Rate of manifesting carriers and other unexpected findings on carrier screening.

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.

Polygenic and environmental determinants of tics in the Avon Longitudinal Study of Parents and Children.

Tourette syndrome (TS) is caused by multiple genetic and environmental factors. Yet, little is known about the interplay of these factors in the occurrence of tics. We investigated whether polygenic risk score (PRS) of TS and pregnancy-related factors together enhance the explained variance of tic occurrence in the Avon Longitudinal Study of Parents and Children (N  = 612; N  = 4,201; 50% male; mean age 13.

Genetic counseling certificate program: A program evaluation of undergraduate exposure to genetic counseling.

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.

Clinical and EEG factors associated with antiseizure medication resistance in idiopathic generalized epilepsy.

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.

Whole-exome sequencing identifies genes associated with Tourette's disorder in multiplex families.

Tourette's Disorder (TD) is a neurodevelopmental disorder (NDD) that affects about 0.7% of the population and is one of the most heritable NDDs. Nevertheless, because of its polygenic nature and genetic heterogeneity, the genetic etiology of TD is not well understood.

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions.

Reproductive male partner testing when the female is identified to be a genetic disease carrier.

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.

Empiric Recurrence Risk Estimates for Chronic Tic Disorders: Implications for Genetic Counseling.

Tourette disorder (TD) and other chronic tic disorders are neurodevelopmental/neuropsychiatric disorders characterized by motor and/or vocal tics. Family studies indicate that TD strongly aggregates within families and that other chronic tic disorders are biologically related such that studies typically combine them into any chronic tic disorder (CTD). Because of stigma, bullying, and comorbidity with other neuropsychiatric disorders, CTDs can severely impact the quality of life of individuals with these disorders.

Development and validation of a predictive model of drug-resistant genetic generalized epilepsy.

Objective: To develop and validate a clinical prediction model for antiepileptic drug (AED)-resistant genetic generalized epilepsy (GGE).

Method: We performed a case-control study of patients with and without drug-resistant GGE, nested within ongoing longitudinal observational studies of AED response at 2 tertiary epilepsy centers. Using a validation dataset, we tested the predictive performance of 3 candidate models, developed from a training dataset.

Polygenic Risk Scores Derived From a Tourette Syndrome Genome-wide Association Study Predict Presence of Tics in the Avon Longitudinal Study of Parents and Children Cohort.

Background: Tourette syndrome (TS) has a well-established genetic background, but its genetic architecture remains largely unknown. The authors investigated the role of polygenic risk scores (PRSs) derived from a TS genome-wide association study in relation to the occurrence of tics and associated traits in a general population cohort.

Methods: Using the most recent TS genome-wide association study (n = 4819 cases; n = 9488 controls) as the discovery sample, PRSs were calculated in Avon Longitudinal Study of Parents and Children participants (n = 8941).

De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD.

Mood disorders in familial epilepsy: A test of shared etiology.

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.

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach.

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings).

De Novo Coding Variants Are Strongly Associated with Tourette Disorder.

Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.

An Analytic Solution to the Computation of Power and Sample Size for Genetic Association Studies under a Pleiotropic Mode of Inheritance.

Our motivation here is to calculate the power of 3 statistical tests used when there are genetic traits that operate under a pleiotropic mode of inheritance and when qualitative phenotypes are defined by use of thresholds for the multiple quantitative phenotypes. Specifically, we formulate a multivariate function that provides the probability that an individual has a vector of specific quantitative trait values conditional on having a risk locus genotype, and we apply thresholds to define qualitative phenotypes (affected, unaffected) and compute penetrances and conditional genotype frequencies based on the multivariate function. We extend the analytic power and minimum-sample-size-necessary (MSSN) formulas for 2 categorical data-based tests (genotype, linear trend test [LTT]) of genetic association to the pleiotropic model.

Targeted Re-Sequencing Approach of Candidate Genes Implicates Rare Potentially Functional Variants in Tourette Syndrome Etiology.

Although the genetic basis of Tourette Syndrome (TS) remains unclear, several candidate genes have been implicated. Using a set of 382 TS individuals of European ancestry we investigated four candidate genes for TS (, and ) in an effort to identify possibly causal variants using a targeted re-sequencing approach by next generation sequencing technology. Identification of possible disease causing variants under different modes of inheritance was performed using the algorithms implemented in VAAST.

Pre- and perinatal complications in relation to Tourette syndrome and co-occurring obsessive-compulsive disorder and attention-deficit/hyperactivity disorder.

Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International Collaborative Genetics study.