Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. CONCLUSIONS: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders.

While genes with an excess of de novo mutations (DNMs) have been identified in children with neurodevelopmental disorders (NDDs), few studies focus on DNM patterns where the sex of affected children is examined separately. We considered ∼8,825 sequenced parent-child trios (n ∼26,475 individuals) and identify 54 genes with a DNM enrichment in males (n = 18), females (n = 17), or overlapping in both the male and female subsets (n = 19). A replication cohort of 18,778 sequenced parent-child trios (n = 56,334 individuals) confirms 25 genes (n = 3 in males, n = 7 in females, n = 15 in both male and female subsets). As expected, we observe significant enrichment on the X chromosome for females but also find autosomal genes with potential sex bias (females, CDK13, ITPR1; males, CHD8, MBD5, SYNGAP1); 6.5% of females harbor a DNM in a female-enriched gene, whereas 2.7% of males have a DNM in a male-enriched gene. Sex-biased genes are enriched in transcriptional processes and chromatin binding, primarily reside in the nucleus of cells, and have brain expression. By downsampling, we find that DNM gene discovery is greatest when studying affected females. Finally, directly comparing de novo allele counts in NDD-affected males and females identifies one replicated genome-wide significant gene (DDX3X) with locus-specific enrichment in females. Our sex-based DNM enrichment analysis identifies candidate NDD genes differentially affecting males and females and indicates that the study of females with NDDs leads to greater gene discovery consistent with the female-protective effect.

Trauma and Autism Spectrum Disorder: Review, Proposed Treatment Adaptations and Future Directions.

Empirical investigations of trauma and post-traumatic stress disorder (PTSD) in individuals with autism spectrum disorder (ASD) are lacking despite indications of increased risk for exposure to potentially traumatic events in this population. Research on the treatment of traumatic stress psychopathology in ASD is even more limited and suggests a critical need for guidance in the area of ASD-specific treatment adaptations. The current paper provides preliminary recommendations for adapting current evidenced-based, trauma-specific interventions, specifically trauma-focused cognitive behavioral therapy (TF-CBT), for individuals with ASD based on well-established and evidence-based practices for working with this population. These adaptations highlight the need to incorporate treatment goals related to ASD core symptoms and associated characteristics during treatment targeting traumatic stress symptoms. Future directions are discussed, including the development of instruments measuring trauma reactions in ASD, empirical investigations of modified trauma interventions for children with ASD to evaluate effectiveness, and collaboration between professionals specializing in ASD and trauma/PTSD to advance research and facilitate effective care for this community.

Epidermal Growth Factor Receptor Inhibitor Skin Rash Prophylaxis in a Community Oncology Setting.

Epidermal growth factor receptor inhibitors (EGFRIs) can potentially cause a debilitating rash despite use of reactive-based treatment. Prophylactic rash management is a controversial rash-mitigating approach. The impact of a prophylactic rash treatment protocol for EGFRIs at a community hospital was evaluated. This was a retrospective, institutional review board-approved examination of patient data for those patients who received EGFRIs from August 1, 2012, through May 31, 2015. Patients were grouped according to treatment with EGFRIs prior to standardized prophylactic rash management protocol (August 1, 2012, through July 31, 2014) and treatment after protocol implementation (September 1, 2014, through May 31, 2015). The outcomes measured included incidence of rash within the 6-week treatment period and occurrence of EGFRI dose reductions and/or delays. Of the 44 patients eligible for the analysis, 29 were evaluated in the reactive treatment group and 15 in the rash prophylaxis group. The incidence of rash over the 6-week EGFRI treatment period was 76% and 47% for the reactive treatment and rash prophylaxis groups, respectively (p = .09). There was a lower incidence of EGFRI dose delays and modifications in the rash prophylaxis group compared to the reactive treatment group: 26.7% and 6.7% compared to 41.4% and 20.7%, respectively. There was an overall decrease in rash incidence seen in patients who received prophylactic intervention; however, due to the failure to meet statistical significance and power, it is not possible to determine if rash prophylaxis decreases EGFRI rash incidence.

Evaluation of actigraphy-measured sleep patterns among children with disabilities and associations with caregivers' educational attainment: results from a cross-sectional study.

