BACKGROUND:Filamin-C (FLNC) gene variants are associated with cardiac and skeletal muscle diseases including a clear role of loss-of-function variants in dilated cardiomyopathy. OBJECTIVE:This study aimed to assess the contribution of rare FLNC variants to hypertrophic cardiomyopathy (HCM)/restrictive cardiomyopathy (RCM). METHODS:Family-based studies in 2 specialist services and statistical modeling of rare FLNC missense variants were conducted, using a cohort of 3289 sarcomere-negative HCM cases and 122,348 genome aggregation database controls. RESULTS:Clinical evaluation of patients with HCM/RCM and a rare FLNC variant identified a distinct electrocardiographic (ECG) repolarization phenotype in 37% (19 of 51 individuals, from 12 families), which was observed in only 1.0% of a control HCM cohort (2 of 197). FLNC variant carriers with the characteristic ECG had smaller left ventricular cavity size, lower contractility, and more severe diastolic dysfunction and were more likely to have a restrictive phenotype. Heart failure death, transplant, or cardiac arrest occurred in at least 1 individual in 7 of the 12 families (58%) in the "ECG-positive" group, and musculoskeletal abnormalities were present in 4 families (33%). 5 of 12 variants (41.7%) in the "ECG-positive" group cosegregated, and 2 were apparently de novo. 11 variants were missense, and 1 splice site. Rare FLNC missense variant burden indicated a low case excess among all HCM cases (etiologic fraction, 0.45; 95% confidence interval, 0.36-0.54), but in "ECG-positive" cases the etiologic fraction was substantially higher (0.98; 95% confidence interval, 0.97-0.99). CONCLUSION:Pathogenic FLNC variants in patients with HCM/RCM are nontruncating and cause a discrete phenotype comprising a characteristic ECG, hypertrophic and restrictive features without hypercontractility, and extracardiac abnormalities.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.

BACKGROUND AND AIMS:Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. METHODS:An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. RESULTS:A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80-30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06-5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27-3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35-9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08-.23). CONCLUSIONS:Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

The ALPK3 gene encodes alpha-protein kinase 3, a cardiac pseudo-kinase of unknown function. Heterozygous truncating variants (ALPK3tv) can cause dominant adult-onset hypertrophic cardiomyopathy (HCM). Here we confirm an excess of ALPK3tv in sarcomere-gene negative HCM patients. Moreover, we generated a novel knock-in mouse model carrying an ALPK3tv (K201X). Homozygous animals displayed hypertrophy and systolic dysfunction. Heterozygous animals demonstrated no obvious baseline; however, they had an aggravated hypertrophic response upon chronic adrenergic challenge. Isolated, unloaded cardiomyocytes from heterozygous and homozygous mice showed reduced basal sarcomere length with prolonged relaxation, whilst calcium transients showed increased diastolic calcium levels. Protein kinase A-mediated phosphorylation, including that of cardiac troponin I, was significantly decreased. In agreement with the cellular HCM phenotype, reduced ratios of myosin heads in the super-relaxed state were measured. Contractile and calcium handling defects were partly corrected by treatment with mavacamten, a novel myosin inhibitor. For the first time with a non-sarcomere HCM variant, we have demonstrated hallmark changes in cardiac contractility and calcium handling. Mavacamten is able to partially rescue the cellular phenotype, hence could be beneficial to HCM patients with ALPK3tv. Moreover, our data points at a potential role of ALPK3 as a modulator of protein kinase A signalling.

