From Genotype to Phenotype
2018; Wolters Kluwer; Volume: 11; Issue: 10 Linguagem: Inglês
10.1161/circgen.118.002316
ISSN2574-8300
AutoresMichael P. Mackley, Karen McGuire, Jenny C. Taylor, Hugh Watkins, Elizabeth Ormondroyd,
Tópico(s)Genetics and Neurodevelopmental Disorders
ResumoHomeCirculation: Genomic and Precision MedicineVol. 11, No. 10From Genotype to Phenotype Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBFrom Genotype to PhenotypeClinical Assessment and Participant Perspective of a Secondary Genomic Finding Associated with Long QT Syndrome Michael Mackley, DPhil, Karen McGuire, BSc, Jenny Taylor, DPhil, Hugh Watkins, MD, PhD and Elizabeth Ormondroyd, PhD, MSc Michael MackleyMichael Mackley Division of Cardiovascular Medicine, Radcliffe Department of Medicine (M.M., H.W., E.O.), University of Oxford, United Kingdom. , Karen McGuireKaren McGuire Oxford University Hospitals NHS Foundation Trust, United Kingdom (K.M.). , Jenny TaylorJenny Taylor Wellcome Trust Centre for Human Genetics (J.T., H.W.), University of Oxford, United Kingdom. National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom (J.T., H.W., E.O.). , Hugh WatkinsHugh Watkins Division of Cardiovascular Medicine, Radcliffe Department of Medicine (M.M., H.W., E.O.), University of Oxford, United Kingdom. Wellcome Trust Centre for Human Genetics (J.T., H.W.), University of Oxford, United Kingdom. National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom (J.T., H.W., E.O.). and Elizabeth OrmondroydElizabeth Ormondroyd Elizabeth Ormondroyd, PhD, MSc, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Level 6, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU United Kingdom. Email E-mail Address: [email protected] Division of Cardiovascular Medicine, Radcliffe Department of Medicine (M.M., H.W., E.O.), University of Oxford, United Kingdom. National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom (J.T., H.W., E.O.). Originally published15 Oct 2018https://doi.org/10.1161/CIRCGEN.118.002316Circulation: Genomic and Precision Medicine. 2018;11:e002316Genomic variants associated with inherited cardiac conditions (ICC) yet detected incidentally (secondary findings [SF]) are likely to arise with increasing frequency as genome sequencing (GS) transitions into clinical practice. Because genotyping has until recently been directed by clinical diagnosis, assessment and management of individuals found to harbor such a variant as a SF are unclear. Here, we illustrate some diagnostic and psychosocial complexities of ICC SF, exemplified by disclosure of a pathogenic variant in KCNQ1, associated with long QT syndrome (LQTS), to a healthy male enrolled in diagnostic GS as an unaffected relative. This early case represents a shift from phenotype-to-genotype to genotype-to-phenotype; we describe clinical evaluation, family history, and a qualitative research interview with the SF recipient, discuss the role of specialist services in variant interpretation, genetic counseling, and clinical assessment, and some challenges of realizing improved health outcomes after disclosure of a SF.SF and ICCGS is an approach for investigation of suspected monogenic conditions and for population studies exploring the contribution of genomic variation to health and disease.1 Screening for and feedback of SF—variants believed to be associated with serious Mendelian health conditions unrelated to the indication for sequencing—are a subject of ongoing debate. Unresolved issues include participant/patient autonomy, clinical utility, and justice.2 Studies of a range of patients, participants, and the public find widespread support for disclosure of SF that relate to potentially actionable disease3 although in practice, a smaller majority choose return of SF than when asked hypothetically.4,5 Alongside clinical GS programmes, such as the UK 100 000 Genomes Project (www.genomicsengland.co.uk), an increasing number of initiatives are beginning to consider the handling of SF in healthy sequenced populations.SF disclosure outcomes, including disease-variant association and behavioral and psychosocial impacts, are expected to inform policy; in advance of this evidence, diverse guidelines and policies have emerged.6 For example, the American College for Medical Genetics and Genomics recommend screening for variants implying risk of potentially life-threatening disease for which intervention is available, in all individuals undergoing clinical GS.7 The American College for Medical Genetics and Genomics recommendation includes a benchmark list of genes, the majority of which are associated with either inherited cardiac disease, which can present as fatal arrhythmia at any age, or cancer predisposition. Inherited cardiac conditions (ICC), including hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmia right ventricular cardiomyopathy, and LQTS, are relatively common (in aggregate ≈1 in 250). These conditions are usually autosomal dominant and genetically heterogeneous, with variable penetrance and expressivity within and between families. Genetic testing and family screening, clinical evaluation based on cardiac imaging and ECG, and risk stratification for sudden cardiac death are well established in clinical practice.8 Individuals at risk of sudden cardiac death can be managed through a combination of lifestyle advice, medical therapy, and implantation of a cardiac defibrillator.Informed variant interpretation underpins clinical genetic testing and is considered key to SF screening and feedback policy2; current practice is aided by large population data sets, such as the Exome Aggregation Consortium cohort and the Genome Aggregation Database,9 and by efforts to establish consistency in classification.10,11 However, until now, genetic testing in inherited disease has been directed by phenotype,10 and existing genotype-phenotype data come almost exclusively from individuals and families with manifest disease. In this setting, the prior probability that a potentially pathogenic variant in a relevant gene is actually pathogenic is high, and the variant in question is, by definition, penetrant at least in the proband. In contrast, phenotype correlation with genotype in unselected populations is largely unknown, and there are indications that penetrance and interpretability of variants may be lower; population prevalence of variants previously considered pathogenic and penetrant is much higher than would be compatible with known disease prevalence.12Clinical CaseGenomic AnalysisB.J. enrolled in GS via a purpose-designed protocol Molecular Genetic Analysis and Clinical Studies of Individuals and Families at Risk of Genetic Disease (MGAC, REC reference 13/WM/0466),13 with the aim of identifying a cause for his child's rare disease. SF policy in MGAC uses an opt-in approach based on the original American College for Medical Genetics and Genomics gene list,7 offered to adult participants. Genomic analysis was targeted to genes associated with the primary condition and American College for Medical Genetics and Genomics gene list.A deletion of 5 base pairs in exon 3 of KCNQ1 was detected in B.J.'s sample. This variant (NM_000218.2 c.573_577del p.R192Cfs*91, genomic location Chr11:hg19:g.2591953_2591957) creates a frame shift with new reading frame ending in a stop codon 91 amino acids downstream. KCNQ1 encodes the α subunit of the slowly activating voltage-gated potassium ion channel and contributes up to 49% of putative pathogenic variants in genetically confirmed LQTS cases.14 Approximately 20% of KCNQ1 variants are predicted to lead to haploinsufficiency, which is a known mechanism of disease associated with a lower risk of cardiac events in patients with LQTS.15 Using current guidelines, supplemented by in-house data from >1500 LQTS gene tests, our accredited National Health Service laboratory interpreted the variant as highly likely pathogenic. The variant was present in 4 individuals with LQTS in the Oxford cohort (with limited segregation data) and has been reported in families and individuals with LQTS16–18 and as a homozygous variant in individuals with Jervell and Lange-Nielsen syndrome.17 The variant is present in genome aggregation database (release 2.0.1) at frequency 0.0016%.The University Hospital Genomic Medicine multidisciplinary team agreed that the variant should be reported. B.J. was informed by his child's clinical geneticist by prearranged web discussion and referred to a specialist ICC clinic for genetic counseling and clinical assessment (Figure 1).Download figureDownload PowerPointFigure 1. Timeline of events. ICC indicates inherited cardiac condition; MDT, multidisciplinary team; and SF, secondary finding.Clinical AssessmentB.J. is an apparently healthy male aged 39 years, with no significant medical history. His occupation is moderately physically demanding in a regulated environment; recreationally, he is a competitive track cyclist who trains intensively 1 to 4 hours, 6 days per week.ECG showed sinus (athletic) bradycardia, rate 37 beats per minute with normal axis and normal conduction. The pattern of repolarization was broadly normal but with a prominent U wave. Absolute QT value 498, QTc using Bazett formula 390 (Figure 2A). A 24-hour Holter monitor showed QT intervals corrected to within the normal range. During an exercise stress test, B.J. achieved 2 minutes of stage VII of Bruce protocol with no arrhythmias. Peak heart rate response low (164 bpm), and heart rate slowing delayed in recovery. QT interval did not show expected shortening during exercise and was prolonged in recovery: 4 minutes into recovery (a time point proposed to have sensitivity and specificity for detecting manifestations of LQT1 genotype) QT was just over 400 ms at heart rate 105 bpm, QTc using Bazett formula 529 (Figure 2B). Cardiac multidisciplinary team discussion concluded that these changes are consistent with a LQT1 phenotype albeit with normal QT interval at rest.Download figureDownload PowerPointFigure 2. Participant electrocardiograms.A, Resting 12 lead. B, Four minutes into recovery after exercise stress test.In light of these results, B.J. was advised to moderate his training, limiting to ≈three quarters of peak work rate; not compete; avoid potentially QT prolonging medication, and begin a noncardioselective β-blocker.Family HistoryB.J. is 1 of 3 healthy offspring, all of whom have children, of living parents. B.J. was unaware of any syncope, sudden or unexplained death in the family. