Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for <i>BRCA1</i> and <i>BRCA2</i> Mutation Carriers: Implications for Risk Prediction

Introduction/Background Ashkenazi-Jewish (AJ) population-based BRCA-testing is acceptable, does not detrimentally impact psychological well-being or quality of life, is cost-effective and amplifies primary prevention for breast cancer (BC) ovarian cancer (OC). However, prospective data describing lifestyle impact are lacking. We report long-term results of a population-based BRCA-testing randomised controlled trial (RCT) on lifestyle behaviour and cancer-risk perception. Methodology We designed a two-arm RCT (ISRCTN-73338115, GCaPPS): (a)Population-Screening (PS) arm; (b) family-history (FH)/Clinical-criteria testing arm. Women and men >18-years in the North-London AJ-population were offered informed pre-test genetic counselling and BRCA testing. Participants were recruited through self-referral. Exclusions included: prior BRCA-testing or first-degree relatives of BRCA-carriers. The intervention included genetic-testing for three AJ BRCA-mutations: 185delAG(c.68_69delAG), 5382insC(c.5266dupC) and 6174delT(c.5946delT). This was undertaken for all participants in the PS-arm; and participants fulfilling FH/clinical-criteria in the FH-arm. Patients filled customised/validated questionnaires at baseline/1-year/2-years/3-years follow-up. Outcome measures included lifestyle/behavioural outcomes. Generalized linear-mixed models adjusted for covariates and appropriate contrast-tests were used for between-group and within-group analysis of lifestyle and behavioural outcomes along-with evaluating factors associated with these outcomes. Outcomes are adjusted for multiple testing (Bonferoni method), with p<0.0039 considered significant. Results 1034 participants were randomized to PS (n=530) or FH (n=504) arms. No significant difference was identified between PS and FH-based BRCA-testing approaches for dietary fruit/vegetable/meat consumption, vitamin intake, alcohol quantity/frequency, smoking behaviour (frequency/cessation), physical activity/exercise or routine breast mammogram screening behaviour, with outcomes not affected by BRCA test result. Cancer-risk perception decreased with time following BRCA-testing with no difference between FH/PS approaches. The risk was found to be lowest in BRCA-negative participants. Men consume fewer fruits, vegetables and vitamins but more meat and alcohol than women (p<0.001). Conclusion Population-based and FH-based AJ BRCA-testing have similar long-term life-style impacts for smoking, alcohol, dietary fruit/vegetable/meat/vitamin, exercise, breast screening participation and reduced cancer-risk perception.

Ashkenazi‐Jewish (AJ) population‐based BRCA testing is acceptable, cost‐effective and amplifies primary prevention for breast & ovarian cancer. However, data describing lifestyle impact are lacking. We report long‐term results of population‐based BRCA testing on lifestyle behaviour and cancer risk perception.

To examine trends in prenatal diagnosis and pre-implantation diagnosis for Huntington disease (HD) in United Kingdom since services commenced.

OBJECTIVE:Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported.DESIGN:This retrospective case series collated data from 18 UK Genetics and Endocrinology departments.PATIENTS:Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included.MEASUREMENTS:Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation.RESULTS:We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively.CONCLUSIONS:This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.

Documenting variation in our genomes is important for research and clinical care. Accuracy in the description of DNA variants is therefore essential. To address this issue, the Human Variome Project convened a committee to evaluate the feasibility of requiring authors to verify that all variants submitted for publication complied with a widely accepted standard for description. After a pilot study of two journals, the committee agreed that requiring authors to verify that variants complied with Human Genome Variation Society nomenclature is a reasonable step toward standardizing the worldwide inventory of human variation.

