Evaluation of two Massive Open Online Courses (MOOCs) in genomic variant interpretation for the NHS workforce.

BACKGROUND: The implementation of the National Genomic Medicine Service in the UK has increased patient access to germline genomic testing. Increased testing leads to more genetic diagnoses but does result in the identification of genomic variants of uncertain significance (VUS). The rigorous process of interpreting these variants requires multi-disciplinary, highly trained healthcare professionals (HCPs). To meet this training need, we designed two Massive Open Online Courses (MOOCs) for HCPs involved in germline genomic testing pathways: Fundamental Principles (FP) and Inherited Cancer Susceptibility (ICS). METHODS: An evaluation cohort of HCPs involved in genomic testing were recruited, with additional data also available from anonymous self-registered learners to both MOOCs. Pre- and post-course surveys and in-course quizzes were used to assess learner satisfaction, confidence and knowledge gained in variant interpretation. In addition, granular feedback was collected on the complexity of the MOOCs to iteratively improve the resources. RESULTS: A cohort of 92 genomics HCPs, including clinical scientists, and non-genomics clinicians (clinicians working in specialties outside of genomics) participated in the evaluation cohort. Between baseline and follow-up, total confidence scores improved by 38% (15.2/40.0) (95% confidence interval [CI] 12.4-18.0) for the FP MOOC and 54% (18.9/34.9) (95%CI 15.5-22.5) for the ICS MOOC (p < 0.0001 for both). Of those who completed the knowledge assessment through six summative variant classification quizzes (V1-6), a mean of 79% of respondents classified the variants such that correct clinical management would be undertaken (FP: V1 (73/90) 81% Likely Pathogenic/Pathogenic [LP/P]; V2 (55/78) 70% VUS; V3 (59/75) 79% LP/P; V4 (62/72) 86% LP/LP. ICS: V5 (66/91) 73% VUS; V6 (76/88) 86% LP/P). A non-statistically significant higher attrition rate was seen amongst the non-genomics workforce when compared to genomics specialists for both courses. More participants from the non-genomics workforce rated the material as "Too Complex" (FP n = 2/7 [29%], ICS n = 1/5 [20%]) when compared to the specialist genomics workforce (FP n = 1/43 [2%], ICS n = 0/35 [0%]). CONCLUSIONS: After completing one or both MOOCs, self-reported confidence in genomic variant interpretation significantly increased, and most respondents could correctly classify variants such that appropriate clinical management would be instigated. Genomics HCPs reported higher satisfaction with the level of content than the non-genomics clinicians. The MOOCs provided foundational knowledge and improved learner confidence, but should be adapted for different workforces to maximise the benefit for clinicians working in specialties outside of genetics.

Mainstreaming of genomics in oncology: a nationwide survey of the genomics training needs of UK oncologists.

OBJECTIVE: Genomics is rapidly changing treatment paradigms for cancers, obligating oncologists to have good genomics knowledge. Through this survey, we aimed to assess the current understanding of cancer genomics among UK oncologists. METHODS: We conducted a web-based nation-wide self-assessment survey of the cancer genomics knowledge of UK clinical and medical oncology trainees and consultants. RESULTS: In total, 150 oncologists (81 consultants and 69 trainees) responded, representing 10% of UK oncologists.Formal training in genomics had not been received by 38.7% of oncologists and 92.7% identified a need for additional genomics training.In total, 71.3% self-reported to have good knowledge of defining somatic and germline mutations, falling to 35.3% for understanding principles of gene expression and regulation. Knowledge of cancer-predisposing syndromes was highest for Lynch syndrome (40.7% good knowledge) and lowest for multiple endocrine neoplasia (14.0% good knowledge).Overall, 49.0% of respondents had consented patients for germline testing, but 80.7% reported a lack of training in genetic counselling. CONCLUSION: Large knowledge gaps have been identified through this survey, highlighting the need for incorporation of improved formal training in cancer genomics for consultants and trainees, with an aim to equip oncologists for advances in clinical practice and to take up genetic mainstreaming confidently.

ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Socio-economic deprivation and cancer incidence in England: Quantifying the role of smoking.