Purpose: Participants in the 100,000 Genomes Project, a clinical/research initiative delivered through the UK National Health Service, were offered screening for " additional fi ndings " (AFs): pathogenic/likely pathogenic secondary fi ndings in genes associated with familial hypercholesterolemia or a cancer predisposition syndrome. Understanding the psychological and behavioral responses to secondary fi ndings can inform the clinical utility of a search and disclose policy. Methods: Thirty-two adult AF recipients took part in semi -structured interviews analyzed using deductive and inductive thematic analysis. Results: Five themes were constructed: cognitive responses to an AF, emotional and psychological responses, personal control, perceived risk of AF -associated disease, and family implications. Many participants had misunderstood or incompletely remembered consent for AFs, and most were surprised or shocked to receive an AF. Although many ultimately appreciated knowing about the risk conferred, some struggled to make sense of their disease risk, which complicated decision making about risk management, particularly for women with a BRCA AF. Recipients sought control through seeking clinical evaluation and information, and informing relatives. Dif fi culties with conceptualizing risk and lack of AFassociated disease family history meant that some hesitated to inform relatives. Conclusion: Genome sequencing programs offering secondary fi ndings require attention to consent processes. Post -disclosure care should aim to promote recipients ' perceived personal control. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. Methods: An observational study in an area representing one-fifth of England. Results: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During postdisclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost 1.4m; pound 8680 pound per clinically significant AF. Conclusion: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings. Crown Copyright 2023 Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

AbstractA substantial proportion of mutations underlying rare Mendelian diseases remain unknown, potentially because they lie in the non-coding genome. Here, we report the mapping of the causal mutation of an autosomal dominant cardiac arrhythmia syndrome, ST Depression Syndrome, which is associated with widespread ST-depression on the electrocardiogram together with risk of sudden death and heart failure, to the non-coding region of theKCNB1locus. Using genetic linkage analysis, we narrowed the associated region to 1cM of the genome and then with a genome editing approach, we show that the mutation, a small complex insertion-deletion, generates ade novogain-of-function enhancer that drives higher expression ofKCNB1in cardiomyocytes. This is the first report of a gain ofde novoenhancer function causing Mendelian disease. Critically, the tissue-specific gain-of-function regulatory change could be predicted using a deep neural network. Application of a similar framework will enable identification of causal non-coding mutations and affected genes in other rare diseases.

Cardiomyopathies are a group of inherited heart muscle disorders. Expressivity is variable and while sometimes mild, complications can result in sudden cardiac death (SCD) at any age, heart failure and stroke. In around a third of patients a monogenic cause is identifiable, and development of genetic therapies that aim to correct the underlying genetic defect is underway. Here we describe results of a survey designed to understand preliminary views of the patient community about genetic therapies in the context of disease burden. The internet survey was publicized with a bespoke information video via patient support groups in the UK and USA; 634 people responded of whom 96% had a personal and/or family history of cardiomyopathy. Findings show that concern about cardiomyopathy-related issues with a future dimension, such as disease progression, is significantly greater than concern about current issues. A total of 93.6% thought that genetic therapies should be developed for cardiomyopathy. A majority would consider participation in a genetic therapy trial in six scenarios varying by age and clinical situation significantly more in the scenario of an adult with symptomatic disease and evident progression than an asymptomatic adult with SCD risk, or a child. In all scenarios, a majority said that the chance genetic therapy would stop or slow progression, and risk of serious adverse and unintended effects, were important considerations. Qualitative analysis of free-text responses found that concern was often informed by family experience. Patient consideration of genetic therapy is likely to require individualized assessment of the benefits and risks.

An increasing number of European research projects return, or plan to return, individual genomic research results (IRR) to participants. While data access is a data subject's right under the General Data Protection Regulation (GDPR), and many legal and ethical guidelines allow or require participants to receive personal data generated in research, the practice of returning results is not straightforward and raises several practical and ethical issues. Existing guidelines focusing on return of IRR are mostly project-specific, only discuss which results to return, or were developed outside Europe. To address this gap, we analysed existing normative documents identified online using inductive content analysis. We used this analysis to develop a checklist of steps to assist European researchers considering whether to return IRR to participants. We then sought feedback on the checklist from an interdisciplinary panel of European experts (clinicians, clinical researchers, population-based researchers, biobank managers, ethicists, lawyers and policy makers) to refine the checklist. The checklist outlines seven major components researchers should consider when determining whether, and how, to return results to adult research participants: 1) Decide which results to return; 2) Develop a plan for return of results; 3) Obtain participant informed consent; 4) Collect and analyse data; 5) Confirm results; 6) Disclose research results; 7) Follow-up and monitor. Our checklist provides a clear outline of the steps European researchers can follow to develop ethical and sustainable result return pathways within their own research projects. Further legal analysis is required to ensure this checklist complies with relevant domestic laws.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) as sociated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene,SVIL, which encodes the actin-binding protein supervillin, showing that rare truncatingSVILvariants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.

