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At least 19 recordsLinked to original sources
PubMed2025

Adjustment for Genotype Imputation Uncertainty Corrects for Inflated Type I Error in Family-Based Association Testing.

Genotype imputation is a widely-used data augmentation approach that is applied to samples of related and/or unrelated individuals. Association testing may then be carried out on the complete data with commonly-used methods. This approach has typically not accounted for the mix of observed and imputed data, although recent work has noted the potential for introduction of confounding in case-control studies. In the Alzheimer's Disease Sequencing Project family sample we found severe inflation of the test statistics in logistic regression analysis following genotype imputation, even after standard covariate adjustments. Here we dissect sources of this inflation, which is driven by three factors: frequency-dependent bias in imputation-induced allele frequencies, differential measurement error, and differential genotyping rates in cases versus controls that introduces confounding. To address the problem, we propose a statistic, imputation deviance (), which can be easily computed from the observed and imputed genotype probabilities. We show that, as an additional fixed-effect covariate, controls the genome-wide inflation in analysis of this family-based sample, and we speculate that use of imputation deviance may also provide a practical approach to correct for genotype imputation effects in other settings, particularly when a data set is unbalanced and includes related individuals.

Humans↗
PubMed2023

Methotrexate-based PROTACs as DHFR-specific chemical probes.

Methotrexate (MTX) is a tight-binding dihydrofolate reductase (DHFR) inhibitor, used as both an antineoplastic and immunosuppressant therapeutic. MTX, like folate undergoes folylpolyglutamate synthetase-mediated γ-glutamylation, which affects cellular retention and target specificity. Mechanisms of MTX resistance in cancers include a decrease in MTX poly-γ-glutamylation and an upregulation of DHFR. Here, we report a series of potent MTX-based proteolysis targeting chimeras (PROTACs) to investigate DHFR degradation pharmacology and one-carbon biochemistry. These on-target, cell-active PROTACs show proteasome- and E3 ligase-dependent activity, and selective degradation of DHFR in multiple cancer cell lines. By comparison, treatment with MTX increases cellular DHFR protein expression. Importantly, these PROTACs produced distinct, less-lethal phenotypes compared to MTX. The chemical probe set described here should complement conventional DHFR inhibitors and serve as useful tools for studying one-carbon biochemistry and dissecting complex polypharmacology of MTX and related drugs. Such compounds may also serve as leads for potential autoimmune and antineoplastic therapeutics.

Humans↗
PubMed2025

Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.

In 1978, for my PhD, I developed the efficient O(n3) dynamic programming algorithm for the-then open problem of RNA secondary structure prediction. This algorithm, now dubbed the "Nussinov algorithm", "Nussinov plots", and "Nussinov diagrams", is still taught across Europe and the U.S. As sequences started coming out in the 1980s, I started seeking genome-encoded functional signals, later becoming a bioinformatics trend. In the early 1990s I transited to proteins, co-developing a powerful computer vision-based docking algorithm. In the late 1990s, I proposed the foundational role of conformational ensembles in molecular recognition and allostery. At the time, conformational ensembles and free energy landscapes were viewed as physical properties of proteins but were not associated with function. The classical view of molecular recognition and binding was based on only two conformations captured by crystallography: open and closed. I proposed that all conformational states preexist. Proteins always have not one folded form-nor two-but many folded forms. Thus, rather than inducing fit, binding can work by shifting the ensembles between states, and this shifting, or redistributing the ensembles to maintain equilibrium, is the origin of the allosteric effect and protein, thus cell, function. This transformative paradigm impacted community views in allosteric drug design, catalysis, and regulation. Dynamic conformational ensemble shifts are now acknowledged as the origin of recognition, allostery, and signaling, underscoring that conformational ensembles-not proteins-are the workhorses of the cell, pioneering the fundamental idea that dynamic ensembles are the driving force behind cellular processes. Nussinov was recognized as pioneer in molecular biology by JMB.

Molecular Biology↗
PubMed2025

Development and extensive sequencing of a broadly-consented Genome in a Bottle matched tumor-normal pair.