OBJECTIVES: To use wrist-actrigrphy to collect objective measures of sleep and to characterise actigraphy-measured sleep patterns among children with disabilities. We also assessed the extent to which, if at all, caregivers' education is associated with children's sleep disturbances. DESIGN: Cross-sectional study. SETTING: A rehabilitation centre in the Patagonia region, Chile. METHODS: This study was conducted among 125 children aged 6-12 years with disabilities (boys: 55.2%) and their primary caregivers in Chile. Children wore ActiSleep monitors for 7 days. A general linear model was fitted to generate least-square means and SEs of sleep efficiency (proportion of the sleep period spent asleep) across caregivers' education levels adjusting for children's age, sex, disability type, caregiver-child relationship and caregivers' age. Multivariable logistic regression analyses were conducted to estimate ORs and 95% CIs of longer sleep latency (≥ 30 min) and longer wake after sleep onset (WASO) (≥ 90 min) (a measure of sleep fragmentation) in relation to caregivers' educational attainment. RESULTS: Median sleep latency was 27.3 min, WASO 88.1 min and sleep duration 8.0 h. Mean sleep efficiency was 80.0%. Caregivers' education was positively and significantly associated with children's sleep efficiency (p trend<0.001). Adjusted mean sleep efficiency was 75.7% (SE=1.4) among children of caregivers high school education. Compared to children whose caregivers had >high school, children of caregivers with

Caregivers' hair cortisol: a possible biomarker of chronic stress is associated with obesity measures among children with disabilities.

BACKGROUND: The stress of caring for a loved one with chronic illness has been associated with childhood obesity. Hair cortisol has been proposed as a novel biomarker of chronic psychological stress. This study aimed to evaluate the associations between caregivers' chronic stress evaluated by hair cortisol concentrations (HCC) and obesity measures among children with disabilities such as autism. METHODS: Eighty-five dyads of children with disabilities and their primary caregivers participated in the study between April and July 2013 in the Patagonia Region, Chile. Trained research staff conducted anthropometric measurements of children and caregivers. Cortisol concentrations, extracted from hair samples with methanol, were quantified using liquid chromatography tandem mass spectrometry. Pearson's correlation coefficients and linear regression models were used to examine the associations between caregiver HCC (log-transformed) and child obesity measures with adjustment for covariates. RESULTS: Caregiver HCC were positively and significantly correlated with child weight (child age- and sex-adjusted r =0.23, P = 0.036), body mass index (BMI) (r = 0.23, P = 0.035), circumferences of neck (r = 0.30, P = 0.006), waist (r = 0.27, P = 0.014), and hip (r = 0.22, P = 0.044). After adjustment for children's age and sex, caregiver HCC were significantly related to child weight (kg) (beta = 4.47, standard error (SE) = 2.09), BMI (kg/m(2)) (beta = 1.52, SE = 0.71), neck circumference (cm) (beta = 1.20, SE = 0.43), waist circumference (cm) (beta = 3.75, SE = 1.50), and hip circumference (cm) (beta = 3.02, SE = 1.48). Caregiver HCC were also positively but not statistically significantly associated with child waist-to-hip ratio (beta = 0.01, SE = 0.01; P = 0.191) or body fat percentage (%) (beta = 2.11, SE = 1.28; P = 0.104). Further adjustment for other covariates including child disability diagnosis and caregiver age, sex, education, current smoking, perceived stress, and caregiver BMI did not change the results substantially. CONCLUSIONS: Chronic stress of caregivers, evaluated by increased cortisol concentrations in hair, was positively associated with obesity measures among children with disabilities.

Smoking and perceived stress in relation to short salivary telomere length among caregivers of children with disabilities.