Public and patient involvement (PPI) - the collaboration in research with members of the public and patients with relevant experience - is becoming well established in health service research in the UK. It is supported by funders and academic institutions. Published principles and guidelines for researchers, developed through consultation and consensus building, are available. Meanwhile, as genome sequencing is adopted into routine health care, translational genomics research and research to evaluate new genomic services are growing. Given the ethical and social implications of offering genome sequencing within a national health service, it is important that researchers give full consideration to planning and implementing meaningful PPI. Here we present five case studies of PPI in a variety of clinical genomic studies, including commentary on positive impacts and suggestions for improvements. We call for funders and academic institutions to continue and increase their efforts to enable and promote PPI across genomic and other health service research.

Background Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. Methods We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. Results Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. Conclusions Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.

Direct-to-consumer genetic tests (DTC-GT) offer a variety of genetic health risk information. Understanding evidence of impacts is required for effective policy to protect consumers and healthcare services. We undertook a systematic review according to PRISMA guidelines, searching five literature databases for articles assessing analytic or clinical validity, or reporting consumer or healthcare professional experience with health risk information derived from DTC-GT, published between November 2014 and July 2020. We performed a thematic synthesis to identify descriptive and analytical themes. Forty-three papers met inclusion criteria. Many consumers submit raw DTC-GT data for third-party interpretation (TPI). DTC-GT sometimes report 'false positive' or incorrectly interpreted rare variants, or that such information can result from TPI. Consumers have high expectations of DTC-GT and TPI, and are broadly satisfied, although many do not act on results. A minority of consumers experience adverse psychological impacts. Healthcare consultations can be complex, and professionals have reservations about the validity and utility of DTC-GT-derived information. The contrast between consumer and health professional perceptions can result in mutual dissatisfaction with consultations. Health risk information from DTC-GT and TPI is broadly valued by consumers but presents complex challenges for healthcare services and some consumers.

Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.

The right ventricle (RV) in hypertrophic cardiomyopathy (HCM) tends to be neglected, as previous efforts have predominantly focused on examining the prognostic value of left ventricular (LV) abnormalities. The objectives of this study were to assess RV function in HCM, changes over time, and association with clinical outcomes. Two hundred and ninety HCM patients with preserved LV ejection fraction (LVEF ≥ 55%) and 30 age- and sex-matched controls underwent cardiovascular magnetic resonance (CMR). All patients were followed up for clinical events for a median duration of 4.4 years. Sixty-three patients had a follow-up CMR undertaken at a median interval of 5.4 years. Main study measures and outcomes were RV function (RV ejection fraction (RVEF) and RV strain) at baseline, temporal changes in RV function over time and prognostic value of RV dysfunction for predicting cardiovascular outcomes in HCM. When compared to controls, HCM patients exhibited lower RV and LV peak global longitudinal systolic strains on feature-tracking analysis of cine images, while RVEF and LVEF were within the normal range. On follow-up CMR, both RV and LV strain parameters decreased over time. RVEF decreased at follow-up (65 ± 7% to 62 ± 7%, P < 0.001) but the change in LVEF was not significant (68 ± 10% to 66 ± 8%, P = 0.30). On clinical follow up, reduced RVEF was an independent predictor of non-sustained ventricular tachycardia (NSVT) [HR 1.10 (95% CI 1.06–1.15), P < 0.001] and composite cardiovascular events (NSVT, stroke, heart failure hospitalisation and cardiovascular death) [HR 1.07 (95% CI 1.03–1.10), P < 0.001]. RV longitudinal strain was an independent predictor of NSVT [HR 1.05 (95% CI 1.01–1.09), P = 0.029]. Patients with RVEF < 55% showed an increased risk of NSVT and composite cardiovascular events. In contrast, LVEF and LV global longitudinal strain were not predictive of such events on multivariable analysis. In HCM, RV function, including RV strain, and LV strain decrease over time despite preserved LVEF. Reduction in RV but not LV function is associated with adverse cardiovascular outcomes. Assessing RV function in early HCM disease might have a role in risk stratification to prevent future cardiovascular events.

