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Background: Genetic variants that severely alter protein products (e.g. nonsense, frameshift) are often associated with disease. For some genes, these predicted loss-of-function variants (pLoFs) are observed throughout the gene, whilst in others, they occur only at specific locations. We hypothesised that, for genes linked with monogenic diseases that display incomplete penetrance, pLoF variants present in apparently unaffected individuals may be limited to regions where pLoFs are tolerated. To test this, we investigated whether pLoF location could explain instances of incomplete penetrance of variants expected to be pathogenic for Mendelian conditions. Methods: We used exome sequence data in 454,773 individuals in the UK Biobank (UKB) to investigate the locations of pLoFs in a population cohort. We counted numbers of unique pLoF, missense, and synonymous variants in UKB in each quintile of the coding sequence (CDS) of all protein-coding genes and clustered the variants using Gaussian mixture models. We limited the analyses to genes with ≥ 5 variants of each type (16,473 genes). We compared the locations of pLoFs in UKB with all theoretically possible pLoFs in a transcript, and pathogenic pLoFs from ClinVar, and performed simulations to estimate the false-positive rate of non-uniformly distributed variants. Results: For most genes, all variant classes fell into clusters representing broadly uniform variant distributions, but genes in which haploinsufficiency causes developmental disorders were less likely to have uniform pLoF distribution than other genes (P < 2.2 × 10−6). We identified a number of genes, including ARID1B and GATA6, where pLoF variants in the first quarter of the CDS were rescued by the presence of an alternative translation start site and should not be reported as pathogenic. For other genes, such as ODC1, pLoFs were located approximately uniformly across the gene, but pathogenic pLoFs were clustered only at the end, consistent with a gain-of-function disease mechanism. Conclusions: Our results suggest the potential benefits of localised constraint metrics and that the location of pLoF variants should be considered when interpreting variants. [ABSTRACT FROM AUTHOR]

Background: Some modifiable risk factors for cancer originate during adolescence. While there is evidence indicating relationships between adverse childhood experiences and health risk behaviours generally, little is known about how childhood adversity influences the engagement of adolescents in cancer risk behaviours. This study aimed to determine the relationship between adverse childhood experiences and adolescent cancer risk behaviours. Methods: Data were collected prospectively from birth to age 18 years on children born to mothers enrolled into the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort study. Multivariable linear regression models assessed relationships of a composite exposure measure comprised of adverse childhood experiences (total number of childhood adversities experienced from early infancy until age 9 years) with multiple cancer risk behaviours. The latter was expressed as a single continuous score for tobacco smoking, alcohol consumption, obesity, unsafe sex, and physical inactivity, at ages 11, 14, 16 and 18 years. Analysis was carried out on the complete case and imputation samples of 1,368 and 7,358 participants respectively. Results: All adolescent cancer risk behaviours increased in prevalence as the adolescents grew older, except for obesity. Each additional adverse childhood experience was associated with a 0.25 unit increase in adolescent cancer risk behaviour (95% CI 0.16–0.34; p < 0.001). Individually, parental substance misuse (β 0.64, 95% CI 0.25–1.03, p < 0.001) and parental separation (β 0.56, 95% CI 0.27–0.86, p < 0.001) demonstrated the strongest evidence of association with engagement in adolescent cancer risk behaviour. Conclusion: Childhood adversity was associated with a greater degree of engagement in adolescent cancer risk behaviours. This finding demonstrates the need for targeted primary and secondary prevention interventions that reduce engagement across multiple cancer risk behaviours for children and adolescents who have experienced adversity in childhood, such as parental substance misuse and separation, and reduce exposure to adversity. [ABSTRACT FROM AUTHOR]

Early years education has received considerable attention in recent years, particularly as a result of longitudinal studies that demonstrate the importance of the first few years in a child's development and educational experience. In 2004, a new approach to early years education, the Foundation Phase, was introduced in Wales. This is a major flagship policy of the recently devolved Welsh Government, and marks a radical departure from the more assessment-driven competency-based approaches to early childhood education that existed prior to the Foundation Phase. Studying approximately 2000 children in Wales who are part of the UK Millennium Cohort Study (MCS), all born in 2000-2001 we investigate the potential impact of the Foundation Phase pilot on a range of key academic and well-being outcome measures. Compared with other children, those attending a Foundation Phase pilot school tended to have lower scores in a number of academic assessments at age seven and lower subjective well-being, in terms of their attitudes to learning and well-being at school. We consider these surprising, yet concerning, results in the context of the methodological limitations to this analysis and propose how the MCS can be further used to substantiate these findings.

Background: Multiple risk behaviours (MRBs), typically beginning in adolescence, are associated with increased risk of adverse health and social outcomes. The association between autism and MRBs is little understood. Methods: Data were from the Avon Longitudinal Study of Parents and Children, an UK-based longitudinal, birth cohort study. Exposures were diagnosed autism and four autistic traits: social communication difficulties, pragmatic language, repetitive behaviours and reduced sociability. Outcomes were participation in up to 14 risk behaviours, including alcohol consumption, smoking, risky sexual behaviours and physical inactivity. Outcome data were collected at ages approximately 12, 14, 16 and 18. Results: Up to 4300 participants were included in latent basis growth curve analyses with adjustment for confounders. Social communication difficulties were associated with an above average level of MRBs engagement at ~12 years (mean difference β 0.26; 95% CI 0.13–0.40), and above average rate of engagement from ages ~12–18 (β 0.08; 95% CI 0.02–0.13). Repetitive behaviours were associated with above average levels of engagement in MRBs at ~12 years (β 0.24; 95% CI 0.09–0.38). Contrastingly, reduced sociability was associated with a reduced rate of engagement in MRBs from ages ~12–18 (β −0.06; 95% CI −0.11 to −0.02). In sex-specific analyses, persisting differences in MRB engagement patterns from ages ~12–18 were observed in males with social communication difficulties and females with reduced sociability temperament. Conclusions: Having elevated levels of some autistic traits appear to have differentiated effects on MRB engagement patterns. These findings could reflect difficulties fitting in and/or coping mechanisms relating to difficulties with fitting in. [ABSTRACT FROM AUTHOR]

BACKGROUND Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits. METHODS We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis. RESULTS A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent–offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent–offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks’ gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78). CONCLUSIONS Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.) [ABSTRACT FROM AUTHOR]

Background: The widespread clinical application of genome-wide sequencing has resulted in many new diagnoses for rare genetic conditions, but testing regularly identifies variants of uncertain significance (VUS). The remarkable rise in the amount of genomic data has been paralleled by a rise in the number of protein structures that are now publicly available, which may have clinical utility for the interpretation of missense and in-frame insertions or deletions. Methods: Within a UK National Health Service genomic medicine diagnostic laboratory, we investigated the number of VUS over a 5-year period that were evaluated using protein structural analysis and how often this analysis aided variant classification. Results: We found 99 novel missense and in-frame variants across 67 genes that were initially classified as VUS by our diagnostic laboratory using standard variant classification guidelines and for which further analysis of protein structure was requested. Evidence from protein structural analysis was used in the re-assessment of 64 variants, of which 47 were subsequently reclassified as pathogenic or likely pathogenic and 17 remained as VUS. We identified several case studies where protein structural analysis aided variant interpretation by predicting disease mechanisms that were consistent with the observed phenotypes, including loss-of-function through thermodynamic destabilisation or disruption of ligand binding, and gain-of-function through de-repression or escape from proteasomal degradation. Conclusions: We have shown that using in silico protein structural analysis can aid classification of VUS and give insights into the mechanisms of pathogenicity. Based on our experience, we propose a generic evidence-based workflow for incorporating protein structural information into diagnostic practice to facilitate variant classification. [ABSTRACT FROM AUTHOR]