Telomere length (TL), the length of repeated DNA sequence that forms protective caps at the end of chromosomes, has emerged as a novel biomarker of cell aging and oxidative stress. There is increasing research exploring the associations of smoking and perceived stress with TL, and the results are inconsistent. This study aimed to examine whether smoking and perceived stress were associated with shortened salivary TL among primary caregivers of children with disabilities. Using a quantitative polymerase chain reaction method, salivary TL was assessed among 89 caregivers aged 19-69 years (87% were women) who took care of disabled children in the Patagonia Region, Chile. Interviewer-administered questionnaires were used to collect information on sociodemographic and lifestyle factors. The 14-item Perceived Stress Scale was used to assess perceived stress. Mean relative TL was 0.92 (standard error = 0.03). Smokers had age-adjusted mean TL that was 0.07 units lower (ß = -0.07, standard error = 0.03; p = 0.012) than non-smokers. Smokers were 2.17 times more likely to have shorter TL ( < 0.73, the lowest quartile of TL) than non-smokers (odds ratio = 3.17; 95% confidence interval = 1.05-9.52) with adjustment for age and perceived stress. Caregivers with higher perceived stress were 2.13 times more likely to have shorter TL (odds ratio = 3.13; 95% confidence interval = 1.03-9.55) than caregivers with lower perceived stress after adjustment for age and smoking. This study provides the first evidence of strong associations between smoking and perceived stress and shortened salivary TL among caregivers of children with disabilities. Larger studies with detailed information on smoking status are warranted to confirm our findings.

Attitudes, beliefs, and perceptions of caregivers and rehabilitation providers about disabled children's sleep health: a qualitative study.

BACKGROUND: Children with disabilities are more likely to have sleep disturbances than children without disabilities. Identifying attitudes, beliefs, knowledge, and perceptions of caregivers and health professionals is essential in developing effective intervention programs to improve disabled children's sleep health. However, no such qualitative data about adults who have key roles in the life and daytime activities of children with disabilities are available. This qualitative study aimed to understand attitudes, beliefs, knowledge, and perceptions about disabled children's sleep hygiene among caregivers and rehabilitation providers of children with disabilities. METHODS: Twenty seven adults, including nine primary caregivers and eighteen rehabilitation providers, participated in five focus group discussions between September and December 2012 at the Rehabilitation Center in Punta Arenas, Chile. A trained facilitator guided focus group discussions using a semi-structured script. Audiotapes and transcripts of focus group discussions were reviewed and analyzed for recurrent themes. RESULTS: Participants identified seven themes related to children's sleep hygiene: lifestyle behaviors, family factors, children's disabilities and/or comorbidities, environmental factors, adults' responsibilities for children's sleep, perception of good sleep, and parental distress about children's sleep problems. While both caregivers and rehabilitation providers recognized the importance of sleep for children's health and functioning, they differed in their understanding of how sleep hygiene practices influence sleep. Rehabilitation providers recognized the negative influence of electronics on sleep and the positive influence of sleep routines. In contrast, caregivers reported use of television/movie watching and stimulants as coping strategies for managing children's sleep problems. CONCLUSIONS: Caregivers may benefit from better understanding the influence of electronics and stimulant use on child sleep health. Rehabilitation providers are well positioned to provide educational messages to both children and caregivers in order to change their attitudes, perceptions, and practices surrounding sleep. These qualitative data are valuable in developing intervention programs aimed at improving sleep health among children with disabilities.

Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection.