Objective To evaluate the association of Jewish cultural and religious identity and denominational affiliation with interest in, intention to undertake and uptake of population-based BRCA (Breast Cancer Gene)-testing. Design Cohort-study set within recruitment to GCaPPS-trial (ISRCTN73338115). Setting London Ashkenazi-Jewish (AJ) population. Population or sample AJ men and women, >18 years. Methods Participants were self-referred, and attended recruitment clinics (clusters) for pre-test counselling. Subsequently consenting individuals underwent BRCA testing. Participants self-identified to one Jewish denomination: Conservative/Liberal/Reform/Traditional/Orthodox/Unaffiliated. Validated scales measured Jewish Cultural-Identity (JI) and Jewish Religious-identity (JR). Four-item Likert-scales analysed initial 'interest' and 'intention to test' pre-counselling. Item-Response-Theory and graded-response models, modelled responses to JI and JR scales. Ordered/multinomial logistic regression modelling evaluated association of JI-scale, JR-scale and Jewish Denominational affiliation on interest, intention and uptake of BRCA testing. Main outcome measures Interest, intention, uptake of BRCA testing. Results In all, 935 AJ women/men of mean age = 53.8 (S.D = 15.02) years, received pre-test education and counselling through 256 recruitment clinic clusters (median cluster size = 3). Denominational affiliations included Conservative/Masorti = 91 (10.2%); Liberal = 82 (9.2%), Reform = 135 (15.1%), Traditional = 212 (23.7%), Orthodox = 239 (26.7%); and Unaffiliated/Non-practising = 135 (15.1%). Overall BRCA testing uptake was 88%. Pre-counselling, 96% expressed interest and 60% intention to test. JI and JR scores were highest for Orthodox, followed by Conservative/Masorti, Traditional, Reform, Liberal and Unaffiliated Jewish denominations. Regression modelling showed no significant association between overall Jewish Cultural or Religious Identity with either interest, intention or uptake of BRCA testing. Interest, intention and uptake of BRCA testing was not significantly associated with denominational affiliation. Conclusions Jewish religious/cultural identity and denominational affiliation do not appear to influence interest, intention or uptake of population-based BRCA testing. BRCA testing was robust across all Jewish denominations. Tweetable abstract Jewish cultural/religious factors do not affect BRCA testing, with robust uptake seen across all denominational affiliations.

The need for precision in scientific communication is long established. In genetics, one area in which it is particularly important that information be communicated accurately is the reporting of DNA variants. Over the past 2 years, a working group convened by the Human Variome Project has considered what requirements might reasonably be made of authors to verify that descriptions of variants submitted for publication comply with a widely accepted standard. Two journals undertook a pilot study to test the feasibility of a requirement that authors verify compliance of their variant descriptions to Human Genome Variation Society (HGVS) standards through the use of a standard tool such as Mutalyzer or …

Introduction/Background Unselected population-based BRCA-testing enables application of genomics on a population-scale to maximise primary-prevention for breast-&-ovarian cancer. We present factors affecting uptake and long-term follow-up results of the GCaPPS-trial comparing population-based and Family-History (FH)/Clinical-criteria based BRCA-testing. Methodology Design: Randomised-Controlled-Trial (ISRCTN73338115) GCaPPS, with two-arms: (a)Population-Screening (PS); (b)FH/Clinical-criteria based testing. Setting: North-London Ashkenazi-Jewish(AJ) population. Population-based RCT (1:1). Participants recruited through self-referral, from North-London AJ-population. Inclusion-criteria: AJ women/men >18years. Exclusion-criteria: prior BRCA-testing or first-degree-relatives of BRCA-carriers. Interventions: Pre-test counselling for BRCA-testing through recruitment-clinics (clusters). Genetic-testing for Jewish BRCA founder-mutations: 185delAG(c.68_69delAG), 5382insC(c.5266dupC) and 6174delT(c.5946delT), for (a)all participants in PS-arm; (b)those fulfilling FH/clinical-criteria in FH-arm. Validated questionnaires (HADS/MICRA/HAI/SF12) analysed psychological well-being/quality-of-life outcomes at baseline, 1-year, 2-years and 3-years follow-up. Linear mixed-models and appropriate contrast-tests analysed the impact of BRCA-testing on psychological and quality-of-life outcomes over 3-years. Socio-demographic/family-history/knowledge/psychological well-being data along-with benefits/risks/cultural-influences (18-item-questionnaire measuring 'attitude') were collected. Logistic-regression models evaluated factors affecting uptake/interest/intention-to undergo BRCA-testing. Results 1034 (women=691/men=343) participants randomized to PS (n=530) or FH (n=504) arms. There was a statistically significant decrease in anxiety(p=0.046) and total anxiety-&-depression scores(p=0.0.012) in the PS-arm compared to FH-arm over 3years. No significant difference was observed between FH/PS arms for depression, health-anxiety, distress, uncertainty, quality-of-life or experience scores associated with BRCA-testing. 18/30(60%) BRCA-carriers identified did not fulfil BRCA-testing clinical-criteria. The total BRCA-prevalence= 2.9%(CI:1.97%,4.12%) (BRCA1=1.55%(CI:0.89%,2.5%); BRCA2=1.35%(CI:0.74%,2.26%)). The BRCA-testing uptake was 88%. Being married/cohabiting had four-fold higher-odds for BRCA-testing uptake(p=0.009). Reduced uncertainty/reassurance were the most important factors affecting decision-making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional-impact/inability to prevent cancer/marriage-ability/ethnic-focus/stigmatization) were significantly associated with lower-odds of undergoing BRCA-testing, discriminating between acceptors and decliners. Conclusion Population-based AJ BRCA-testing has high acceptability, doesn't adversely affect long-term psychological well-being or quality-of-life, decreases anxiety and could identify up-to 150% additional BRCA-carriers. Pre-test counselling increases awareness of disadvantages/limitations of BRCA-testing, influencing final cost-benefit perception and decision-making on undergoing testing. Disclosure IJ and UM have a financial interest in Abcodia, Ltd., a company formed to develop academic and commercial development of biomarkers for screening and risk prediction. IJ is a member of the board of Abcodia Ltd, a Director of Women's Health Specialists Ltd and received consultancy from Beckton Dickinson. RM declares research funding from The Eve Appeal and Cancer Research UK into population testing and from Barts & the London Charity and Rose Trees Trust outside this work, an honorarium for grant review from Israel National Institute for Health Policy Research and honorarium for advisory board membership from Astrazeneca/MSD. RM is supported by an NHS Innovation Accelerator (NIA) Fellowship for population testing. The other authors declare no conflict of interest.