Abstract An increasing number of European research projects return, or plan to return, individual genomic research results (IRR) to participants. While data access is a data subject’s right under the GDPR, and many legal and ethical guidelines allow or require participants to receive personal data generated in research, the practice of returning results is not straightforward and raises several practical and ethical issues. Existing guidelines focusing on return of IRR are mostly project-specific, only discuss which results to return, or were developed outside Europe. To address this gap, we analysed existing normative documents identified online using inductive content analysis. We used this analysis to develop a checklist of steps to assist European researchers considering whether to return IRR to participants. We then sought feedback on the checklist from an interdisciplinary panel of European experts (clinicians, clinical researchers, population-based researchers, biobank managers, ethicists, lawyers and policy makers) to refine the checklist. The checklist outlines seven major components researchers should consider when determining whether, and how, to return results to adult research participants: 1) Consider which results to return; 2) Develop a plan for return of results; 3) Obtain participant informed consent; 4) Collect and analyse data; 5) Confirm results; 6) Disclose research results; 7) Follow-up and monitor. Our checklist provides a clear outline of the steps European researchers can follow to develop ethical and sustainable result return pathways within their own research projects. Further legal analysis is required to ensure this checklist complies with relevant domestic laws.

Background: A novel familial arrhythmia syndrome, cardiac ryanodine receptor (RyR2) calcium release deficiency syndrome (CRDS), has recently been described. We evaluated a large and well characterized family to assess provocation testing, risk factor stratification and response to therapy in CRDS. Methods: We present a family with multiple unheralded sudden cardiac deaths and aborted cardiac arrests, primarily in children and young adults, with no clear phenotype on standard clinical testing. Results: Genetic analysis, including whole genome sequencing, firmly established that a missense mutation in RYR2, Ala4142Thr, was the underlying cause of disease in the family. Functional study of the variant in a cell model showed RyR2 loss-of-function, indicating that the family was affected by CRDS. EPS (Electrophysiological Study) was undertaken in 9 subjects known to carry the mutation, including a survivor of aborted sudden cardiac death, and the effects of flecainide alone and in combination with metoprolol were tested. There was a clear gradation in inducibility of nonsustained and sustained ventricular arrhythmia between subjects at EPS, with the survivor of aborted sudden cardiac death being the most inducible subject. Administration of flecainide substantially reduced arrhythmia inducibility in this subject and abolished arrhythmia in all others. Finally, the effects of additional metoprolol were tested; it increased inducibility in 4/9 subjects. Conclusions: The Ala4142Thr mutation of RYR2 causes the novel heritable arrhythmia syndrome CRDS, which is characterized by familial sudden death in the absence of prior symptoms or a recognizable phenotype on ambulatory monitoring or exercise stress testing. We increase the experience of a specific EPS protocol in human subjects and show that it is helpful in establishing the clinical status of gene carriers, with potential utility for risk stratification. Our data provide evidence that flecainide is protective in human subjects with CRDS, consistent with the effect previously shown in a mouse model.

BACKGROUND:The causes of cardiomyopathy in children are less well described than in adults. We evaluated the clinical diagnoses and genetic causes of childhood cardiomyopathy and outcomes of cascade genetic testing in family members.METHODS:We recruited children from a pediatric cardiology service or genetic heart diseases clinic. We performed Sanger, gene panel, exome or genome sequencing and classified variants for pathogenicity using American College of Molecular Genetics and Genomics guidelines.RESULTS:Cardiomyopathy was diagnosed in 221 unrelated children aged ≤18 years. Children mostly had hypertrophic cardiomyopathy (n=98, 44%) or dilated cardiomyopathy (n=89, 40%). The highest genetic testing diagnostic yields were in restrictive cardiomyopathy (n=16, 80%) and hypertrophic cardiomyopathy (n=65, 66%), and lowest in dilated cardiomyopathy (n=26, 29%) and left ventricular noncompaction (n=3, 25%). Pathogenic variants were primarily found in genes encoding sarcomere proteins, with TNNT2 and TNNI3 variants associated with more severe clinical outcomes. Ten children (4.5%) had multiple pathogenic variants. Genetic test results prompted review of clinical diagnosis in 14 families with syndromic, mitochondrial or metabolic gene variants. Cascade genetic testing in 127 families confirmed 24 de novo variants, recessive inheritance in 8 families, and supported reclassification of 12 variants.CONCLUSIONS:Genetic testing of children with cardiomyopathy supports a precise clinical diagnosis, which may inform prognosis.

