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Objectives: To ascertain the rate of unexpected findings on carrier screening (CS) and assess whether implications are disclosed to patients. Methods: We performed a retrospective observational study of subjects who had CS after pre‐test counseling from a licensed genetic counselor at a large tertiary care center. We quantified the rate of unexpected finding on CS, defined as manifesting carriers (MCs), genotypes predicting phenotype, and chromosome abnormalities. We determined how often patients were informed of implications. We performed subgroup analyses by type of unexpected finding and calculated odds ratios (OR) and 95% confidence intervals (CI) for carrier testing methodology (genotype) and number of genes tested. Results: A total of 4685 patients had CS over the selected time frame. Of those patients, 412 patients (8.8%) had one unexpected finding and 29 patients (0.6%) had two or more findings. In total, 466 unexpected findings were identified, including 437 MC conditions, 23 genotypes predicting phenotype, and 6 chromosome abnormalities. Patients were informed of the implications for MCs, genotypes predicting phenotype, and chromosome abnormalities in 27.6%, 91.3%, and 100% of cases, respectively. More unexpected findings were detected with sequencing compared to genotyping (OR 2.21 and 95% CI 1.76–2.76) and with ≥200 gene panels compared to <200 gene panels (OR 1.79 and 95% CI 1.47–2.17). Conclusion: This study highlights that nondisclosure of unexpected findings on CS is common and underscores the need for further research to improve post‐test counseling and follow‐up. Key points: What is already known about this topic? Previous studies have examined carrier screening (CS) detection rates, but less is known about unexpected findings and whether implications are disclosed to patients. What does this study add? Unexpected findings are common on CS.Most unexpected findings are manifesting carriers (MCs). Patients infrequently had post‐test counseling about their implications and were counseled more frequently about chromosomal abnormalities and genotypes predicting phenotype.This study shows provider education about the frequency of unexpected findings and post‐test counseling about their implications is important to ensure patients have comprehensive genetic counseling. [ABSTRACT FROM AUTHOR]

Undergraduate genetic counseling exposure can generate interest in a growing field, help students prepare to apply to graduate‐level programs, and introduce underrepresented populations to the career. One form of exposure that currently exists is the Genetic Counseling Certificate Program (GCCP), which is offered to undergraduate students at Rutgers University. To determine the effectiveness, benefits, and limitations of the GCCP, a program evaluation was conducted. Former GCCP students were surveyed to assess how they perceived the program. Overall, most students thought the program successfully met its objectives and thought their participation in the GCCP was beneficial. Because it is viewed favorably by former students, implementing something similar to the GCCP may be an option for institutions looking to offer additional opportunities to their undergraduates. Not only could creating programs like the GCCP enhance undergraduates' knowledge of the genetic counseling profession, but it could also contribute toward diversification of the field. [ABSTRACT FROM AUTHOR]

Objective: We sought to determine which combination of clinical and electroencephalography (EEG) characteristics differentiate between an antiseizure medication (ASM)–resistant vs ASM‐responsive outcome for patients with idiopathic generalized epilepsy (IGE). Methods: This was a case‐control study of ASM‐resistant cases and ASM‐responsive controls with IGE treated at five epilepsy centers in the United States and Australia between 2002 and 2018. We recorded clinical characteristics and findings from the first available EEG study for each patient. We then compared characteristics of cases vs controls using multivariable logistic regression to develop a predictive model of ASM‐resistant IGE. Results: We identified 118 ASM‐resistant cases and 114 ASM‐responsive controls with IGE. First, we confirmed our recent finding that catamenial epilepsy is associated with ASM‐resistant IGE (odds ratio [OR] 3.53, 95% confidence interval [CI] 1.32–10.41, for all study subjects) after covariate adjustment. Other independent factors seen with ASM resistance include certain seizure‐type combinations (absence, myoclonic, and generalized tonic‐clonic seizures [OR 7.06, 95% CI 2.55–20.96]; absence and generalized tonic‐clonic seizures [OR 4.45, 95% CI 1.84–11.34]), as well as EEG markers of increased generalized spike‐wave discharges (GSWs) in sleep (OR 3.43, 95% CI 1.12–11.36 for frequent and OR 7.21, 95% CI 1.50–54.07 for abundant discharges in sleep) and the presence of generalized polyspike trains (GPTs; OR 5.49, 95% CI 1.27–38.69). The discriminative ability of our final multivariable model, as measured by area under the receiver‐operating characteristic curve, was 0.80. Significance: Multiple clinical and EEG characteristics independently predict ASM resistance in IGE. To improve understanding of a patient's prognosis, clinicians could consider asking about specific seizure‐type combinations and track whether they experience catamenial epilepsy. Obtaining prolonged EEG studies to record the burden of GSWs in sleep and assessing for the presence of GPTs may provide additional predictive value. [ABSTRACT FROM AUTHOR]

Objective: To quantify carrier testing uptake rates for male partners of women found to be a carrier(s) for autosomal recessive conditions and to understand reasons for declining testing (uptake rate). Methods: A retrospective chart review of 513 female patients seen at Rutgers‐Robert Wood Johnson Medical School found to be carriers through expanded carrier screening (ECS) panels. The aims of this study were to determine how often their male partner chose testing, reasons for declining and the type of methodology chosen for their screening. Results: Male partner uptake rate was 77%. We identified that the most significant barrier to male partner testing is female patients not following up on their own carrier screening results, thus missing the opportunity for partner testing. When male partners were provided options for testing, the most reported reason for declining is the belief it would have no impact on pregnancy management (20%). A carrier couple rate of 8.3% was identified of partners tested. Conclusion: Despite a relatively high male testing uptake rate, a quarter of carrier females did not proceed with testing their partner. To ascertain fetal risk, results for both parents is necessary. Pretest counseling should stress need for potential male partner follow‐up testing. [ABSTRACT FROM AUTHOR]

Summary: Objective: Mood disorders are the most common comorbid conditions in epilepsy, but the cause remains unclear. One possible explanation is a shared genetic susceptibility to epilepsy and mood disorders. We tested this hypothesis by evaluating lifetime prevalence of mood disorders in relatives with and without epilepsy in families containing multiple individuals with epilepsy, and comparing the findings with rates from a general population sample. Methods: The Composite International Diagnostic Interview was administered to 192 individuals from 60 families, including 110 participants with epilepsy of unknown cause (50 focal epilepsy [FE], 42 generalized epilepsy [GE], 6 FE and GE, 12 unclassifiable) and 82 relatives without epilepsy (RWOE). Odds ratios (ORs) for lifetime prevalence of mood disorders in participants with versus without epilepsy were computed through logistic regression, using generalized estimation equations to account for familial clustering. Standardized prevalence ratios (SPRs) were used to compare prevalence in family members with general population rates. Results: Compared with RWOE, ORs for mood disorders were significantly increased in participants with FE (OR = 2.4, 95% confidence interval [CI] = 1.1‐5.2) but not in those with GE (OR = 1.0, 95% CI = 0.4‐2.2). In addition, prevalence of mood disorders was increased in individuals with epilepsy who had ≥1 relative with FE. Compared with general population rates, mood disorders were significantly increased in individuals with FE but not in those with GE. Rates were also increased in RWOE, but not significantly so (SPR = 1.4, P = .14). Significance: These findings are consistent with the hypothesis of shared genetic susceptibility to epilepsy and mood disorders, but suggest (1) the effect may be restricted to FE, and (2) the shared genetic effect on risk of mood disorders and epilepsy may be restricted to individuals with epilepsy, that is, to those in whom the genetic risk for epilepsy is “penetrant.” [ABSTRACT FROM AUTHOR]

Objective: To examine the seizure trajectories of adults with epilepsy developing drug-resistant epilepsy (DRE) and to identify the predictors of seizure trajectory outcome. Methods: Adult patients failing two antiepileptic drugs (AEDs) due to inefficacy and starting their third AED at a tertiary epilepsy center were followed for seizure trajectory outcome during medical management. Seizure trajectories were categorized into one of four patterns: (1) course with constant seizures; (2) fluctuating course; (3) delayed attainment of seizure freedom (seizure freedom delayed for >12 months after start of the study, but patient stayed in seizure freedom); and (4) early attainment of seizure freedom (within 12 months of starting study). Multiple ordinal logistic regression models were used to estimate the association between trajectory categories and clinical factors. Results: Four hundred three adult patients met the eligibility criteria. Of these, 212 (53%) never achieved a seizure-free period of a year or more. The trajectories of 63 patients (16%) had a complex fluctuating trajectory, 62 (15%) had delayed onset of seizure freedom, and 66 (16%) had an early seizure freedom. Independent predictors associated with more favorable outcome trajectories were epilepsy type and length of follow-up. Specifically, compared to patients with focal epilepsy of temporal lobe, patients with focal epilepsy of occipital lobe (OR 3.80, 95% confidence interval [CI] 1.00-14.51, p = 0.04), generalized genetic (OR 3.23, 95% CI 1.88-5.57, p < 0.0001), unclear epilepsy type (OR 3.82, 95% CI 1.53-9.52, p < 0.005), and both focal and generalized epilepsy(OR 11.73, 95% CI 1.69-81.34, p = 0.01) were significantly more likely to experience a better trajectory pattern. Significance: Examination of patterns of seizure trajectory of patients with incident DRE showed that 31% were in continuous seizure freedom at the end of the observation period. [ABSTRACT FROM AUTHOR]

Background Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. Methods We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). Results The polymorphism rs3096140 in glial cell line-derived neurotrophic factor gene ( GDNF) was significant in the discovery cohort after correction ( P = 1.5 × 10−4). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort ( P = 0.01). No association with any comorbidity was found. Conclusions As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

ABSTRACT To evaluate the hypothesis that functionally over-expressing alleles of the serotonin transporter (SERT) gene (solute carrier family 6, member 4, SLC6A4) are present in Tourette's disorder (TD), just as we previously observed in obsessive compulsive disorder (OCD), we evaluated TD probands (N = 151) and controls (N = 858). We genotyped the refined SERT-linked polymorphic region 5-HTTLPR/rs25531 and the associated rs25532 variant in the SLC6A4 promoter plus the rare coding variant SERT isoleucine-to-valine at position 425 (I425V). The higher expressing 5-HTTLPR/rs25531 LA allele was more prevalent in TD probands than in controls (χ2 = 5.75; P = 0.017; odds ratio [OR], 1.35); and, in a secondary analysis, surprisingly, it was significantly more frequent in probands who had TD alone than in those who had TD plus OCD (Fisher's exact test; P = 0.0006; OR, 2.29). Likewise, the higher expressing LAC haplotype (5-HTTLPR/rs25531/rs25532) was more frequent in TD probands than in controls ( P = 0.024; OR, 1.33) and also in the TD alone group versus the TD plus OCD group ( P = 0.0013; OR, 2.14). Furthermore, the rare gain-of-function SERT I425V variant was observed in 3 male siblings with TD and/or OCD and in their father. Thus, the cumulative count of SERT I425V becomes 1.57% in OCD/TD spectrum conditions versus 0.15% in controls, with a recalculated, family-adjusted significance of χ2 = 15.03 ( P < 0.0001; OR, 9.0; total worldwide genotyped, 2914). This report provides a unique combination of common and rare variants in one gene in TD, all of which are associated with SERT gain of function. Thus, altered SERT activity represents a potential contributor to serotonergic abnormalities in TD. The present results call for replication in a similarly intensively evaluated sample. © 2013 Movement Disorder Society [ABSTRACT FROM AUTHOR]

The behavioral and cognitive features of the leucine-rich repeat kinase G2019S mutation in Parkinson's disease in the Ashkenazi Jewish population are not well described; therefore, we sought to more systematically characterize these features using a semistructured psychiatric interview and neuropsychological testing. Twenty-one Ashkenazi Jewish patients having the leucine-rich repeat kinase G2019S mutation were compared with age- and sex-matched Ashkenazi Jewish patients with Parkinson's disease without mutations. Although overall rates of affective disorders were not greater in mutation carriers, the carriers exhibited a 6-fold increased risk of premorbid affective disorders (odds ratio, 6.0; P = .10), as determined by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV. Of interest, we identified 2 leucine-rich repeat kinase carriers with bipolar disorder; no mutation-negative subjects had this diagnosis. Performance on the Hopkins Verbal Learning Test-Revised, Judgment of Line Orientation, and Frontal Assessment Battery was consistent with previous reports and did not differ between groups. Study findings suggest a possible association between premorbid mood disorders and leucine-rich repeat kinase Parkinson's disease, warranting further evaluation. © 2011 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Depression is the most common comorbid condition in epilepsy. The cause of this comorbidity is unknown, and could involve psychosocial consequences of epilepsy, treatment side effects, seizure manifestations, or common neurobiologic mechanisms. One hypothesis of particular interest is a shared genetic susceptibility to epilepsy and depression. We tested this hypothesis by studying depressive symptoms in families with an identified genetic form of epilepsy: autosomal dominant partial epilepsy with auditory features caused by mutations in the leucine-rich, glioma inactivated 1 gene ( LGI1). A standardized depression screen was administered to 94 individuals from 11 families with mutations in LGI1, including 38 mutation carriers with epilepsy (AC), 11 clinically unaffected mutation carriers (UC), and 45 noncarriers (NC). Current depressive symptom scores were significantly higher in AC than in NC, an association that remained after excluding depressive symptoms that appeared likely to be caused by antiepileptic medication use. However, scores did not differ between UC and NC. Although LGI1 mutation carriers who were clinically affected with epilepsy had increased depressive symptoms, mutation carriers without epilepsy did not. These findings suggest that the increase in depressive symptoms in affected individuals from these families is related to epilepsy or its treatment rather than to LGI1 mutations per se. [ABSTRACT FROM AUTHOR]