Background: Adolescent multiple risk behaviour (MRB) is associated with negative outcomes such as police arrests, unemployment and premature mortality and morbidity. What is unknown is whether MRB is associated with socioeconomic status (SES) in adulthood. We test whether adolescent MRB is associated with socioeconomic status (SES) in young adulthood and whether it is moderated by early life SES variables. Methods: Prospective cohort studies; British Cohort Study 1970 (BCS70) and Avon Longitudinal Study of Parents and Children (ALSPAC), born in 1991–1992, were used and two comparable MRB variables were derived. Logistic regression was used to determine the association between MRB and young adult SES. The moderating effect of three early life SES variables was assessed using logistic regression models with and without interaction parameters. Evidence to support the presence of moderation was determined by likelihood ratio tests ≤p = 0.05. Multiple imputation was used to account for missing data. Results: Adolescents had a median of two risk behaviours in BCS70 and three in ALSPAC. Adolescent MRB was negatively associated with young adult SES (university degree attainment) in BCS70 (OR 0.81, 95% CI: 0.76, 0.86) and ALSPAC (OR 0.85, 95% CI: 0.82, 0.88). There was a dose response relationship, with each additional risk behaviour resulting in reduced odds of university degree attainment. MRB was associated occupational status at age 34 in BCS70 (OR 0.86 95% CI: 0.82, 0.90). In BCS70, there was evidence that maternal education (p = 0.03), parental occupational status (p = 0.009) and household income (p = 0.03) moderated the effect of adolescent MRB on young adult SES in that the negative effect of MRB is stronger for those with low socioeconomic backgrounds. No evidence of moderation was found in the ALSPAC cohort. Conclusions: Adolescence appears to be a critical time in the life course to address risk behaviours, due to the likelihood that behaviours established here may have effects in adulthood. Intervening on adolescent MRB could improve later SES outcomes and thus affect health outcomes later in life. Evidence for a moderation effect in the BCS70 but not ALSPAC suggests that more detailed measures should be investigated to capture the nuance of contemporary young adult SES. [ABSTRACT FROM AUTHOR]

Background: Childhood adversity strongly predicts adolescent multiple health risk behaviours (MRBs) such as alcohol/tobacco use, self‐harm and physical inactivity, and both adversities and MRBs are associated with premature mortality and several chronic health conditions that are among the leading causes of death in adults. It is therefore important to understand the relationship between adversities and MRBs and what could mediate any association. The aim of this study was to explore whether childhood psychopathology mediates associations between adversities and MRBs. Methods: Participants were young people in the Avon Longitudinal Study of Parents and Children (ALSPAC) (N = 5,799). Using structural equation modelling, we explored the associations between adversities before 9 years and MRBs at age 16 years. We also explored potential mediating pathways through dimensional psychopathology measured by the Strength and Difficulties Questionnaire subscales at age 12 years. Results: There were strong positive associations between adversities and MRBs (β.25, 95% CI 0.20, 0.31, p <.001) suggesting that each additional adversity is associated with a 0.25 increase in number of MRBs out of 13 total risk behaviours. We found robust evidence of mediating pathways from adversities through conduct problems (β.05, 95% CI 0.03, 0.06, p <.001), hyperactivity/inattention (β.02, 95% CI 0.01, 0.03, p <.001) and peer relationship problems (β −.02, 95% CI −0.03, −0.02, p <.001) to MRBs. Conclusions: Increased conduct problems and hyperactivity/inattention appear to partially explain the relationship between adversities and MRBs. Peer relationship problems also appear to reduce the association between adversities and MRBs, and further research is needed to understand how to encourage peer connectivity without increasing risk of MRBs. These results suggest that interventions aimed at reducing MRBs among those exposed to childhood adversities could focus on prevention of behavioural problems. [ABSTRACT FROM AUTHOR]