The Journal of Medical Genetics ( JMG ) is now in its 55th year of publication. In that time, both medical genetics and scientific publishing have changed almost beyond recognition. In 1964, it would have seemed inconceivable that when there was a pressing need to reach a diagnosis, a patient could have almost all of their expressed genes sequenced and analysed in the space of a few days.1 The advent of exome and whole-genome sequencing has changed medical genetics. Research studies such as Deciphering developmental disorders 2 3 have shown the potential of genomics in the clinic. Large-scale initiatives such as the 100 000 Genomes Project will help transform medical …

Raul E. Piña-Aguilar, Sheila Simpson, David Craufurd, Daniela Rae, Abdulrahman Ahlshatti, Angus Clarke, Huw Dorkins, Karen Doye, Nayana Lahiri, Alison Lashwood, Collen Lynch, Claire Miller, Sally Morton, Mary O’Driscoll, Oliver W. Quarrell, Mark Strong, Charlotte Tomlinson, Peter Turnpenny, on behalf of the UK HD Predictive Testing Consortium, Zosia Miedzybrodzka School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK

Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.

Objective To evaluate factors affecting unselected population‐based BRCA testing in Ashkenazi Jews ( AJ ). Design Cohort‐study set within recruitment to the GCaPPS trial (ISRCTN73338115). Setting North London AJ population. Population or sample Ashkenazi Jews women/men >18 years, recruited through self‐referral. Methods Ashkenazi Jews women/men underwent pre‐test counselling for BRCA testing through recruitment clinics (clusters). Consenting individuals provided blood samples for BRCA testing. Data were collected on socio‐demographic/family history/knowledge/psychological well‐being along with benefits/risks/cultural influences (18‐item questionnaire measuring ‘attitude’). Four‐item Likert‐scales analysed initial ‘interest’ and ‘intention‐to‐test’ pre‐counselling. Uni‐ and multivariable logistic regression models evaluated factors affecting uptake/interest/intention to undergo BRCA testing. Statistical inference was based on cluster robust standard errors and joint Wald tests for significance. Item‐Response Theory and graded‐response models modelled responses to 18‐item questionnaire. Main outcome measures Interest, intention, uptake, attitude towards BRCA testing. Results A total of 935 individuals (women = 67%/men = 33%; mean age = 53.8 ( SD = 15.02) years) underwent pre‐test genetic‐counselling. During the pre‐counselling, 96% expressed interest in and 60% indicated a clear intention to undergo BRCA testing. Subsequently, 88% opted for BRCA testing. BRCA ‐related knowledge ( P = 0.013) and degree‐level education ( P = 0.01) were positively and negatively (respectively) associated with intention‐to‐test. Being married/cohabiting had four‐fold higher odds for BRCA testing uptake ( P = 0.009). Perceived benefits were associated with higher pre‐counselling odds for interest in and intention to undergo BRCA testing. Reduced uncertainty/reassurance were the most important factors contributing to decision‐making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional impact/inability to prevent cancer/marriage ability/ethnic focus/stigmatisation) were significantly associated with lower odds of uptake of BRCA testing, and discriminated between acceptors and decliners. Male gender/degree‐level education ( P = 0.001) had weaker correlations, whereas having children showed stronger ( P = 0.005) associations with attitudes towards BRCA testing. Conclusions BRCA testing in the AJ population has high acceptability. Pre‐test counselling increases awareness of disadvantages/limitations of BRCA testing, influencing final cost‐benefit perception and decision‐making on undergoing testing. Tweetable abstract BRCA testing in Ashkenazi Jews has high acceptability and uptake. Pre‐test counselling facilitates informed decision‐making.