European Journal of Cancer CareVolume 31, Issue 3 e13584 COMMENTARYOpen Access Genomic sequencing in oncology: Considerations for integration in routine cancer care Belinda Rahman, Belinda Rahman Radcliffe Department of Medicine, University of Oxford, Oxford, UK NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UKSearch for more papers by this authorAlastair Lamb, Alastair Lamb Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK Department of Urology, Oxford University Hospitals NHS Foundation Trust, Oxford, UKSearch for more papers by this authorAndrew Protheroe, Andrew Protheroe Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK Department of Oncology, University of Oxford, Oxford, UKSearch for more papers by this authorKetan Shah, Ketan Shah Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK Department of Oncology, University of Oxford, Oxford, UKSearch for more papers by this authorJoyce Solomons, Joyce Solomons Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UKSearch for more papers by this authorJonathan Williams, Jonathan Williams Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UKSearch for more papers by this authorElizabeth Ormondroyd, Corresponding Author Elizabeth Ormondroyd liz.ormondroyd@cardiov.ox.ac.uk orcid.org/0000-0002-9116-4064 Radcliffe Department of Medicine, University of Oxford, Oxford, UK NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK Correspondence Elizabeth Ormondroyd, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. Email: liz.ormondroyd@cardiov.ox.ac.ukSearch for more papers by this author Belinda Rahman, Belinda Rahman Radcliffe Department of Medicine, University of Oxford, Oxford, UK NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UKSearch for more papers by this authorAlastair Lamb, Alastair Lamb Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK Department of Urology, Oxford University Hospitals NHS Foundation Trust, Oxford, UKSearch for more papers by this authorAndrew Protheroe, Andrew Protheroe Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK Department of Oncology, University of Oxford, Oxford, UKSearch for more papers by this authorKetan Shah, Ketan Shah Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK Department of Oncology, University of Oxford, Oxford, UKSearch for more papers by this authorJoyce Solomons, Joyce Solomons Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UKSearch for more papers by this authorJonathan Williams, Jonathan Williams Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UKSearch for more papers by this authorElizabeth Ormondroyd, Corresponding Author Elizabeth Ormondroyd liz.ormondroyd@cardiov.ox.ac.uk orcid.org/0000-0002-9116-4064 Radcliffe Department of Medicine, University of Oxford, Oxford, UK NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK Correspondence Elizabeth Ormondroyd, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. Email: liz.ormondroyd@cardiov.ox.ac.ukSearch for more papers by this author First published: 05 April 2022 https://doi.org/10.1111/ecc.13584 [Correction added on 27 April, after first online publication: The first name of the sixth author was corrected in this version.] AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat 1 INTRODUCTION In the United Kingdom (UK), efforts to incorporate genome sequencing into clinical care were significantly boosted by implementation of the 100,000 Genomes Project in 2014. The UK now transitions to the next phase of delivering genomic sequencing within the National Health Service (NHS) via the Genomic Medicine Service (GMS). A National Genomic Test Directory has been developed to specify the genomic tests that can be ordered and funded by the NHS, including testing criteria, scope and technology. Mainstreaming of genomic sequencing is a key component of the GMS which enables multispecialty clinicians, including oncologists, to directly order specific genomic tests aimed at improving access to testing for their patients. In practice, how genomic sequencing will be adopted and used within oncology remains unclear. A systematic review of factors for successful implementation of genomic medicine in routine health care identified the need for practice reform, genomics education and training, validation of clinical utility and cost-effectiveness, and adaptations to models of care (Pearce et al., 2019). In particular, the integration of genomics into mainstream oncology will require '… upskilling other healthcare professionals in genomics' to manage genomic testing capacity, interpretation of results and implementation of changes in clinical care (Bancroft et al., 2020). Healthcare professionals' views on the implementation of genomic sequencing into NHS clinical practice reported several concerns including lack of preparedness of non-genetics clinicians (Sanderson et al., 2019). This commentary reflects on some of the factors to consider for integrating genomic sequencing in oncology and how they may impact the roles of the health professionals involved. 