed at >30X coverage per sample on the Illumina HiSeq X ten instrument. Sequence alignment to the human reference genome (UCSC hg19) was performed using the BWA algorithm, and variant calling which includes SNVs and indels was performed using GATK (Broad Institute) and CNVs and structural variants were called using Genome STRiP (Broad Institute). Filtering of common variants (MAF>1%) was performed using population databases. Coding variants were annotated using ANNOVAR, SNPEff, VEP, OMIM, HGMD and CLINVAR and functional annotation of non-coding variants was performed using ENCODE, ENSEMBL, FANTOM and VISTA. We restricted our subsequent analyses to rare variants and compared the burden of predicted protein altering variants and functional non-coding variants between ET cases and unaffected controls within and across families. Results: Among the 8 ET families analyzed, we identified several gene regions (coding and non-coding) with burden of rare variants co-segregating with ET within families, that have been previously reported to be associated with neurodegenerative disease pathways. A total of 11/18 (61%) of gene regions identified are within conserved transcription factor binding sites and 7 gene regions are within coding exons (39%). Here, we summarize our findings in these 8 ET families. Conclusions: Our study suggests that comprehensive WGS analysis in ET families and cohorts is warranted. Study Supported by: NIH R01 NS073872. Disclosure: Dr. Clark has nothing to disclose. Dr. Odgerel has nothing to disclose. Dr. Hernandez has nothing to disclose. Dr. Ottman has nothing to disclose. Dr. Louis has nothing to disclose.

Summary Background Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. Methods We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. Findings We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7–3·2, p=9·1 × 10 −8 ; familial non-acquired focal epilepsy 3·6, 2·7–4·9, p=1·1 × 10 −17 ). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10 −8 ) that were lower than expected from a random sampling of genes. Interpretation We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. Funding National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK.

Gene identification in epilepsy has mainly been limited to large families segregating genes of major effect and de novo mutations in epileptic encephalopathies. Many families that present with common non-acquired focal epilepsies and genetic generalized epilepsies remain unexplained. We assembled a cohort of 'genetically enriched' common epilepsies by collecting and phenotyping families containing multiple individuals with unprovoked seizures. We aimed to determine if specific clinical epilepsy features aggregate within families, and whether this segregation of phenotypes may constitute distinct 'familial syndromes' that could inform genomic analyses. Families with three or more individuals with unprovoked seizures were studied across multiple international centres. Affected individuals were phenotyped and classified according to specific electroclinical syndromes. Families were categorized based on syndromic groupings of affected family members, examined for pedigree structure and phenotypic patterns and, where possible, assigned specific familial epilepsy syndromes. A total of 303 families were assembled and analysed, comprising 1120 affected phenotyped individuals. Of the 303 families, 117 exclusively segregated generalized epilepsy, 62 focal epilepsy, and 22 were classified as genetic epilepsy with febrile seizures plus. Over one-third (102 families) were observed to have mixed epilepsy phenotypes: 78 had both generalized and focal epilepsy features within the same individual (n = 39), or within first or second degree relatives (n = 39). Among the genetic generalized epilepsy families, absence epilepsies were found to cluster within families independently of juvenile myoclonic epilepsy, and significantly more females were affected than males. Of the 62 familial focal epilepsy families, two previously undescribed familial focal syndrome patterns were evident: 15 families had posterior quadrant epilepsies, including seven with occipito-temporal localization and seven with temporo-parietal foci, and four families displayed familial focal epilepsy of childhood with multiple affected siblings that was suggestive of recessive inheritance. The findings suggest (i) specific patterns of syndromic familial aggregation occur, including newly recognized forms of familial focal epilepsy; (ii) although syndrome-specificity usually occurs in multiplex families, the one-third of families with features of both focal and generalized epilepsy is suggestive of shared genetic determinants; and (iii) patterns of features observed across families including pedigree structure, sex, and age of onset may hold clues for future gene identification. Such detailed phenotypic information will be invaluable in the conditioning and interpretation of forthcoming sequencing data to understand the genetic architecture and inter-relationships of the common epilepsy syndromes.

Epileptic encephalopathies (EEs) are the most clinically important group of severe early-onset epilepsies. Next-generation sequencing has highlighted the crucial contribution of de novo mutations to the genetic architecture of EEs as well as to their underlying genetic heterogeneity. Our previous whole-exome sequencing study of 264 parent-child trios revealed more than 290 candidate genes in which only a single individual had a de novo variant. We sought to identify additional pathogenic variants in a subset (n = 27) of these genes via targeted sequencing in an unsolved cohort of 531 individuals with a diverse range of EEs. We report 17 individuals with pathogenic variants in seven of the 27 genes, defining a genetic etiology in 3.2% of this unsolved cohort. Our results provide definitive evidence that de novo mutations in SLC1A2 and CACNA1A cause specific EEs and expand the compendium of clinically relevant genotypes for GABRB3. We also identified EEs caused by genetic variants in ALG13, DNM1, and GNAO1 and report a mutation in IQSEC2. Notably, recurrent mutations accounted for 7/17 of the pathogenic variants identified. As a result of high-depth coverage, parental mosaicism was identified in two out of 14 cases tested with mutant allelic fractions of 5%-6% in the unaffected parents, carrying significant reproductive counseling implications. These results confirm that dysregulation in diverse cellular neuronal pathways causes EEs, and they will inform the diagnosis and management of individuals with these devastating disorders.

The syndrome known as nocturnal frontal lobe epilepsy is recognized worldwide and has been studied in a wide range of clinical and scientific settings (epilepsy, sleep medicine, neurosurgery, pediatric neurology, epidemiology, genetics). Though uncommon, it is of considerable interest to practicing neurologists because of complexity in differential diagnosis from more common, benign sleep disorders such as parasomnias, or other disorders like psychogenic nonepileptic seizures. Moreover, misdiagnosis can have substantial adverse consequences on patients' lives. At present, there is no consensus definition of this disorder and disagreement persists about its core electroclinical features and the spectrum of etiologies involved. To improve the definition of the disorder and establish diagnostic criteria with levels of certainty, a consensus conference using formal recommended methodology was held in Bologna in September 2014. It was recommended that the name be changed to sleep-related hypermotor epilepsy (SHE), reflecting evidence that the attacks are associated with sleep rather than time of day, the seizures may arise from extrafrontal sites, and the motor aspects of the seizures are characteristic. The etiology may be genetic or due to structural pathology, but in most cases remains unknown. Diagnostic criteria were developed with 3 levels of certainty: witnessed (possible) SHE, video-documented (clinical) SHE, and video-EEG-documented (confirmed) SHE. The main research gaps involve epidemiology, pathophysiology, treatment, and prognosis.

Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.

Summary Objective Autosomal dominant lateral temporal epilepsy (ADLTE) is a focal epileptic syndrome characterized by auditory or aphasic auras. Mutations in the LGI1 gene account for

Industrialized regions in Poland are characterized by high ambient pollution, including polycyclic aromatic hydrocarbons (PAHs) from coal burning for industry and home heating. In experimental bioassays, certain PAHs are transplacental carcinogens and developmental toxicants. Biologic markers can facilitate evaluation of effects of environmental PAHs on the developing infant. We measured the amount of PAHs bound to DNA (PAH-DNA adducts) in maternal and umbilical white blood cells. The cohort consisted of 70 mothers and newborns from Krakow, Poland, an industrialized city with elevated air pollution. Modulation of adduct levels by genotypes previously linked to risk of lung cancer, specifically glutathione S-transferase MI (GSTM1) and cytochrome P4501A1 (CYP1A1) Msp restriction fragment length polymorphism (RFLP), was also investigated. There was a dose-related increase in maternal and newborn adduct levels with ambient pollution at the women's place of residence among subjects who were not employed away from home (p < or = 0.05). Maternal smoking (active and passive) significantly increased maternal (p < or = 0.01) but not newborn adduct levels. Neither CYP1A1 Msp nor GSTM1 polymorphisms was associated with maternal adducts. However, adducts were significantly higher in newborns heterozygous or homozygous for the CYP1A1 Msp RFLP compared to newborns without the RFLP (p = 0.04). Results indicate that PAH-induced DNA damage in mothers and newborns is increased by ambient air pollution. In the fetus, this damage appears to be enhanced by the CYP1A1 Mspl polymorphism. Images Figure 1

This study explores neurologists’ and psychiatrists’ knowledge, attitudes, and practices concerning genetic tests. Psychiatrists (n = 5,316) and neurologists (n = 2,167) on the American Medical Association master list who had agreed to receive surveys were sent an email link to a survey about their attitudes and practices regarding genetic testing; 372 psychiatrists and 163 neurologists responded. A higher proportion of neurologists (74 %) than psychiatrists (14 %) who responded to the survey had ordered genetic testing in the past 6 months. Overall, most respondents thought that genetic tests should be performed more frequently, but almost half believed genetic tests could harm patients psychologically and considered legal protections inadequate. Almost half of neurologists (49 %) and over 75 % of psychiatrists did not have a genetics professional to whom to refer patients; those who had ordered genetic tests were more likely than those who did not do so to have access to a genetic counselor. Of respondents, 10 % had received patient requests not to document genetic information and 15 % had received inquiries about direct‐to‐consumer genetic testing. Neurologists reported themselves to be relatively more experienced and knowledgeable about genetics than psychiatrists. These data, the first to examine several important issues concerning knowledge, attitudes and behaviors of neurologists and psychiatrists regarding genetic tests, have important implications for future practice, research, and education.

This report is a practical reference guide for genetic testing of SCN1A, the gene encoding the 1 subunit of neuronal voltage-gated sodium channels (protein name: Nav1.1). Mutations in this gene are frequently found in Dravet syndrome (DS), and are sometimes found in genetic epilepsy with febrile seizures plus (GEFS+), migrating partial seizures of infancy (MPSI), other infantile epileptic encephalopathies, and rarely in infantile spasms. Recommendations for testing: (1) Testing is particularly useful for people with suspected DS and sometimes in other early onset infantile epileptic encephalopathies such as MPSI because genetic confirmation of the clinical diagnosis may allow optimization of antiepileptic therapy with the potential to improve seizure control and developmental outcome. In addition, a molecular diagnosis may prevent the need for unnecessary investigations, as well as inform genetic counseling. (2) SCN1A testing should be considered in people with possible DS where the typical initial presentation is of a developmentally normal infant presenting with recurrent, febrile or afebrile prolonged, hemiclonic seizures or generalized status epilepticus. After age 2, the clinical diagnosis of DS becomes more obvious, with the classical evolution of other seizure types and developmental slowing. (3) In contrast to DS, the clinical utility of SCN1A testing for GEFS+ remains questionable. (4) The test is not recommended for children with phenotypes that are not clearly associated with SCN1A mutations such as those characterized by abnormal development or neurologic deficits apparent at birth or structural abnormalities of the brain. Interpreting test results: (1) Mutational testing of SCN1A involves both conventional DNA sequencing of the coding regions and analyses to detect genomic rearrangements within the relevant chromosomal region: 2q24. Interpretation of the test results must always be done in the context of the electroclinical syndrome and often requires the assistance of a medical geneticist, since many genomic variations are possible and it is essential to differentiate benign polymorphisms from pathogenic mutations. (2) Missense variants may have no apparent effect on the phenotype (benign polymorphisms) or may represent mutations underlying DS, MPSI, GEFS+, and related syndromes and can provide a challenge in interpretation. (3) Conventional methods do not detect variations in introns or promoter or regulatory regions; therefore, a negative test does not exclude a pathogenic role of SCN1A in a specific phenotype. (4) It is important to note that a negative test does not rule out the clinical diagnosis of DS or other conditions because genes other than SCN1A may be involved. Obtaining written informed consent and genetic counseling should be considered prior to molecular testing, depending on the clinical situation and local regulations.

Essential tremor (ET) is a progressive disorder, worsening gradually with time in most patients. Yet there are few data on the factors that influence rate of progression. ET is a highly familial disorder, and physicians often care for patients who have other affected family members. Do ET families differ from one another with respect to rate of progression? Are some families slower progressors and other families faster progressors? We are unaware of published data.ET probands and relatives were enrolled in a cross-sectional genetic study at Columbia University. Rate of progression was calculated as total tremor score ÷ log disease duration.There were 100 enrollees (28 probands, 72 relatives). Data from 78 enrollees (23 probands, 55 relatives) were selected for final analysis. The mean familial rate of progression ranged from as little as 8.4 to as much as 34.3, a4-fold difference. In an analysis of variance, we found significant evidence of heterogeneity in the log rate of progression across families (p0.001), with more than one-half (i.e., 55.4%) of the total variance in the log rate of progression explained by the family grouping.Familial factors seem to affect rate of tremor progression in ET. There was a 4-fold difference across families in observed mean rate of progression; thus, some families seemed to be more rapid progressors than others. We hope these data may be used by clinicians to provide basic prognostic and family guidance information to their patients and families with ET.

Idiopathic generalized epilepsy (IGE) is a complex disease with high heritability, but little is known about its genetic architecture. Rare copy-number variants have been found to explain nearly 3% of individuals with IGE; however, it remains unclear whether variants with moderate effect size and frequencies below what are reliably detected with genome-wide association studies contribute significantly to disease risk. In this study, we compare the exome sequences of 118 individuals with IGE and 242 controls of European ancestry by using next-generation sequencing. The exome-sequenced epilepsy cases include study subjects with two forms of IGE, including juvenile myoclonic epilepsy (n = 93) and absence epilepsy (n = 25). However, our discovery strategy did not assume common genetic control between the subtypes of IGE considered. In the sequence data, as expected, no variants were significantly associated with the IGE phenotype or more specific IGE diagnoses. We then selected 3,897 candidate epilepsy-susceptibility variants from the sequence data and genotyped them in a larger set of 878 individuals with IGE and 1,830 controls. Again, no variant achieved statistical significance. However, 1,935 variants were observed exclusively in cases either as heterozygous or homozygous genotypes. It is likely that this set of variants includes real risk factors. The lack of significant association evidence of single variants with disease in this two-stage approach emphasizes the high genetic heterogeneity of epilepsy disorders, suggests that the impact of any individual single-nucleotide variant in this disease is small, and indicates that gene-based approaches might be more successful for future sequencing studies of epilepsy predisposition., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Background Mutations in parkin are a known genetic risk factor for early onset Parkinson’s disease (EOPD) but their role in non-motor manifestations is not well established. Genetic factors for depression are similarly not well characterized. We investigate the role of parkin mutations in depression among those with EOPD and their relatives. Methods We collected psychiatric information using the Patient Health Questionnaire and Beck Depression Inventory II on 328 genotyped individuals including 88 probands with early onset PD (41 with parkin mutations, 47 without) and 240 first and second-degree relatives without PD. Results Genotype was not associated with depression risk among probands. Among unaffected relatives of EOPD cases, only compound heterozygotes ( n = 4), and not heterozygotes, had significantly increased risk of depressed mood (OR = 14.1; 95% CI 1.2–163.4), moderate to severe depression (OR = 17.8; 95% CI 1.0–332.0), depression (score ≥ 15) on the Beck Depression Inventory II (BDI-II) (OR = 51.9; 95% CI 4.1–657.4), and BDI-II total depression score ( β = 8.4; 95% CI 2.4–11.3) compared to those without parkin mutations. Conclusions Relatives of EOPD cases with compound heterozygous mutations and without diagnosed PD may have a higher risk of depression compared to relatives without parkin mutations. These findings support evidence of a genetic contribution to depression and may extend the phenotypic spectrum of parkin mutations to include non-motor manifestations that precede the development of PD

Background: In epilepsy as in other disorders, family history information is often obtained by asking patients about the medical histories of their relatives rather than interviewing or examining the relatives directly. The accuracy of this type of information for epilepsy and other seizure disorders is unclear. Methods: This study used data from the Genetic Epidemiology of Seizure Disorders in Rochester study, a population-based investigation including all Rochester, MN, residents born ≥1920 with incidence of unprovoked seizures from 1935 to 1994 (case probands) and control probands matched by age, gender, and prior Rochester residency period. Seizure disorders in the first-degree relatives of case and control probands were ascertained by reviewing the relatives9 medical records. Case and control probands were interviewed about seizures in their first-degree relatives using a validated 9-question screening interview. Interviewers were blinded to case-control status. Results: Sensitivity of the family history (i.e., proportion of relatives with medical record–documented seizures who screened positive in the proband interview) was 62% (32/52) for epilepsy, 50% (7/14) for isolated unprovoked seizures, and 56% (9/16) for febrile seizures. Sensitivity did not differ by case/control status of the proband. Sensitivity was much higher for probands reporting on their offspring or siblings than their parents. Among relatives with epilepsy, 90% of offspring and 80% of siblings but only 32% of parents screened positive. Conclusions: Family histories of epilepsy are reasonably accurate for siblings and offspring, but are underreported in parents. Family histories of other seizure disorders are underreported.

Background: Autosomal dominant partial epilepsy with auditory features (ADPEAF) is an idiopathic focal epilepsy syndrome with auditory symptoms or receptive aphasia as major ictal manifestations, frequently associated with mutations in the leucine-rich, glioma inactivated 1 ( LGI1 ) gene. Although affected subjects do not have structural abnormalities detected on routine MRI, a lateral temporal malformation was identified through high resolution MRI in one family. We attempted to replicate this finding and to assess auditory and language processing in ADPEAF using fMRI and magnetoencephalography (MEG). Methods: We studied 17 subjects (10 affected mutation carriers, 3 unaffected carriers, 4 noncarriers) in 7 ADPEAF families, each of which had a different LGI1 mutation. Subjects underwent high-resolution structural MRI, fMRI with an auditory description decision task (ADDT) and a tone discrimination task, and MEG. A control group comprising 26 volunteers was also included. Results: We found no evidence of structural abnormalities in any of the 17 subjects. On fMRI with ADDT, subjects with epilepsy had significantly less activation than controls. On MEG with auditory stimuli, peak 2 auditory evoked field latency was significantly delayed in affected individuals compared to controls. Conclusions: These findings do not support the previous report of a lateral temporal malformation in autosomal dominant partial epilepsy with auditory features (ADPEAF). However, our fMRI and magnetoencephalography data suggest that individuals with ADPEAF have functional impairment in language processing.

Prior studies suggest that obsessive-compulsive symptoms (OCS) and disorder (OCD) are co-morbid with dystonia. We tested if OCS/OCD is a clinical manifestation of the DYT1 dystonia mutation by interviewing members of families with an identified DYT1 mutation, and classifying by manifesting carriers (MC), non-manifesting carriers (NMC), and non-carriers (NC). We found that OCD/OCS are not increased in DYT1 mutation carriers compared with NC, nor is OCD associated with manifesting DYT1 dystonia.

Collection of data from families containing multiple affected individuals is essential for genetic research on the epilepsies. Despite the obvious importance of this type of work, almost nothing has been published about methods for the identification and enrollment of eligible families or expected participation rates (1–3). Guidelines are needed to maximize efficiency of family recruitment, because extensive resources may be required to gather a sample size of sufficient statistical power. Complexities in data collection for genetic studies arise both in the identification of eligible families and in subject enrollment once they are identified. Families containing multiple affected individuals are rare, and family history information collected routinely in clinical practice is often insufficiently detailed to assess their eligibility for a specific study protocol. Working with families also presents unique problems for data collection (1,2). In most clinical studies, subject recruitment takes place at the level of the individual; each potential subject is contacted directly and decides whether or not to participate. In genetic linkage studies, however, recruitment requires the participation of a minimum number and constellation of individuals within each family. Only an initial contact person can be contacted directly; other family members cannot be contacted until a participating relative identifies them and obtains permission (2). Other special barriers to participation in genetic research include concerns about privacy and confidentiality, genetic discrimination, collection of the blood sample, or revealing a diagnosis to other family members (1,2,4–9). We describe the strategies used for family recruitment and data collection, participation rates, and factors affecting participation in a genetic linkage study of epilepsy. For investigators planning genetic studies, the results provide valuable information about what participation rates to expect and how to improve efficiency.

We tested the hypothesis that the comorbidity of migraine and epilepsy results from a shared genetic susceptibility to the two disorders. We used semistructured telephone interviews to collect information on migraine and epilepsy in the families (parents, siblings, and offspring) of 1,967 adult probands with epilepsy. Epilepsy was defined as a lifetime history of two or more unprovoked seizures, and migraine as self-reported severe headaches with two or more of the following symptoms: unilateral pain, throbbing pain, visual aura, or nausea. As a first test of the hypothesis of shared susceptibility, we assessed risk of migraine in relatives of probands with genetic versus nongenetic forms of epilepsy, using two proxy measures of genetic susceptibility-a first-degree family history of epilepsy and idiopathic/cryptogenic (versus postnatal symptomatic) etiology. Neither of these two measures was associated with risk of migraine in relatives. As a second test, we assessed risk of epilepsy in the relatives of probands with versus without migraine. With the exception of one subgroup (sons of female probands), risk of epilepsy in relatives was not associated with the proband's history of migraine. This pattern of results is inconsistent with the hypothesis of a shared genetic susceptibility to migraine and epilepsy.

We assessed the relations of genetic and environmental factors in the etiology of epilepsy. The study population comprised 9,705 first-degree relatives of 1,951 adults with epilepsy ascertained from voluntary organizations. We calculated standardized morbidity ratios for specific etiologies of epilepsy in the relatives of probands with the same etiologies, using population incidence rates from Rochester, MN, as the reference. Relatives of probands with idiopathic/cryptogenic epilepsy had increased risk for idiopathic/cryptogenic epilepsy and for epilepsy associated with neurological deficit presumed present at birth (cerebral palsy or mental retardation) but not for symptomatic epilepsy associated with postnatal central nervous system insults. Relatives of probands with neurodeficits had increased risks for idiopathic/cryptogenic epilepsy. Risk for epilepsy was not increased among relatives of probands with postnatal symptomatic epilepsy. The degree of increased risk of idiopathic/cryptogenic epilepsy in relatives of probands with idiopathic/cryptogenic epilepsy diminished with increasing age of the relatives; risk was not increased at age 35 or older. These findings support the possibility of a shared genetic susceptibility to epilepsy and cerebral palsy, and suggest that the genetic contributions to postnatal symptomatic epilepsy are minimal.

The risk of family history of ischemic heart disease independent of other well described risk factors has remained difficult to quantitate. Significant coronary artery disease was determined by coronary arteriography to be present in 223 patients and absent in 57 control subjects. Age, sex, blood pressure, serum cholesterol, cigarette smoking and the presence of diabetes and left ventricular hypertrophy on the electrocardiogram were tabulated for each patient and the data used to assign a risk score based on the American Heart Association multivariate model. Subjects were stratified and matched according to risk score to estimate risk of family history independent of familial aggregation of these seven other risk factors. Angina, myocardial infarction, cardiac death and any ischemic heart disease were ascertained in 1,319 first degree relatives. Odds ratios for overall, stratified and matched comparisons of these end points in relatives of patients and control subjects ranged between 2.0 and 3.9 (p less than 0.01 for all comparisons), indicating a higher frequency of all ischemic heart disease end points in relatives of patients with documented coronary artery disease. Life table comparison of patients at lowest risk with those at higher risk showed significantly greater cumulative frequency and earlier age of onset of all ischemic heart disease end points in relatives of low risk patients. These observations indicate that some of the risk associated with family history is independent of familial aggregation of other known risk factors and suggest that the independent effects of family history may be most important in individuals who otherwise are at low risk.