NCAD v1.0: a database for non-coding variant annotation and interpretation.

The application of whole genome sequencing is expanding in clinical diagnostics across various genetic disorders, and the significance of non-coding variants in penetrant diseases is increasingly being demonstrated. Therefore, it is urgent to improve the diagnostic yield by exploring the pathogenic mechanisms of variants in non-coding regions. However, the interpretation of non-coding variants remains a significant challenge, due to the complex functional regulatory mechanisms of non-coding regions and the current limitations of available databases and tools. Hence, we develop the non-coding variant annotation database (NCAD, http://www.ncawdb.net/), encompassing comprehensive insights into 665,679,194 variants, regulatory elements, and element interaction details. Integrating data from 96 sources, spanning both GRCh37 and GRCh38 versions, NCAD v1.0 provides vital information to support the genetic diagnosis of non-coding variants, including allele frequencies of 12 diverse populations, with a particular focus on the population frequency information for 230,235,698 variants in 20,964 Chinese individuals. Moreover, it offers prediction scores for variant functionality, five categories of regulatory elements, and four types of non-coding RNAs. With its rich data and comprehensive coverage, NCAD serves as a valuable platform, empowering researchers and clinicians with profound insights into non-coding regulatory mechanisms while facilitating the interpretation of non-coding variants.

Quantitative thresholds for variant enrichment in 13,845 cases: improving pathogenicity classification in genetic hearing loss.

BACKGROUND: The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines recommend using variant enrichment among cases as "strong" evidence for pathogenicity per the PS4 criterion. However, quantitative support for PS4 thresholds from real-world Mendelian case-control cohorts is lacking. METHODS: To address this gap, we evaluated and established PS4 thresholds using data from the Chinese Deafness Genetics Consortium. A total of 9,050 variants from 13,845 patients with hearing loss (HL) and 6,570 ancestry-matched controls were analyzed. Positive likelihood ratio and local positive likelihood ratio values were calculated to determine the thresholds corresponding to each strength of evidence across three variant subsets. RESULTS: In subset 1, consisting of variants present in both cases and controls with an allele frequency (AF) in cases ≥ 0.0005, an odds ratio (OR) ≥ 6 achieved strong evidence, while OR ≥ 3 represented moderate evidence. For subset 2, which encompassed variants present in both cases and controls with a case AF < 0.0005, and subset 3, comprising variants found only in cases and absent from controls, we defined the PS4_Supporting threshold (OR > 2.27 or allele count ≥ 3) and the PS4_Moderate threshold (allele count ≥ 6), respectively. Reanalysis applying the adjusted PS4 criteria changed the classification of 15 variants and enabled diagnosis of an additional four patients. CONCLUSIONS: Our study quantified evidence strength thresholds for variant enrichment in genetic HL cases, highlighting the importance of defining disease/gene-specific thresholds to improve the precision and accuracy of clinical genetic testing.

Expanding the mutational and clinical spectrum of Chinese intellectual disability patients with two novel CTCF variants.

CCCTC-Binding Factor (CTCF) is a protein-coding gene involved in transcriptional regulation, insulator activity, and regulation of chromatin structure, and is closely associated with intellectual developmental disorders. In this study, we report two unrelated Chinese patients with intellectual disability (ID). According to variant interpretation results from exome sequencing data and RNA-seq data, we present two novel heterozygous CTCF variants, NM_006565.3:c.1519_2184del (p. Glu507_Arg727delins47) and NM_006565.3:c.1838_1852del (p.Glu613_Pro617del), found in two distinct unrelated patients, respectively. Moreover, RNA-seq data of patient 1 indicated the absence of the mutant transcript, while in patient 2, the RNA-seq data revealed a CTCF mRNA transcript with a deletion of 15 nucleotides. Notably, the RNA sequencing data revealed 507 differentially expressed genes shared between these two patients. Specifically, among them, 194 were down-regulated, and 313 were up-regulated, primarily involved in gene regulation and cellular response. Our study expands the genetic and clinical spectrum of CTCF and advances our understanding of the pathogenesis of CTCF in vivo.

Whole exome sequencing and transcriptome analysis in two unrelated patients with novel SET mutations.

The human SET nuclear proto-oncogene (SET) gene is a protein-coding gene that encodes proteins that affects chromatin remodeling and gene transcription. Mutations in the SET gene have been reported to cause intellectual disability (ID) and epilepsy. In this study, we collected and analyzed clinical, genetic, and transcript features of two unrelated Chinese patients with ID. Both patients were characterized by moderate intellectual disability. Whole-exome sequencing identified two novel heterozygous mutations in the SET gene: NM_001122821.1:c.532-3 T > A and NM_001122821.1:c.3 G > C (p.0?). Additionally, RNA sequencing revealed widespread dysregulation of genes involved in NF-kB signaling and neuronal system in these two patients. To our knowledge, this is the first report of SET mutations causing ID in the Chinese population, broadening the genetic and ethnic spectrum of SET-related disorders and highlighting the importance of screening for SET gene variants.