BACKGROUND: More deprived populations typically experience higher cancer incidence rates and smoking prevalence compared to less deprived populations. We calculated the proportion of cancer cases attributable to smoking by socio-economic deprivation in England and estimated the impact smoking has on the deprivation gap for cancer incidence. METHODS: Data for cancer incidence (2013-2017), smoking prevalence (2003-2007) and population estimates (2013-2017) were split by sex, age-group and deprivation quintile. Relative risk estimates from meta-analyses were used to estimate the population attributable fraction (PAF) for 15 cancer types associated with smoking. The deprivation gap was calculated using age-specific incidence rates by deprivation quintile. RESULTS: Smoking-related cancer PAFs in England are 2.2 times larger in the most deprived quintile compared to the least deprived quintile (from 9.7% to 21.1%). If everyone had the same smoking prevalence as the least deprived quintile, 20% of the deprivation gap in cancer incidence could have been prevented. If nobody smoked, 61% of the deprivation gap could have been prevented. CONCLUSIONS: The majority of the deprivation gap in cancer incidence could have been prevented in England between 2013-2017 if nobody had smoked. Policy makers should ensure that tobacco control policies reduce overall smoking prevalence by tackling smoking inequalities.

Differences in cancer incidence by broad ethnic group in England, 2013-2017.

BACKGROUND: Cancer incidence variation between population groups can inform public health and cancer services. Previous studies have shown cancer incidence rates vary by ethnic group in England. Since their publication, the completeness of ethnicity recording in cancer data has improved, and relevant inequalities (e.g. risk factor prevalence and healthcare access) may have changed. METHODS: Age-standardised incidence rates were calculated for Asian, Black, Mixed/Multiple and White ethnic groups in England in 2013-2017, using almost 3 million diagnoses across 31 cancer sites. Rate ratios were calculated with the White ethnic group as reference. Sensitivity analyses used imputed ethnicity for cases with missing data and perturbed population estimates. RESULTS: Incidence rates for most cancer sites and ethnic group and sex combinations were lower in non-White minority ethnic groups compared with the corresponding White group, with particularly low rate ratios (below 0.5) for melanoma skin cancer and some smoking-related cancers (lung, bladder and oesophageal cancers). Exceptions included prostate cancer (2.1 times higher in males of Black ethnicity), myeloma (2.7-3.0 times higher in people of Black ethnicity), several gastrointestinal cancers (1.1-1.9 times higher in people of Black ethnicity, 1.4-2.2 times higher in people of Asian ethnicity), Hodgkin lymphoma (1.1 times higher in males of Asian ethnicity, 1.3 times higher in males of Black ethnicity) and thyroid cancers (1.4 times higher in people of Asian ethnicity, 1.2 times higher in people of Black ethnicity). Sensitivity analyses did not materially alter these results (rate ratios changed by a maximum of 12 percentage points, the direction and significance of results were unchanged in all but two cancer site/sex/ethnic group combinations). CONCLUSIONS: People of non-White minority ethnicity in England generally have lower cancer risk than the White population, though there are a number of notable exceptions. These results should galvanise efforts to better understand the reasons for this variation, and the possible impact on cancer services, patient experiences and outcomes.

Updated fraction of cancer attributable to lifestyle and environmental factors in Denmark in 2018.

Environmental exposures and avoidable risk factors account for a large proportion of cancer burden. Exposures and lifestyle vary over time and between populations, which calls for updated and population-specific quantification of how various avoidable risk factors influence cancer risk to plan and design rational and targeted prevention initiatives. The study considered 12 risk-factor groups categorized as class I carcinogens by IARC/WCRF. Exposure data was derived from national studies and surveys and were linked to cancer incidence in 2018 based on the nationwide Danish Cancer Registry. In 2018, 23,078 men and 21,196 women were diagnosed with cancer excluding non-melanoma skin cancer, in Denmark. Of these, 14,235 (32.2%) were estimated to be attributable to avoidable class I carcinogens. Tobacco smoking accounted for 14.6% of total cancers, followed by UV-radiation that accounted for 5.8%. Based on exposure data from 2008, one-third of the cancers in Denmark in 2018 are estimated to be caused by class I carcinogens with tobacco use being the main contributor followed by UV-radiation. Our results should be integrated with public health policies to effectively increase awareness and promote strategies to decrease risk factor exposures at population level.

Systematic Profiling of DNMT3A Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor.

Clonal hematopoiesis is a prevalent age-related condition associated with a greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations are unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, and found that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and acute myeloid leukemia development. We investigated the mechanisms underlying the instability using a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and potential therapeutic significance for patients with hematologic disease. SIGNIFICANCE: DNMT3A has emerged as the most important epigenetic regulator and tumor suppressor in the hematopoietic system. Our study represents a systematic and high-throughput method to characterize the molecular impact of DNMT3A missense mutations and the discovery of a regulated destruction mechanism of DNMT3A offering new prognostic and future therapeutic avenues.See related commentary by Ma and Will, p. 23.This article is highlighted in the In This Issue feature, p. 1.

Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.

PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity.

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.

Unacceptable failures: the final report of the Lancet Commission into liver disease in the UK.

This final report of the Lancet Commission into liver disease in the UK stresses the continuing increase in burden of liver disease from excess alcohol consumption and obesity, with high levels of hospital admissions which are worsening in deprived areas. Only with comprehensive food and alcohol strategies based on fiscal and regulatory measures (including a minimum unit price for alcohol, the alcohol duty escalator, and an extension of the sugar levy on food content) can the disease burden be curtailed. Following introduction of minimum unit pricing in Scotland, alcohol sales fell by 3%, with the greatest effect on heavy drinkers of low-cost alcohol products. We also discuss the major contribution of obesity and alcohol to the ten most common cancers as well as measures outlined by the departing Chief Medical Officer to combat rising levels of obesity-the highest of any country in the west. Mortality of severely ill patients with liver disease in district general hospitals is unacceptably high, indicating the need to develop a masterplan for improving hospital care. We propose a plan based around specialist hospital centres that are linked to district general hospitals by operational delivery networks. This plan has received strong backing from the British Association for Study of the Liver and British Society of Gastroenterology, but is held up at NHS England. The value of so-called day-case care bundles to reduce high hospital readmission rates with greater care in the community is described, along with examples of locally derived schemes for the early detection of disease and, in particular, schemes to allow general practitioners to refer patients directly for elastography assessment. New funding arrangements for general practitioners will be required if these proposals are to be taken up more widely around the country. Understanding of the harm to health from lifestyle causes among the general population is low, with a poor knowledge of alcohol consumption and dietary guidelines. The Lancet Commission has serious doubts about whether the initiatives described in the Prevention Green Paper, with the onus placed on the individual based on the use of information technology and the latest in behavioural science, will be effective. We call for greater coordination between official and non-official bodies that have highlighted the unacceptable disease burden from liver disease in England in order to present a single, strong voice to the higher echelons of government.

The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients.

CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.

Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature.

Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype-up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50-90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome.

The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants.

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novoDNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS.

The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015.

BACKGROUND: Changing population-level exposure to modifiable risk factors is a key driver of changing cancer incidence. Understanding these changes is therefore vital when prioritising risk-reduction policies, in order to have the biggest impact on reducing cancer incidence. UK figures on the number of risk factor-attributable cancers are updated here to reflect changing behaviour as assessed in representative national surveys, and new epidemiological evidence. Figures are also presented by UK constituent country because prevalence of risk factor exposure varies between them. METHODS: Population attributable fractions (PAFs) were calculated for combinations of risk factor and cancer type with sufficient/convincing evidence of a causal association. Relative risks (RRs) were drawn from meta-analyses of cohort studies where possible. Prevalence of exposure to risk factors was obtained from nationally representative population surveys. Cancer incidence data for 2015 were sourced from national data releases and, where needed, personal communications. PAF calculations were stratified by age, sex and risk factor exposure level and then combined to create summary PAFs by cancer type, sex and country. RESULTS: Nearly four in ten (37.7%) cancer cases in 2015 in the UK were attributable to known risk factors. The proportion was around two percentage points higher in UK males (38.6%) than in UK females (36.8%). Comparing UK countries, the attributable proportion was highest in Scotland (41.5% for persons) and lowest in England (37.3% for persons). Tobacco smoking contributed by far the largest proportion of attributable cancer cases, followed by overweight/obesity, accounting for 15.1% and 6.3%, respectively, of all cases in the UK in 2015. For 10 cancer types, including two of the five most common cancer types in the UK (lung cancer and melanoma skin cancer), more than 70% of UK cancer cases were attributable to known risk factors. CONCLUSION: Tobacco and overweight/obesity remain the top contributors of attributable cancer cases. Tobacco smoking has the highest PAF because it greatly increases cancer risk and has a large number of cancer types associated with it. Overweight/obesity has the second-highest PAF because it affects a high proportion of the UK population and is also linked with many cancer types. Public health policy may seek to mitigate the level of harm associated with exposure or reduce exposure levels-both approaches may effectively impact cancer incidence. Differences in PAFs between countries and sexes are primarily due to varying prevalence of exposure to risk factors and varying proportions of specific cancer types. This variation in turn is affected by socio-demographic differences which drive differences in exposure to theoretically avoidable 'lifestyle' factors. PAFs at UK country level have not been available previously and they should be used by policymakers in devolved nations. PAFs are estimates based on the best available data, limitations in those data would generally bias toward underestimation of PAFs. Regular collection of risk factor exposure prevalence data which corresponds with epidemiological evidence is vital for analyses like this and should remain a priority for the UK Government and devolved Administrations.

Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.

Correction: Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height.

[This corrects the article DOI: 10.18632/oncotarget.385.].

Modelling the implications of reducing smoking prevalence: the benefits of increasing the UK tobacco duty escalator to public health and economic outcomes.

INTRODUCTION: Taxing tobacco is one of the most effective ways to reduce smoking prevalence, mitigate its devastating consequential health harms and progress towards a tobacco-free society. This study modelled the health and economic impacts of increasing the existing cigarette tobacco duty escalator (TDE) in the UK from the current 2% above consumer price inflation to 5%. METHODS: A two-stage modelling process was used. First, a non-linear multivariate regression model was fitted to cross-sectional smoking data, creating longitudinal projections from 2015 to 2035. Second, these projections were used to predict the future incidence, prevalence and cost of 17 smoking-related diseases using a Monte Carlo microsimulation approach. A sustained increase in the duty escalator was evaluated against a baseline of continuing historical smoking trends and the existing duty escalator. RESULTS: A sustained increase in the TDE is projected to reduce adult smoking prevalence to 6% in 2035, from 10% in a baseline scenario. After increasing the TDE, only 65% of female and 60% of male would-be smokers would actually be smoking in 2035. The intervention is projected to avoid around 75 200 new cases of smoking-related diseases between 2015 and 2035. In 2035 alone, £49 m in National Health Service and social care costs and £192 m in societal premature mortality and morbidity costs are projected to be avoided. CONCLUSION: Increasing the UK TDE to 5% above inflation could effectively reduce smoking prevalence, prevent diseases and avoid healthcare costs. It would deliver substantial progress towards a tobacco-free society and should be implemented by the UK Government with urgency.

Modelling the implications of reducing smoking prevalence: the public health and economic benefits of achieving a 'tobacco-free' UK.

INTRODUCTION: Smoking is still the most preventable cause of cancer, and a leading cause of premature mortality and health inequalities in the UK. This study modelled the health and economic impacts of achieving a 'tobacco-free' ambition (TFA) where, by 2035, less than 5% of the population smoke tobacco across all socioeconomic groups. METHODS: A non-linear multivariate regression model was fitted to cross-sectional smoking data to create projections to 2035. These projections were used to predict the future incidence and costs of 17 smoking-related diseases using a microsimulation approach. The health and economic impacts of achieving a TFA were evaluated against a predicted baseline scenario, where current smoking trends continue. RESULTS: If trends continue, the prevalence of smoking in the UK was projected to be 10% by 2035-well above a TFA. If this ambition were achieved by 2035, it could mean 97 300 +/- 5 300 new cases of smoking-related diseases are avoided by 2035 (tobacco-related cancers: 35 900+/- 4 100; chronic obstructive pulmonary disease: 29 000 +/- 2 700; stroke: 24 900 +/- 2 700; coronary heart disease: 7600 +/- 2 700), including around 12 350 diseases avoided in 2035 alone. The consequence of this health improvement is predicted to avoid £67 +/- 8 million in direct National Health Service and social care costs, and £548 million in non-health costs, in 2035 alone. CONCLUSION: These findings strengthen the case to set bold targets on long-term declines in smoking prevalence to achieve a tobacco 'endgame'. Results demonstrate the health and economic benefits that meeting a TFA can achieve over just 20 years. Effective ambitions and policy interventions are needed to reduce the disease and economic burden of smoking.

Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability.

To explore the genetic architecture of human overgrowth syndromes and human growth control, we performed experimental and bioinformatic analyses of 710 individuals with overgrowth (height and/or head circumference ≥+2 SD) and intellectual disability (OGID). We identified a causal mutation in 1 of 14 genes in 50% (353/710). This includes HIST1H1E, encoding histone H1.4, which has not been associated with a developmental disorder previously. The pathogenic HIST1H1E mutations are predicted to result in a product that is less effective in neutralizing negatively charged linker DNA because it has a reduced net charge, and in DNA binding and protein-protein interactions because key residues are truncated. Functional network analyses demonstrated that epigenetic regulation is a prominent biological process dysregulated in individuals with OGID. Mutations in six epigenetic regulation genes-NSD1, EZH2, DNMT3A, CHD8, HIST1H1E, and EED-accounted for 44% of individuals (311/710). There was significant overlap between the 14 genes involved in OGID and 611 genes in regions identified in GWASs to be associated with height (p = 6.84 × 10-8), suggesting that a common variation impacting function of genes involved in OGID influences height at a population level. Increased cellular growth is a hallmark of cancer and there was striking overlap between the genes involved in OGID and 260 somatically mutated cancer driver genes (p = 1.75 × 10-14). However, the mutation spectra of genes involved in OGID and cancer differ, suggesting complex genotype-phenotype relationships. These data reveal insights into the genetic control of human growth and demonstrate that exome sequencing in OGID has a high diagnostic yield.