Many important medical conditions may be the result of an inherited mutation in one of a number of different genes. Technical advances have reduced the cost of whole genome sequencing and whole exome sequencing to a level where it is now feasible to analyse multiple genes in one test. Every human carries several hundred potentially pathogenic coding variants, so a major challenge is to understand which of these is relevant to the patient’s disease. This requires considerable computing power, the use of international unaffected “normal” population and disease cohort databases, clinical scientist input as well as a medical context provided by accurate phenotyping and understanding of Bayesian probability. The guidelines of the American College of Medical Genetics provide a useful framework for the evaluation and reporting of sequence variants. In England, the 100,000 Genomes Project was established within the National Health Service to introduce these technologies into mainstream healthcare. From January 2019, genomic laboratory hubs will deliver a genomics service. In this paper, we review what has been learnt from the project to date and consider how other health care systems could use similar approaches.

Purpose: There is little long-term, population-based data on uptake of prenatal diagnosis for Huntington disease (HD), a late-onset autosomal dominant neurodegenerative disorder, and the effect of the availability of preimplantation genetic diagnosis (PGD) on families' decisions about conventional prenatal diagnosis is not known. We report trends in prenatal diagnosis and preimplantation diagnosis for HD in the United Kingdom since services commenced. Methods: Long-term UK-wide prospective case record-based service evaluation in 23 UK Regional Genetic Centres 1988-2015, and four UK PGD centers 2002-2015. Results: From 1988 to 2015, 479 prenatal diagnoses were performed in the UK for HD. An exclusion approach was used in 150 (31%). The annual rate of HD prenatal diagnosis has remained around 18 (3.5/million) over 27 years, despite a steady increase in the use of PGD for HD since 2002. Conclusion: Although increasing number of couples are choosing either direct or exclusion PGD to prevent HD in their offspring, both direct and exclusion prenatal diagnosis remain important options in a health system where both PGD and prenatal diagnosis are state funded. At-risk couples should be informed of all options available to them, preferably prepregnancy.

Background Newer approaches to genetic counselling are required for population-based testing. We compare traditional face-to-face genetic counselling with a DVD-assisted approach for population-based BRCA1/2 testing.Methods A cluster-randomised non-inferiority trial in the London Ashkenazi Jewish population. Inclusion criteria Ashkenazi Jewish men/women >18 years; exclusion criteria: (a) known BRCA1/2 mutation, (b) previous BRCA1/2 testing and (c) first-degree relative of BRCA1/2 carrier. Ashkenazi Jewish men/women underwent pre-test genetic counselling prior to BRCA1/2 testing in the Genetic Cancer Prediction through Population Screening trial (ISRCTN73338115). Genetic counselling clinics (clusters) were randomised to traditional counselling (TC) and DVD-based counselling (DVD-C) approaches. DVD-C involved a DVD presentation followed by shorter face-to-face genetic counselling. Outcome measures included genetic testing uptake, cancer risk perception, increase in knowledge, counselling time and satisfaction (Genetic Counselling Satisfaction Scale). Random-effects models adjusted for covariates compared outcomes between TC and DVD-C groups. One-sided 97.5% CI was used to determine non-inferiority. Secondary outcomes: relevance, satisfaction, adequacy, emotional impact and improved understanding with the DVD; cost-minimisation analysis for TC and DVD-C approaches.Results 936 individuals (clusters=256, mean-size=3.6) were randomised to TC (n=527, clusters=134) and DVD-C (n=409, clusters=122) approaches. Groups were similar at baseline, mean age=53.9 (SD=15) years, women=66.8%, men=33.2%. DVD-C was non-inferior to TC for increase in knowledge (d=-0.07; lower 97.5% CI=-0.41), counselling satisfaction (d=-0.38, 97.5% CI=1.2) and risk perception (d=0.08; upper 97.5% CI=3.1). Group differences and CIs did not cross non-inferiority margins. DVD-C was equivalent to TC for uptake of genetic testing (d=-3%; lower/upper 97.5% CI -7.9%/1.7%) and superior for counselling time (20.4 (CI 18.7 to 22.2) min reduction (p<0.005)). 98% people found the DVD length and information satisfactory. 85-89% felt it improved their understanding of risks/benefits/implications/purpose of genetic testing. 95% would recommend it to others. The cost of genetic counselling for DVD-C=7787 pound and TC=17 pound 307. DVD-C resulted in cost savings=9520 pound (14 pound/volunteer).Conclusions DVD-C is an effective, acceptable, non-inferior, time-saving and cost-efficient alternative to TC.