Whole-genome sequencing combined RNA-sequencing analysis of patients with mutations in SET binding protein 1.

SET binding protein 1 (SETBP1) is essential for human development, and pathogenic germline variants in SETBP1 lead to a recognizable developmental syndrome and variable clinical features. In this study, we assessed a patient with facial dysmorphism, intellectual disability and delayed motor development. Whole genome sequencing identified a novel de novo variation of the SETBP1 (c.2631C > A; p. S877R) gene, which is located in the SKI domain, as a likely pathogenic variant for the proband's phenotype. RNA sequencing was performed to investigate the potential molecular mechanism of the novel variation in SETBP1. In total, 77 and 38 genes were identified with aberrant expression and splicing, respectively. Moreover, the biological functions of these genes were involved in DNA/protein binding, expression regulation, and the cell cycle, which may advance our understanding of the pathogenesis of SETBP1 in vivo.

Efficacy and safety of ofatumumab and bendamustine followed by ofatumumab maintenance in patients with relapsed indolent non-Hodgkin lymphoma after prior rituximab.

In indolent non-Hodgkin's lymphoma (iNHL), patients treated with rituximab, alone or in combination with various chemotherapeutic agents eventually relapse. This study evaluated the combination of ofatumumab and bendamustine, followed by maintenance ofatumumab in patients with relapsed iNHL with prior sensitivity to rituximab. Among the 49 patients enrolled, 24.5% achieved a complete response (CR) and 42.9% achieved a partial response (PR), with an overall response rate of 67.3% at the end of the induction therapy. Additionally, six patients with PR during induction phase achieved CR during the maintenance phase. Treatment-related adverse event was observed in 95.9% patients. The most common hematologic and biochemical abnormalities were decrease in lymphocytes (85.7%) and increase in glucose (91.8%), respectively. Overall, 42.9% progressed and 14.3% died during the study. Thus, ofatumumab in combination with bendamustine, followed by ofatumumab maintenance, was effective in the treatment of patients with iNHL with a manageable safety profile (NCT01294579).

Meta-analysis of Cigarette Smoking and Musculoskeletal Injuries in Military Training.

PURPOSE: Tobacco use is common among military personnel, as is musculoskeletal injury during training. In a review of the literature on musculoskeletal injuries, there was mixed evidence on the role of smoking as a risk factor. The purpose of this study is to review and analyze the literature on the impact of cigarette smoking on lower-extremity overuse injuries in military training. METHODS: We performed a literature search on articles published through October 2016. Search terms focused on lower-extremity overuse musculoskeletal injuries and cigarette smoking in military populations. We conducted a meta-analysis overall and by sex, including smoking intensity. RESULTS: We identified 129 potential studies and selected 18 based on quality. The overall rate ratio for smoking was 1.31, 1.31 for men, and 1.23 for women. Overall and for each sex, rate ratios were significantly greater than 1.0 for each intensity level of smoking. CONCLUSIONS: Smoking is a moderate risk factor for musculoskeletal injury and may account for a meaningful proportion of injuries among men and women due to the high prevalence of smoking and injury in this population. Although enlistees are not allowed to smoke during basic training, their risk of injury remains high, indicating that smokers may remain at increased risk for medium- to long-term duration.

Preenlistment and Early Service Risk Factors for Traumatic Brain Injury in the Army and Marine Corps: FY 2002-2010.

OBJECTIVE: To determine the preenlistment and early service risk factors for traumatic brain injury (TBI)-related disability in Army and Marine Corps service members. DESIGN: Matched case-control design. MAIN OUTCOME: TBI disability discharges. SUBJECTS: Army and Marine Corps service members with an enlistment record and disability discharge for TBI were included as cases. Controls were selected from the enlisted population with no disability evaluation record and were matched on fiscal year of enlistment, sex, and service at a ratio of 5:1. RESULTS: Older age at enlistment resulted in a significantly increased risk for TBI disability in the crude and adjusted models (adjusted odds ratio [aOR] = 1.49; 95% confidence interval [CI], 1.16-1.91). An enlistment military occupational specialty (MOS) with a combat arms designation resulted in an almost 3-fold increased odds of TBI disability compared with other MOS categories (aOR = 2.75; 95% CI, 2.46-3.09). This remained a significant risk factor for TBI disability in the multivariate model (aOR = 2.74; 95% CI, 2.45-3.08). CONCLUSION: Results from this study help inform the existing body of military TBI research by highlighting the preenlistment demographic and early service risk factors for TBI disability. Further research into the role of age on TBI disability in the military is merited.

Pre-enlistment hearing loss and hearing loss disability among US soldiers and marines.