BACKGROUND: Prevention of chronic chagasic cardiomyopathy (CCC) by treating infected populations with trypanocidal therapy (TT) remains a challenge. Despite a renewed enthusiasm for TT, uncertainty regarding its efficacy, concerns about its safety and limited availability remain barriers for a wider use of conventional drugs. We have updated a previous version of this review. OBJECTIVES: To systematically search, appraise, identify and extract data from eligible studies comparing the outcome of cohorts of seropositive individuals to Trypanosoma cruzi exposed to TT versus placebo or no treatment. SEARCH METHODS: We sought eligible studies in electronic databases (Cochrane Central Register of Controlled Trials (CENTRAL), Issue 1, 2014); MEDLINE (Ovid, 1946 to January week 5 2014); EMBASE (Ovid, 1980 to 2014 week 6) and LILACS (up to 6 May 2010)) by combining terms related with the disease and the treatment. The search also included a Google search, handsearch for references in review or selected articles, and search of expert files. We applied no language restrictions. SELECTION CRITERIA: Review authors screened the retrieved references for eligibility (those dealing with human participants treated with TT) and then assessed the pre-selected studies in full for inclusion. We included randomised controlled trials (RCTs) and observational studies that provided data on either mortality or clinical progression of CCC after at least four years of follow-up. DATA COLLECTION AND ANALYSIS: Teams of two review authors independently carried out the study selection, data extraction and risk of bias assessment, with a referee resolving disagreement within the pairs. Data collection included study design, characteristics of the population and interventions or exposures and outcome measures. We defined categories of outcome data as parasite-related (positive serology, xenodiagnosis or polymerase chain reaction (PCR) after TT) and participant-related (including efficacy outcomes such as progression towards CCC, all-cause mortality and side effects of TT). We reported pooled outcome data as Mantel-Haenszel odds ratios (OR) or standardised mean differences (SMD) along with 95% confidence intervals (CI), using a random-effects model. I(2) statistics provided an estimate of heterogeneity across studies. We conducted an exploratory meta-regression analysis of the relationship between positive-serology and progression of CCC or mortality. MAIN RESULTS: We included 13 studies involving 4229 participants (six RCTs, n = 1096, five RCTs of intermediate risk of bias, one RCT of high risk of bias; four non-randomised experiments, n = 1639 and three observational studies, n = 1494). Ten studies tested nitroderivative drugs nifurtimox or benznidazole (three exposed participants to allopurinol, one to itraconazole). Five studies were conducted in Brazil, five in Argentina, one in Bolivia, one in Chile and one in Venezuela.TT was associated with substantial, but heterogeneous reductions on parasite-related outcomes such as positive serology (9 studies, OR 0.21, 95% CI 0.10 to 0.44, I(2) = 76%), positive PCR (2 studies, OR 0.50, 95% CI 0.27 to 0.92, I(2) = 0%), positive xenodiagnosis after treatment (6 studies, OR 0.35, 95% CI 0.14 to 0.86, I(2) = 79%), or reduction on antibody titres (3 studies, SMD -0.56, 95% CI -0.89 to -0.23, I(2) = 28%). Efficacy data on patient-related outcomes was largely from non-RCTs. TT with nitroderivatives was associated with potentially important, but imprecise and inconsistent reductions in progression of CCC (4 studies, 106 events, OR 0.74, 95% CI 0.32 to 1.73, I(2) = 66%) and mortality after TT (6 studies, 99 events, OR 0.55, 95% CI 0.26 to 1.14, I(2) = 48%). The overall median incidence of any severe side effects among 1475 individuals from five studies exposed to TT was 2.7%, and the overall discontinuation of this two-month therapy in RCTs (5 studies, 134 events) was 20.5% (versus 4.3% among controls) and 10.4% in other five studies (125 events). AUTHORS' CONCLUSIONS: Despite the evidence that TT reduced parasite-related outcomes, the low quality and inconsistency of the data for patient-important outcomes must be treated with caution. More geographically diverse RCTs testing newer forms of TT are warranted in order to 1. estimate efficacy more precisely, 2. explore factors potentially responsible for the heterogeneity of results and 3. increase knowledge on the efficacy/tolerance balance of conventional TT.

Daytime sleepiness, poor sleep quality, eveningness chronotype, and common mental disorders among Chilean college students.

OBJECTIVES: To evaluate whether daytime sleepiness, poor sleep quality, and morningness and eveningness preferences are associated with common mental disorders (CMDs) among college students. METHODS: A total of 963 college students completed self-administered questionnaires that collected information about sociodemographic characteristics, sleep quality characteristics, CMDs, and other lifestyle behaviors. RESULTS: The prevalence of CMDs was 24.3% (95% confidence interval [CI] [21.5%, 27.1%]) among all students. Prevalence estimates of both excessive daytime sleepiness and poor sleep quality were higher among females (35.4% and 54.4%) than males (22.0% and 45.8%). Cigarette smoking was statistically significantly and positively associated with having CMDs (p = .034). Excessive daytime sleepiness (odds ratio [OR] = 3.65; 95% CI [2.56, 4.91]) and poor sleep quality (OR = 4.76; 95% CI [3.11, 7.29]) were associated with increased odds of CMDs. CONCLUSION: Given the adverse health consequences associated with both sleep disorders and CMDs, improving sleep hygiene among college students is imperative to public health.