To investigate the cumulative probabilities of ≥12 month seizure remission and seizure relapse following remission, and to test the associations of clinical characteristics with these two study end points in a prevalence cohort of intractable adult epilepsy patients during medical management. A retrospective cohort study of intractable epilepsy patients seen in 2001 at a single center was conducted. Kaplan–Meier analysis was used to estimate the cumulative probabilities of seizure remission and subsequent seizure relapse. Cox proportional hazards models were used to estimate the association (1) between clinical factors and ≥12 month seizure remission and (2) between clinical factors and seizure relapse following remission. One hundred eighty-seven subjects met the eligibility criteria for intractable epilepsy. The estimate of probability of remission was about 4% per year. Seizure remission was temporary for some individuals, as 5 out of 20 subjects with remission ultimately relapsed. No clinical factors predicted the likelihood of achieving ≥12 month seizure remission or subsequent seizure relapse. Some people with intractable epilepsy achieve ≥12 month seizure remission during medical treatment. Remission, however, is only temporary for some individuals. We were unable to identify clear predictors for remission. [ABSTRACT FROM AUTHOR]

Myoclonus-dystonia (M-D) due to SGCE mutations is characterized by early onset myoclonic jerks, often associated with dystonia. Penetrance is influenced by parental sex, but other sex effects have not been established. In 42 affected individuals from 11 families with identified mutations, we found that sex was highly associated with age at onset regardless of mutation type; the median age onset for girls was 5 years versus 8 years for boys ( P < 0.0097). We found no association between mutation type and phenotype. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Drug-resistant epilepsy in adults: Outcome trajectories after failure of two medications" is presented.

There is comorbidity and a possible genetic connection between Bipolar disease (BP) and panic disorder (PD). Genes may exist that increase risk to both PD and BP. We explored this possibility using data from a linkage study of PD (120 multiplex families; 37 had > or =1 BP member). We calculated 2-point lodscores maximized over male and female recombination fractions by classifying individuals with PD and/or BP as affected (PD + BP). Additionally, to shed light on possible heterogeneity, we examine the pedigrees containing a bipolar member (BP+) separately from those that do not (BP-), using a Predivided-Sample Test (PST). Linkage evidence for common genes for PD + BP was obtained on chromosomes 2 (lodscore = 4.6) and chromosome 12 (lodscore = 3.6). These locations had already been implicated using a PD-only diagnosis, although at both locations this was larger when a joint PD + BP diagnosis was used. Examining the BP+ families and BP- families separately indicates that both BP+ and BP- pedigrees are contributing to the peaks on chromosomes 2 and 12. However, the PST indicates different evidence of linkage is obtained from BP+ and BP- pedigrees on chromosome 13. Our findings are consistent with risk loci for the combined PD + BP phenotype on chromosomes 2 and 12. We also obtained evidence of heterogeneity on chromosome 13. The regions on chromosomes 12 and 13 identified here have previously been implicated as regions of interest for multiple psychiatric disorders, including BP., (2009 Wiley-Liss, Inc.)

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., ((c) 2006 Wiley-Liss, Inc.)

Clinical and animal studies suggest a role for pathways regulated by cyclic-AMP in anxiety. Mouse gene deletion studies, our own linkage findings on chromosome 10, and a recently published genetic association study by Domschke et al. [2003: Am J Med Genet 117B:70-78] suggest that the cAMP responsive element modulator (CREM) may be involved in panic disorder. We have employed a family-based design to investigate the role of DNA sequence variations in the gene for CREM in panic disorder. We have genotyped 613 individuals in 70 panic disorder pedigrees, as well as 42 parent/offspring triads. Subjects were genotyped at two informative single nucleotide polymorphisms (SNPs) and three polymorphic microsatellites in the CREM genomic region; and the data were analyzed for genetic association and linkage. Linkage analysis employing several diagnostic/genetic models produced a maximum lod score of 0.63 for SNP-1, located in the 5' UTR of CREM, under a dominant model with a broad diagnostic definition of panic disorder. Non-parametric analysis, using the NPL statistic or FBAT, also did not support any linkage or association between the markers and panic disorder. All five markers (spanning 77 kb) used in the study showed modest, but significant linkage disequilibrium. Analysis of 2-, 3-, 4-, or 5-marker haplotypes using TRANSMIT failed to find any globally significant results; however, individual haplotypes containing a single allele of MS-3 were nominally associated with panic disorder. These findings provide little additional evidence for a susceptibility locus for panic disorder either within the CREM gene or in a nearby region of chromosome 10p11 in our sample., (Copyright 2003 Wiley-Liss, Inc.)