Hearing loss is a common condition among US adults, with some evidence of increasing prevalence in young adults. Noise-induced hearing loss attributable to employment is a significant source of preventable morbidity world-wide. The US military population is largely comprised of young adult males serving in a wide variety of occupations, many in high noise-level conditions, at least episodically. To identify accession and service-related risk factors for hearing-related disability, matched case-control study of US military personnel was conducted. Individuals evaluated for hearing loss disability in the US Army and Marine Corps were frequency matched to controls without history of disability evaluation on service and enlistment year. Conditional logistic regression was used to examine the association between accession and service-related factors and hearing-related disability evaluations between October 2002 and September 2010. Individuals with medically disqualifying audiograms or hearing loss diagnoses at application for military service were 8 and 4 times more likely, respectively, to have a disability evaluation related to hearing loss, after controlling for relevant accession, demographic, and service-related factors. Conservative hearing loss thresholds on pre-enlistment audiograms, stricter hearing loss medical waiver policies or qualified baseline audiograms pre-enlistment are needed in the U.S military. Industrial corporations or labor unions may also benefit from identifying individuals with moderate hearing loss at the time of employment to ensure use of personal protective equipment and engineer controls of noise.

Personality Assessment Questionnaire as a pre-accession screen for risk of mental disorders and early attrition in U. S. Army recruits.

Personality assessment tools have been studied as predictors of performance in civilian and military work settings. The Tailored Adaptive Personality Assessment System (TAPAS) was developed to improve selection of new military recruits by predicting motivational outcomes such as job effort, physical fitness, and drive to perform at high standards. The purpose of this study is to examine the utility of TAPAS as a predictor of psychiatric morbidity and early discharge in a sample of 15,082 Army, active duty, enlisted, nonprior service recruits. Associations between TAPAS personality dimension score quintiles and mental disorder diagnoses, attrition, and health care utilization in United States Army recruits who took TAPAS in the fiscal year 2010 were analyzed using multivariate logistic regression and log-linear modeling. TAPAS physical conditioning dimension scores were predictive of mental disorder diagnosis and attrition, with TAPAS scorers in the lowest quintile at increased odds of early discharge (odds ratio [OR]: 2.08, 95% CI 1.73, 2.51), mental disorder diagnosis (OR: 1.41, 95% CI 1.20, 1.66) and greater mental health care utilization (1.61, 95% CI 1.46, 1.78) compared with TAPAS scorers in the highest quintile. Results indicated that TAPAS may have an important use as a mental health fitness screening tool for those who wish to serve in the military by identifying a limited high risk group of applicants for mental health diagnostic evaluation. TAPAS may augment current cognitive and educational screens and potentially reduce the burden of mental disorders and premature attrition.

A noncognitive temperament test to predict risk of mental disorders and attrition in U.S. Army recruits.

UNLABELLED: U.S. military accession mental health screening includes cognitive testing and questions regarding the applicants' past mental health history. This process relies on applicants' knowledge of and willingness to disclose symptoms and conditions. Applicants have a strong incentive to appear qualified, which has resulted in a long history of frequent mental health conditions presenting during recruit training. OBJECTIVE: To assess the predictive value of a pre-enlistment noncognitive temperament test score for risk of mental disorders and attrition in the first year of service. METHODS: A retrospective cohort study was conducted on non-high school diploma U.S. Army active duty recruits who took the Assessment of Individual Motivation (AIM). Multivariate logistic regression models were used to determine associations between AIM score quintiles, mental disorders, and attrition. RESULTS: AIM scorers in the lowest quintile were at increased risk for a mental disorder (OR, 1.44; 95% CI, 1.35-1.53) and of discharge (OR, 1.65; 95% CI, 1.44-1.68) compared to AIM scorers in the highest quintile, with significant linear trends for decreased risk with increasing AIM score. CONCLUSIONS: AIM offers the potential to improve screening of military applicants and reduce mental disorders and attrition in new recruits beyond the current process.

National estimates of seroincidence and seroprevalence for herpes simplex virus type 1 and type 2 among US military adults aged 18 to 29 years.

BACKGROUND: While population-based seroprevalence studies of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are widespread, seroincidence studies are largely limited to select or high-risk populations. The US military offers a potential population to derive national seroincidence rate estimates for young adults (ages 18-29). METHODS: We used banked, longitudinal serum specimens collected in a cohort of 1094 military personnel aged 18 to 30 years who served between 1989 and 2005 to estimate national HSV-1 and HSV-2 seroincidence and seroprevalence for the young, adult military population, weighted according to the US Census. Serum was tested with indirect ELISA (enzyme-linked immunosorbent assay). RESULTS: Estimated national seroincidence rates for the US young, adult military population were 9.1 per 100 person-years (95% confidence interval: 4.6-13.5) for HSV-1 and 6.2 (95% confidence interval: 3.1-9.3) for HSV-2. Female sex and black race were associated with significantly higher HSV-2 seroconversion rates. Our estimated HSV1/2 seroprevalences were comparable to US national data provided by National Health and Nutrition Examination Surveys' serosurveys except for non-Hispanic blacks and Hispanics. CONCLUSION: Although these US 2000 Census-weighted estimates of HSV-1 and HSV-2 seroincidence apply only to young, military adults, they nonetheless supply, to our knowledge, the only national figures that might be used to predict US national HSV1/2 seroincidence in young adults. Thus, we believe that our findings in this military population can be used to inform the planning of HSV-1 and 2 prevention measures in the general, young-adult US population.