The Genome in a Bottle Consortium (GIAB), hosted by the National Institute of Standards and Technology (NIST), is developing new matched tumor-normal samples, the first explicitly consented for public dissemination of genomic data and cell lines. Here, we describe a comprehensive genomic dataset from the first individual, HG008, including DNA from an adherent, epithelial-like pancreatic ductal adenocarcinoma (PDAC) tumor cell line and matched normal cells from duodenal and pancreatic tissues. Data for the tumor-normal matched samples comes from seventeen distinct state-of-the-art whole genome measurement technologies, including high depth short and long-read bulk whole genome sequencing (WGS), single cell WGS, Hi-C, and karyotyping. These data will be used by the GIAB Consortium to develop matched tumor-normal benchmarks for somatic variant detection. We expect these data to facilitate innovation for whole genome measurement technologies, de novo assembly of tumor and normal genomes, and bioinformatic tools to identify small and structural somatic variants. This first-of-its-kind broadly consented open-access resource will facilitate further understanding of sequencing methods used for cancer biology.

Humans↗
PubMed2017

A New Natural Product Analog of Blasticidin S Reveals Cellular Uptake Facilitated by the NorA Multidrug Transporter.

The permeation of antibiotics through bacterial membranes to their target site is a crucial determinant of drug activity but in many cases remains poorly understood. During screening efforts to discover new broad-spectrum antibiotic compounds from marine sponge samples, we identified a new analog of the peptidyl nucleoside antibiotic blasticidin S that exhibited up to 16-fold-improved potency against a range of laboratory and clinical bacterial strains which we named P10. Whole-genome sequencing of laboratory-evolved strains of Staphylococcus aureus resistant to blasticidin S and P10, combined with genome-wide assessment of the fitness of barcoded Escherichia coli knockout strains in the presence of the antibiotics, revealed that restriction of cellular access was a key feature in the development of resistance to this class of drug. In particular, the gene encoding the well-characterized multidrug efflux pump NorA was found to be mutated in 69% of all S. aureus isolates resistant to blasticidin S or P10. Unexpectedly, resistance was associated with inactivation of norA, suggesting that the NorA transporter facilitates cellular entry of peptidyl nucleosides in addition to its known role in the efflux of diverse compounds, including fluoroquinolone antibiotics.

Bacterial Proteins↗
PubMed2025

IgStrand: A universal residue numbering scheme for the immunoglobulin-fold (Ig-fold) to study Ig-proteomes and Ig-interactomes.

The Immunoglobulin fold (Ig-fold) is found in proteins from all domains of life and represents the most populous fold in the human genome, with current estimates ranging from 2 to 3% of protein coding regions. That proportion is much higher in the surfaceome where Ig and Ig-like domains orchestrate cell-cell recognition, adhesion and signaling. The ability of Ig-domains to reliably fold and self-assemble through highly specific interfaces represents a remarkable property of these domains, making them key elements of molecular interaction systems: the immune system, the nervous system, the vascular system and the muscular system. We define a universal residue numbering scheme, common to all domains sharing the Ig-fold in order to study the wide spectrum of Ig-domain variants constituting the Ig-proteome and Ig-Ig interactomes at the heart of these systems. The "IgStrand numbering scheme" enables the identification of Ig structural proteomes and interactomes in and between any species, and comparative structural, functional, and evolutionary analyses. We review how Ig-domains are classified today as topological and structural variants and highlight the "Ig-fold irreducible structural signature" shared by all of them. The IgStrand numbering scheme lays the foundation for the systematic annotation of structural proteomes by detecting and accurately labeling Ig-, Ig-like and Ig-extended domains in proteins, which are poorly annotated in current databases and opens the door to accurate machine learning. Importantly, it sheds light on the robust Ig protein folding algorithm used by nature to form beta sandwich supersecondary structures. The numbering scheme powers an algorithm implemented in the interactive structural analysis software iCn3D to systematically recognize Ig-domains, annotate them and perform detailed analyses comparing any domain sharing the Ig-fold in sequence, topology and structure, regardless of their diverse topologies or origin. The scheme provides a robust fold detection and labeling mechanism that reveals unsuspected structural homologies among protein structures beyond currently identified Ig- and Ig-like domain variants. Indeed, multiple folds classified independently contain a common structural signature, in particular jelly-rolls. Examples of folds that harbor an "Ig-extended" architecture are given. Applications in protein engineering around the Ig-architecture are straightforward based on the universal numbering.

Humans↗
PubMed2023

Diverse evolutionary rates and gene duplication patterns among families of functional olfactory receptor genes in humans.

In humans, odors are detected by ~400 functional olfactory receptor (OR) genes. The superfamily of functional OR genes can be further divided into tens of families. In large part, the OR genes have experienced extensive tandem duplications, which have led to gene gains and losses. However, whether different OR gene families have experienced distinct modes of gene duplication has yet to be reported. We conducted comparative genomic and evolutionary analyses for human functional OR genes. Based on analysis of human-mouse 1-1 orthologs, we found that human functional OR genes show higher-than-average evolutionary rates, and there are significant differences among families of functional OR genes. Via comparison with seven vertebrate outgroups, families of human functional OR genes show different extents of gene synteny conservation. Although the superfamily of human functional OR genes is enriched in tandem and proximal duplications, there are particular families which are enriched in segmental duplications. These findings suggest that human functional OR genes may be governed by different evolutionary mechanisms and that large-scale gene duplications have contributed to the early evolution of human functional OR genes.

Humans↗
PubMed2007

Identification of novel genetic loci for intraocular pressure: a genomewide scan of the Beaver Dam Eye Study.

OBJECTIVE: To identify genetic loci that control intraocular pressure (IOP). METHODS: We performed a genomewide scan of IOP, using 486 pedigrees ascertained through a population-based cohort, the Beaver Dam Eye Study. Linkage analysis was performed using the modified Haseman-Elston regression models and variance components linkage analysis. RESULTS: Seven regions of interest were identified on chromosomes 2, 5, 6, 7, 12, 15, and 19. The novel linkage region on chromosome 19p had an empirical multipoint P value of 6.1 x 10(-5). Two of the regions (2 and 19) were especially interesting since each has been identified as a potential linkage region for blood pressure. CONCLUSIONS: The results of this genomewide scan provide evidence that a quantitative trait locus may influence elevated IOP and may colocalize with blood pressure loci. These loci may control systemic pressure reflected in the eye and vascular system. CLINICAL RELEVANCE: Glaucoma is a leading cause of blindness in the world, and the identification of genes that contribute to this disease is essential. Elevated IOP is a principal risk factor for primary open-angle glaucoma and an intriguing quantitative trait that may strongly influence the development of disease.

Adult↗
PubMed2007

Confirmation of linkage to ocular refraction on chromosome 22q and identification of a novel linkage region on 1q.

OBJECTIVE: To localize genes influencing ocular refraction in subjects in the Beaver Dam Eye Study. Previous studies establish that myopia clusters within families and linkage to myopia has been demonstrated on 2q, 4q, 12q, 17q, 18q, 22q, and Xq. Few studies have examined genetic effects across the entire range of refraction, though linkages to 1p, 3q, 4q, 8p, and 11p have been reported, and our previous analysis of the Beaver Dam Eye Study demonstrated substantial heritability for refraction (68%). METHODS: We conducted nonparametric sibling-pair and genome-wide linkage analyses on spherical equivalent adjusting for age, education, and nuclear sclerosis, in 834 sibling pairs in 486 extended pedigrees. RESULTS: We identified a novel region of suggestive linkage on 1q (multipoint, P<.00019) and replicated the 22q region (multipoint, P = .0033) previously linked to myopia. Additionally, there was some evidence of linkage to 7p (multipoint, P = .0023). CONCLUSION: Refraction is a complex trait influenced by both genes and environment. Our work confirms a previously reported linkage region on 22q and identifies 2 novel regions of linkage on 1q and 7p. CLINICAL RELEVANCE: Further, genetic research is needed to finemap this trait to identify the causative gene. Modifying the actions of such a gene might lead to a reduction in the risk of refractive error.

Adult↗
PubMed2006

What is familial about familial bipolar disorder? Resemblance among relatives across a broad spectrum of phenotypic characteristics.

CONTEXT: Current diagnostic criteria for bipolar affective disorder define a phenotype that is highly heritable, yet clinically variable. A more homogeneous definition might facilitate genetic and other studies, but the best approach is unclear. Familial features of bipolar disorder should help define more homogeneous subtypes, but there are few data indicating which clinical features of bipolar disorder are the most familial. OBJECTIVE: To study the familiality of phenotypic features in families ascertained through individuals with bipolar affective disorder. DESIGN: The study comprises 1246 individuals in 172 multiplex families ascertained for genetic linkage studies of bipolar disorder. The familiality of 40 diverse phenotypic features was studied using mixed-effects regression analysis. RESULTS: Substance abuse, alcoholism, psychosis, history of suicide attempt, and the level of social functioning were all strongly familial in this sample. Several other traits, including clinical subtype, earliest age at onset, and comorbid panic disorder, showed a suggestion of familiality that did not hold up to conservative correction for multiple testing. CONCLUSIONS: This is the largest and most comprehensive study to assess the familiality of phenotypic features in bipolar disorder. Our results suggest that comorbid conditions and social functioning should be considered along with other familial clinical features in formulating subtypes of bipolar disorder suitable for further studies. Familial variables may help reduce diagnostic heterogeneity in genetic and other biological studies.

Adult↗
PubMed2005

Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease.

CONTEXT: Sickle cell disease is characterized by a state of nitric oxide resistance and limited bioavailability of l-arginine, the substrate for nitric oxide synthesis. We hypothesized that increased arginase activity and dysregulated arginine metabolism contribute to endothelial dysfunction, pulmonary hypertension, and patient outcomes. OBJECTIVE: To explore the role of arginase in sickle cell disease pathogenesis, pulmonary hypertension, and mortality. DESIGN: Plasma amino acid levels, plasma and erythrocyte arginase activities, and pulmonary hypertension status as measured by Doppler echocardiogram were prospectively obtained in outpatients with sickle cell disease. Patients were followed up for survival up to 49 months. SETTING: Urban tertiary care center and community clinics in the United States between February 2001 and March 2005. PARTICIPANTS: Two hundred twenty-eight patients with sickle cell disease, aged 18 to 74 years, and 36 control participants. MAIN OUTCOME MEASURES: Plasma amino acid levels, plasma and erythrocyte arginase activities, diagnosis of pulmonary hypertension, and mortality. RESULTS: Plasma arginase activity was significantly elevated in patients with sickle cell disease, with highest activity found in patients with secondary pulmonary hypertension. Arginase activity correlated with the arginine-ornithine ratio, and lower ratios were associated with greater severity of pulmonary hypertension and with mortality in this population (risk ratio, 2.5; 95% confidence interval [CI], 1.2-5.2; P = .006). Global arginine bioavailability, characterized by the ratio of arginine to ornithine plus citrulline, was also strongly associated with mortality (risk ratio, 3.6; 95% CI, 1.5-8.3; P<.001). Increased plasma arginase activity was correlated with increased intravascular hemolytic rate and, to a lesser extent, with markers of inflammation and soluble adhesion molecule levels. CONCLUSIONS: These data support a novel mechanism of disease in which hemolysis contributes to reduced nitric oxide bioavailability and endothelial dysfunction via release of erythrocyte arginase, which limits arginine bioavailability, and release of erythrocyte hemoglobin, which scavenges nitric oxide. The ratios of arginine to ornithine and arginine to ornithine plus citrulline are independently associated with pulmonary hypertension and increased mortality in patients with sickle cell disease.

Adult↗
PubMed2005

Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers.