Background: An estimated 40% of cancer cases in the UK in 2015 were attributable to cancer risk behaviours. Tobacco smoking, alcohol consumption, obesity, and unprotected sexual intercourse are known causes of cancer and there is strong evidence that physical inactivity is associated with cancer. These cancer risk behaviours co-occur however little is known about how they pattern longitudinally across adolescence and early adulthood. Using data from ALSPAC, a prospective population-based UK birth cohort study, we explored patterns of adolescent cancer risk behaviours and their associations with cancer risk behaviours in early adulthood.Methods: Six thousand three hundred fifty-one people (46.0% of ALSPAC participants) provided data on all cancer risk behaviours at one time during adolescence, 1951 provided data on all cancer risk behaviours at all time points. Our exposure measure was quartiles of a continuous score summarising cumulative exposure to cancer risk behaviours and longitudinal latent classes summarising distinct categories of adolescents exhibiting similar patterns of behaviours, between age 11 and 18 years. Using both exposure measures, odds of harmful drinking (Alcohol Use Disorders Identification Test-C ≥ 8),daily tobacco smoking, nicotine dependence (Fagerström test ≥4), obesity (BMI ≥30), high waist circumference (females: ≥80 cm and males: ≥94 cm, and high waist-hip ratio (females: ≥0.85 and males: ≥1.00) at age 24 were estimated using logistic regression analysis.Results: We found distinct groups of adolescents characterised by consistently high and consistently low engagement in cancer risk behaviours. After adjustment, adolescents in the top quartile had greater odds of all outcomes in early adulthood: nicotine dependency (odds ratio, OR = 5.37, 95% confidence interval, CI = 3.64-7.93); daily smoking (OR = 5.10, 95% CI =3.19-8.17); obesity (OR = 4.84, 95% CI = 3.33-7.03); high waist circumference (OR = 2.48, 95% CI = 1.94-3.16); harmful drinking (OR = 2.04, 95% CI = 1.57-2.65); and high waist-hip ratio (OR = 1.88, 95% CI = 1.30-2.71), compared to the bottom quartile. In latent class analysis, adolescents characterised by consistently high-risk behaviours throughout adolescence were at higher risk of all cancer risk behaviours at age 24, except harmful drinking.Conclusions: Exposure to adolescent cancer risk behaviours greatly increased the odds of cancer risk behaviours in early adulthood. Interventions to reduce these behaviours should target multiple rather than single risk behaviours and should focus on adolescence. [ABSTRACT FROM AUTHOR]

Early years education has received considerable attention in recent years, particularly as a result of longitudinal studies that demonstrate the importance of the first few years in a child’s development and educational experience. In 2004, a new approach to early years education, the Foundation Phase, was introduced in Wales. This is a major flagship policy of the recently devolved Welsh Government, and marks a radical departure from the more assessment-driven competency-based approaches to early childhood education that existed prior to the Foundation Phase. Studying approximately 2000 children in Wales who are part of the UK Millennium Cohort Study (MCS), all born in 2000–2001 we investigate the potential impact of the Foundation Phase pilot on a range of key academic and well-being outcome measures. Compared with other children, those attending a Foundation Phase pilot school tended to have lower scores in a number of academic assessments at age seven and lower subjective well-being, in terms of their attitudes to learning and well-being at school. We consider these surprising, yet concerning, results in the context of the methodological limitations to this analysis and propose how the MCS can be further used to substantiate these findings. [ABSTRACT FROM PUBLISHER]

The article discusses the development of genetic testing from analysis of specific genes to sequencing of the whole genome. It explains the diagnosis power of genome sequencing, and the genetic aetiology of numerous disorders that offer opportunities to prevent, diagnose, and manage diseases. The article discusses how to interpret genomic variants in an individual especially when he or she has no known family history or symptoms of a disease.

Editorial. Introduces a series of articles from the 1999 Women's Studies Network conference in Great Britain published in the May-August 2001 issue of the `Women's Studies International Forum.' Objective for writing the articles published in the journal; Topics discussed, with emphasis on the theme of developing a materialist discursive feminism; How authors presented the article theme.

The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A , HNF4A , and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%–97%). We highlight that pathogenic variants in HNF1A , HNF4A , and GCK are not ultra-rare in the population. For HNF1A and HNF4A , we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list. The prevalence of pathogenic variants in common MODY-associated genes are ∼1:1,500 in the population. The penetrance of pathogenic HNF1A and HNF4A variants, but not of GCK variants, is substantially lower when found incidentally. Our findings are important for incidental reporting of pathogenic variants in MODY and other monogenic disorders. [ABSTRACT FROM AUTHOR]

The article focuses on the Deciphering Developmental Disorders (DDD) study, a project of the Wellcome Trust Sanger Institute and the British National Health Service's Regional Genetics Services that will perform phenotyping and genomic analysis for children with severe undiagnosed developmental disorders. The study uses the Human Phenotype Ontology (HPO) protocol to facilitate association analysis between phenotypes and genomic variants. The DDD's role in identifying the genetic basis of diseases is addressed.

Many rare monogenic diseases are known to be caused by deleterious variants in thousands of genes, however the same variants can also be found in people without the associated clinical phenotypes. The penetrance of these monogenic variants is generally unknown in the wider population, as they are typically identified in small clinical cohorts of affected individuals and families with highly penetrant variants. Here, we investigated the phenotypic effect of rare, potentially deleterious variants in genes and loci where similar variants are known to cause monogenic developmental disorders (DDs) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 monoallelic DDG2P genes by using whole-exome-sequencing data from ∼200,000 individuals and rare copy-number variants overlapping known DD loci by using SNP-array data from ∼500,000 individuals. We found that individuals with these likely deleterious variants had a mild DD-related phenotype, including lower fluid intelligence, slower reaction times, lower numeric memory scores, and longer pairs matching times compared to the rest of the UK Biobank cohort. They were also shorter, had a higher BMI, and had significant socioeconomic disadvantages: they were less likely to be employed or be able to work and had a lower income and higher deprivation index. Our findings suggest that many genes routinely tested within pediatric genetics have deleterious variants with intermediate penetrance that may cause lifelong sub-clinical phenotypes in the general adult population. [ABSTRACT FROM AUTHOR]

Large copy-number variants (CNVs) are strongly associated with both developmental delay and cancer, but the type of disease depends strongly on when and where the mutation occurred, i.e., germline versus somatic. We used microarray data from UK Biobank to investigate the prevalence and penetrance of large autosomal CNVs and chromosomal aneuploidies using a standard CNV detection algorithm not designed for detecting mosaic variants. We found 160 individuals that carry >10 Mb copy number changes, including 56 with whole chromosome aneuploidies. Nineteen (12%) individuals had a diagnosis of Down syndrome or other developmental disorder, while 84 (52.5%) individuals had a diagnosis of hematological malignancies or chronic myeloproliferative disorders. Notably, there was no evidence of mosaicism in the blood for many of these large CNVs, so they could easily be mistaken for germline alleles even when caused by somatic mutations. We therefore suggest that somatic mutations associated with blood cancers may result in false estimates of rare variant penetrance from population biobanks. [ABSTRACT FROM AUTHOR]

Rare damaging variants in a large number of genes are known to cause monogenic developmental disorders (DDs) and have also been shown to cause milder subclinical phenotypes in population cohorts. Here, we show that carrying multiple (2-5) rare damaging variants across 599 dominant DD genes has an additive adverse effect on numerous cognitive and socioeconomic traits in UK Biobank, which can be partially counterbalanced by a higher educational attainment polygenic score (EA-PGS). Phenotypic deviators from expected EA-PGS could be partly explained by the enrichment or depletion of rare DD variants. Among carriers of rare DD variants, those with a DD-related clinical diagnosis had a substantially lower EA-PGS and more severe phenotype than those without a clinical diagnosis. Our results suggest that the overall burden of both rare and common variants can modify the expressivity of a phenotype, which may then influence whether an individual reaches the threshold for clinical disease., (© 2024. The Author(s).)

Background: Previous research on the relationship between children's depressive and externalising symptoms, experience of school, and academic attainment is inconclusive. The aims of this study were (i) to test bidirectional associations between children's school experience and depressive and externalising symptoms at age 10-11 and 13-14, (ii) to ascertain whether school experience age 13-14 is associated with academic attainment age 16, and (iii) to test whether school experience mediates the relationship between depressive or externalising symptoms and attainment., Methods: Data was used from the Avon Longitudinal Study of Parents and Children (n=6,409). A cross-lagged model was used to investigate bidirectional associations between school experience (enjoyment and connectedness) and depression and externalising at age 10-11 and 13-14. The same framework was used to test if school experience aged 13-14 mediated associations of depressive and externalising symptoms with later attainment., Results: Depressive and externalising symptoms at 10-11 were negatively associated with school connectedness (depressive: standardised β=-0.06, CI: -0.11, 0.01; externalizing: β=-0.13, CI: -0.17, -0.08), and school enjoyment at 13-14 (depressive β=-0.04, -0.08, 0.03; externalising: β=-0.08, CI: -0.13, -0.03). School enjoyment at 13-14 was positively associated with attainment at 16 (β=0.10, CI: 0.04, 0.15), and partially mediated associations between depressive and externalising symptoms at 10-11 and attainment at 16 (depressive: proportion mediated 2.2%, CI: -1.5, 5.9; externalising: proportion mediated; 4.7%, CI: 0.7, 10.1,)., Limitations: Results may be subject to residual confounding., Conclusions: School enjoyment is a potentially modifiable risk factor that may affect educational attainment of adolescents with depressive or externalising symptoms., (Copyright © 2021. Published by Elsevier B.V.)

We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in a crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin and distilled water were performed 1, 3 and 5 h after dosing. Mean concentrations evoking ≥2 coughs (C2) and ≥5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·h -1 ) over 24 h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored.24 CC patients and 12 HV were randomised (mean age 61 and 38 years, respectively). The cough challenge threshold increased for ATP by 4.7-fold (C2, p≤0.001) and 3.7-fold (C5, p=0.007) for gefapixant versus placebo in CC patients; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). The distilled water C2 and C5 thresholds increased significantly (p<0.001) by a factor of 1.4 and 1.3, respectively, in CC patients. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and the least squares mean cough severity VAS was 18.0 mm lower for gefapixant versus placebo in CC patients. Dysgeusia was the most frequent adverse event (75% of HV and 67% of CC patients).ATP-evoked cough was significantly inhibited by gefapixant 100 mg, demonstrating peripheral target engagement. Cough count and severity were reduced in CC patients. Distilled water may also evoke cough through a purinergic pathway., Competing Interests: Conflict of interest: A.H. Morice has received consulting fees from Afferent, Merck Sharp & Dohme, Boehringer Ingelheim, Pfizer, and Proctor & Gamble; lecture fees from Boehringer Ingelheim and AstraZeneca; and grant support from Proctor & Gamble. Conflict of interest: M.M. Kitt is a former employee of Afferent Pharmaceuticals and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock in the company. Conflict of interest: A.P. Ford is a former employee of Afferent Pharmaceuticals and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock in the company. Conflict of interest: A.M. Tershakovec is a former employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock in the company. Conflict of interest: W-C. Wu was an employee of Merck Sharp & Dohme, Corp, during the conduct of the study. Conflict of interest: K. Brindle has nothing to disclose. Conflict of interest: R. Thompson has nothing to disclose. Conflict of interest: S. Thackray-Nocera has nothing to disclose. Conflict of interest: C. Wright has nothing to disclose., (Copyright ©ERS 2019.)

More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as "clinically relevant" variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM&#95;175914.4) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old. We also observed associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g., heterozygous carriers of the ERCC4 c.2395C>T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Improving timely access to evidence-based treatment for people aged 14-65 years experiencing a first episode psychosis (FEP) or an at-risk mental state (ARMS) for psychosis is a national priority within the United Kingdom. An early intervention in psychosis (EIP) access and waiting time standard has been set which has extended the age range and acceptance criteria for services., Methods: This descriptive evaluation reports upon the referrals and access to treatment times within an EIP service over the first year of operating in line with the access and waiting time standard. Patient pathways and post-assessment status are also described., Results: The service received 406 referrals, of which 88% (n = 357) were assessed. The mean length of time to treatment was 1.5 weeks, with 88% being seen within 2 weeks. Of those who engaged in an assessment, 34% (n = 138) were identified as ARMS cases and 30% (n = 123) were identified as FEP. Over 35 year olds accounted for 22% (n = 80) of the total accepted cases., Conclusions: The findings indicate clinical and operational issues, which will need careful consideration in the future planning of services. The high number of ARMS cases highlights the importance of clear treatment pathways and targeted interventions and may suggest a need to commission distinct ARMS services. The number of people who met the extended age and service acceptance criteria may suggest a need to adapt or redesign clinical services to meet the age-specific needs of over 35 year olds and those with an ARMS. It is unclear how changes to the remit of EIP services will impact upon future clinical outcomes., (© 2018 John Wiley & Sons Australia, Ltd.)

Purpose: Given the rapid pace of discovery in rare disease genomics, it is likely that improvements in diagnostic yield can be made by systematically reanalyzing previously generated genomic sequence data in light of new knowledge., Methods: We tested this hypothesis in the United Kingdom-wide Deciphering Developmental Disorders study, where in 2014 we reported a diagnostic yield of 27% through whole-exome sequencing of 1,133 children with severe developmental disorders and their parents. We reanalyzed existing data using improved variant calling methodologies, novel variant detection algorithms, updated variant annotation, evidence-based filtering strategies, and newly discovered disease-associated genes., Results: We are now able to diagnose an additional 182 individuals, taking our overall diagnostic yield to 454/1,133 (40%), and another 43 (4%) have a finding of uncertain clinical significance. The majority of these new diagnoses are due to novel developmental disorder-associated genes discovered since our original publication., Conclusion: This study highlights the importance of coupling large-scale research with clinical practice, and of discussing the possibility of iterative reanalysis and recontact with patients and health professionals at an early stage. We estimate that implementing parent-offspring whole-exome sequencing as a first-line diagnostic test for developmental disorders would diagnose >50% of patients.

Objectives: To explore the association between adolescent multiple risk behaviours (MRBs) and educational attainment., Design: Prospective population-based UK birth cohort study., Setting: Avon Longitudinal Study of Parents and Children (ALSPAC), a UK birth cohort of children born in 1991-1992., Participants: Data on some or all MRB measures were available for 5401 ALSPAC participants who attended a clinic at age 15 years and/or completed a detailed questionnaire at age 16 years. Multiple imputation was used to account for missing data., Primary Outcome Measures: Capped General Certificate of Secondary Education (GCSE) score and odds of attaining five or more GCSE examinations at grades A*-C. Both outcome measures come from the National Pupil Database and were linked to the ALSPAC data., Results: Engagement in MRB was strongly associated with poorer educational attainment. Each additional risk equated to -6.31 (95% CI -7.03 to -5.58, p<0.001) in capped GCSE score, equivalent to a one grade reduction or reduced odds of attaining five or more A*-C grades of 23% (OR 0.77, 95% CI 0.74 to 0.81, p<0.001). The average cohort member engaged in 3.24 MRB and therefore have an associated reduction in GCSE score equivalent to three and a half grades in one examination, or reduced odds of attaining five or more A*-C grades of 75%., Conclusion: Engagement in adolescent MRB is strongly associated with poorer educational attainment at 16 years. Preventing MRB could improve educational attainment and thereby directly and indirectly improve longer-term health., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.