2 CLINICIAN UPTAKE OF GENOMIC SEQUENCING Whilst integration of genomics into standard NHS care will be transformational, practice of genomic genomic medicine and optimal utilisation of genomic information needs to be established in oncology. Factors such as perceived utility and confidence influence the uptake of genomic medicine by non-genetics specialists (Crellin et al., 2019). As noted, 'Their [clinicians'] perception of the utility of genomic testing, then, will be an important determinant of whether it sees widespread uptake into clinical medicine' (Raghavan & Vassy, 2014). There may be uncertainty amongst clinicians as to the role of genomic medicine in improving patient care beyond current clinical practice (Crellin et al., 2019; Zebrowski et al., 2019). The lack of clear treatment guidelines for somatic testing and referral guidance for germline testing has been seen as barriers to uptake (Vetsch et al., 2019). For some cancer types, there is proven clinical utility of genomic medicine; a persuasive example of this has been the recent development and licencing of PARP-inhibitors for somatic or germline mutated high grade serous ovarian cancer. Whilst there are other promising advances, currently genomic sequencing identifies a minority of patients with actionable genetic alterations where corresponding targeted therapies are available and approved for use in their specific condition (Berger & Mardis, 2018). In part, this is due to the lack of treatments that are available for use beyond their labelled indication, leading to a reliance on clinical trials or expanded access programmes; currently, it may be difficult to access drugs outside of their licenced indications regardless of the mode of action of the drug. 3 GENOMICS KNOWLEDGE AND CONFIDENCE There is a growing body of literature around oncologists' genomics knowledge and confidence. Oncology clinicians report some confidence regarding genomics; however, nearly a quarter indicated lack of confidence in their knowledge of genomics and ability to make treatment recommendations based on genomic data (Gray et al., 2014). Furthermore, a third of medical oncologists did not feel confident communicating personalised genomic results to their patients (Chow-White et al., 2017). In the context of paediatric oncology, confidence in the interpretation, use and discussion of both somatic and germline oncology testing-based genomic test results was low (Johnson et al., 2017). A recent survey found oncologists were more confident in using single-gene tests and less confident in using whole genome or exome sequencing to guide patient care (de Moor et al., 2020). Involvement with genomics-based research and/or teaching may influence familiarity and confidence with genomics. Knowledge scores, perceived understanding and preparedness for genomic testing were higher amongst clinicians with a parallel academic role (Innocent et al., 2014). Similarly, oncologists practising outside major metropolitan areas reported less knowledge about new genetic technologies (Chow-White et al., 2017). High genomic confidence has also been associated with specific clinical roles such as being a medical oncologist or researcher-clinician (Gray et al., 2014). 4 EXPANDING CLINICAL ROLES TO SUPPORT GENOMIC SEQUENCING Clinical geneticists and genetic counsellors, with training and expertise in both genetics, genomics and counselling skills, are '… ideally placed to educate and support other healthcare professionals delivering genomic medicine' (Kohut et al., 2019), particularly in managing pathogenic germline variants, variants of unknown significance and secondary findings. Developments in genomic sequencing, introduction of the new GMS and expansion of mainstreaming approaches to testing in the UK are increasingly impacting the role of genetic counsellors and the context in which they practice (Patch & Middleton, 2018, 2019). More genetic counsellors are undergoing training in variant interpretation to assist in managing the vast amounts of data generated from genome sequencing (Wain et al., 2020). With genomic sequencing largely focusing on acquired variants from somatic testing, genetic counsellors may also need to develop expertise in paired tumour-normal genomics. Embedding clinical geneticists and genetic counsellors in oncology clinics and departments, possibly with supplementary oncology training, may facilitate mainstreaming approaches. In the UK, the NHS has described nurses as being key to the implementation of the GMS across health services (NHS Health Education England, 2020); some oncology centres have already moved to nurse-led services for providing mainstreamed BRCA germline testing in breast and ovarian cancers (Percival et al., 2016). In order to support this role, nurses need strong foundations in genetics and genomics. However, research has shown low levels of genomic literacy and confidence amongst nurses in using genomics (Wright et al., 2018). Despite the development of educational resources and core competencies for integrating genomics into nursing practice (Kirk et al., 2014), key education challenges remain, such as lack of curriculum time and insufficient number of educators. Other reported barriers included limited access and resources for clinical decision support and clinical implications of genetic variation. 5 INTERPRETING GENOMIC SEQUENCING DATA Interpretation of genomic data is increasingly complex; the functional impact of genomic alterations—clinically relevant mutations—must be assessed for actionability and therapeutic options. Due to the complexity of reports and data produced from sequencing, misinterpretation by non-genetics specialists may lead to inappropriate estimation of disease risk and/or further diagnostic tests (Vassy et al., 2015). Genomic 'knowledge banks' which catalogue matched genomic-clinical data may support genomic data interpretation and clinical decision-making, although they do not replace expert analysis and guidance. An emerging group of non-medical specialists who will play a key role in the interpretation and translation of cancer genomics are scientists specifically trained in clinical application of these technologies, known in the UK as Clinical Scientists (Carretero-Puche et al., 2020). With data science, computational and biomedical expertise, clinical scientists integrate genomic sequencing and clinical data producing genomic reports to inform therapeutic decision-making. These roles will be in demand in hospital settings, and close collaboration with oncology health professionals in multidisciplinary contexts is crucial to harnessing the potential of genomic data for cancer patients, although greater recognition of this role from clinicians may be needed (Gomez-Lopez et al., 2019). 6 NEW APPROACHES TO MULTIDISCIPLINARY WORKING A multidisciplinary approach combining expertise from genomics, clinical genetics, oncology, pathology and clinical science is central to delivering effective, timely and high-quality care for cancer patients and families. Harnessing these disciplines via 'molecular tumour boards' (MTBs) is vital to support the implementation of genomic sequencing data in oncology (van de Haar et al., 2019). This may also impact clinical practice; oncologists reported greater confidence in interpreting tumour genome sequencing results at centres with dedicated MTBs (Gingras et al., 2016). MTBs provide an integrated setting to draw together these diverse clinical and scientific roles and encourage collaborative exchange. However, there are implementation challenges such as resource, capacity and lack of standard guidelines for MTB function, testing and tools (van der Velden et al., 2017). In the UK, multidisciplinary clinical meetings, typically comprising surgical, medical and clinical oncologists, radiologists and pathologists, are already commonplace. How MTBs could supplement, rather than be in addition to, these meetings to incorporate genomic medicine in clinical decision-making requires consideration. This is an exciting time for genomic medicine with continuing clinical and technological advances. The implementation of the national GMS is an important step towards delivering equitable access to genomic testing and developing high quality personalised care for patients and families in the UK. One of the key factors in achieving effective integration of genomic medicine in routine care is readiness and ability of key professionals to embrace and drive this transformation. Continued education and support as well as collaborative and multidisciplinary working are essential to fully harness the benefits of genomic medicine for cancer patients. ACKNOWLEDGEMENT We would like to thank Dr David Church for his insight into this article. CONFLICT OF INTEREST All authors declare no conflict of interest. FUNDING INFORMATION This work was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Open Research DATA AVAILABILITY STATEMENT Data sharing is not applicable to this article as no new data were created or analysed in this paper. REFERENCES Bancroft, E. K., Kohut, K., & Eeles, R. A. (2020). 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