CONTEXT: Obesity, diabetes mellitus, and glucose intolerance have been associated with increased pancreatic cancer risk; however, prediagnostic serum insulin concentration has not been evaluated as a predictor of this malignancy. OBJECTIVE: To investigate whether prediagnostic fasting glucose and insulin concentrations and insulin resistance are associated with subsequent incidence of exocrine pancreatic cancer in a cohort of male smokers. DESIGN, SETTING, AND PARTICIPANTS: A case-cohort prospective study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985-1988) cohort of 29,133 male Finnish smokers ages 50 to 69 years. The study included 400 randomly sampled subcohort control participants and 169 incident pancreatic cancer cases that occurred after the fifth year of follow-up. All participants were followed up through December 2001 (up to 16.7 years of follow-up). MAIN OUTCOME MEASURES: Incident exocrine pancreatic cancer identified from the Finnish Cancer Registry. RESULTS: After adjusting for age, smoking, and body mass index, higher baseline fasting serum concentrations of glucose, insulin, and insulin resistance were positively associated with pancreatic cancer. The presence of biochemically defined diabetes mellitus (glucose, > or =126 mg/dL [> or =6.99 mmol/L]) and insulin concentration in the highest vs lowest quartile both showed a significant 2-fold increased risk (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.04-4.35; and HR, 2.01; 95% CI, 1.03-3.93; respectively). There were significant interactions for all the biomarker exposures by follow-up time, such that the positive associations were stronger among the cases that occurred more than 10 years after baseline (highest vs lowest quartile: glucose, HR, 2.16; 95% CI, 1.05-4.42; P for trend = .02; insulin, HR, 2.90; 95% CI, 1.22-6.92; P for trend = .005; and insulin resistance, HR, 2.71; 95% CI, 1.19-6.18; P for trend = .006). CONCLUSIONS: These results support the hypothesis that exposure to higher insulin concentrations and insulin resistance predicts the risk of exocrine pancreatic cancer.

Blood Glucose↗
PubMed2006

Prevalence of visual impairment in the United States.

CONTEXT: The prevalence of visual impairment in the US public has not been surveyed nationally in several decades. OBJECTIVE: To estimate the number of US individuals aged 12 years or older who have impaired distance vision due to uncorrected refractive error. DESIGN, SETTING, AND PARTICIPANTS: The National Health and Nutrition Examination Survey (NHANES), using a multistage probability sampling design, included a vision evaluation in a mobile examination center. Visual acuity data were obtained from 13,265 of 14,203 participants (93.4%) who visited the mobile examination center in 1999-2002. Visual impairment was defined as presenting distance visual acuity of 20/50 or worse in the better-seeing eye. Visual impairment due to uncorrected refractive error was defined as (presenting) visual impairment that improved, aided by automated refraction results, to 20/40 or better in the better-seeing eye. MAIN OUTCOME MEASURES: Presenting distance visual acuity (measured with usual corrective lenses, if any) and distance visual acuity after automated refraction. RESULTS: Overall, 1190 study participants had visual impairment (weighted prevalence, 6.4%; 95% confidence interval [CI], 6.0%-6.8%), and of these, 83.3% could achieve good visual acuity with correction (95% CI, 80.9%-85.8%). Extrapolating these findings to the general US population, approximately 14 million individuals aged 12 years or older have visual impairment (defined as distance visual acuity of 20/50 or worse), and of these, more than 11 million individuals could have their vision improved to 20/40 or better with refractive correction. CONCLUSIONS: Visual impairment due to uncorrected refractive error is a common condition in the United States. Providing appropriate refractive correction to those individuals whose vision can be improved is an important public health endeavor with implications for safety and quality of life.

Adolescent↗
PubMed2006

Effect of youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians.

CONTEXT: The long-term outcome of persons with youth-onset type 2 diabetes mellitus has not been well described. OBJECTIVE: To compare incidence of diabetic end-stage renal disease (ESRD) and mortality in Pima Indians with youth- and older-onset type 2 diabetes mellitus. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal population-based study conducted between 1965 and 2002 in Pima Indians from the state of Arizona. Participants were divided into 2 groups: (1) youth-onset type 2 diabetes mellitus (onset <20 years of age) and (2) older-onset type 2 diabetes mellitus (onset > or =20 - <55 years of age). Events and person-years of follow-up were stratified in a time-dependent fashion by decades of age. End-stage renal disease was defined as dialysis attributed to diabetic nephropathy or death from diabetic nephropathy. MAIN OUTCOME MEASURES: Incidence rate of diabetic ESRD and mortality between 25 and 55 years of age, according to age at onset of type 2 diabetes mellitus. RESULTS: Among the 1856 diabetic participants, 96 had youth-onset type 2 diabetes mellitus. The age-sex-adjusted incidence of diabetic ESRD was 25.0 cases per 1000 person-years (95% confidence interval [CI], 6.7-43.1) in youth-onset diabetes mellitus and 5.4 cases per 1000 person-years (95% CI, 4.4-6.4) in older-onset diabetes mellitus (incidence rate ratio, 4.6; 95% CI, 2.2-9.8). Age-specific incidence rates were higher in participants with youth-onset diabetes mellitus at all ages. Between 25 and 55 years of age, the age-sex-adjusted death rate from natural causes was 15.4 deaths per 1000 person-years (95% CI, 0.2-30.5) in participants with youth-onset diabetes mellitus and 7.3 deaths per 1000 person-years (95% CI, 5.9-8.7) in individuals with older-onset diabetes mellitus (death rate ratio, 2.1; 95% CI, 0.8-5.7). Compared with nondiabetic participants, the death rate was 3.0 times as high in individuals with youth-onset diabetes mellitus (95% CI, 1.1-8.0) and 1.4 times as high in individuals with older-onset diabetes mellitus (95% CI, 1.1-1.8). In a subset of 1386 participants with complete data for all covariates who were observed from the onset of diabetes mellitus, the age at onset of diabetes mellitus was not associated with the incidence of ESRD (hazard ratio, 1.0; 95% CI, 0.9-1.2) after adjusting for sex, mean arterial pressure, body mass index (calculated as weight in kilograms divided by height in meters squared), plasma glucose concentration, smoking, hypoglycemic medicines, and blood pressure medicines in a Cox proportional-hazards model. CONCLUSIONS: Early-onset type 2 diabetes mellitus is associated with substantially increased incidence of ESRD and mortality in middle age. The longer duration of diabetes mellitus by middle age in individuals diagnosed younger than age 20 years largely accounts for these outcomes.

Adolescent↗
PubMed2005

Screening for new MTHFR polymorphisms and NTD risk.

The enzyme, 5,10-methylenetetrahydrofolate reductase (MTHFR) plays a key role in cellular folate metabolism. The A222V (677C->T) polymorphism is a confirmed neural tube defect (NTD) risk factor within Irish and other populations. To search for other unknown single nucleotide polymorphisms (SNPs) that might play a role in the etiology of NTDs, we examined the entire MTHFR coding region in healthy individuals (n = 100). SNPs were identified using sequencing and database analysis and allele frequencies were determined in our Irish population. We identified P39P (116C->T; T allele frequency 0.13) and previously reported R594Q (1793G->A; Q allele frequency 0.07). We screened a large ethnically homogeneous Irish NTD cohort (n>1,300) for P39P and R594Q. A possible association between NTD cases and P39P (P = 0.034) was found but this was not confirmed by transmission disequilibrium testing. R594Q also showed some evidence of a NTD case association (P = 0.07). Further analysis indicated these observations are due to linkage disequilibrium with A222V (677C->T), and therefore these new SNPs are unlikely to be independent risk factors for NTDs. As rates of NTDs differ between ethnic groups, we examined allele and genotype frequencies of P39P and R594Q within African-American and American-Caucasian populations. This is the first NTD association study of both R594Q and the novel P39P. The association with NTD risk reported for these SNPs is driven by the linkage disequilibrium with the A222V (677C->T) NTD risk factor.

Base Sequence↗
PubMed2005

Turner syndrome: four challenges across the lifespan.

Turner syndrome (TS) is a sex chromosome condition that occurs in approximately 1/2,500 live female births. Despite the prevalence of this chromosomal condition, the challenges these women face throughout their lives are not fully understood. This qualitative research study aimed to characterize the subjective experiences of individuals with TS throughout their lifespan, to investigate their concerns and obstacles, and to offer insight into the strengths and weaknesses of health care delivery, as they perceived them. Ninety-seven girls and women with TS and 21 parents consented to participate in this interview study. Interviews were semi-structured and open-ended in design. Questions sought to elicit responses relating to existing concerns associated with their condition and positive and negative health care experiences. Participants were divided into four age categories (childhood, adolescence, adulthood, and mature adulthood) to facilitate a comparative analysis across the age spectrum. Regardless of age, infertility was the most frequently cited concern followed closely by short stature. Sexual development and function and general health were also viewed as challenges by a number of participants in each age group. Although the relative weight of these four concerns tended to shift based upon the individual's age and life experiences, all four issues remained significant throughout the lifespan. Enhanced awareness of the evolving physical and psychological challenges faced by girls and women with TS may help health care providers (HCPs) improve the quality of life for these individuals.

Adolescent↗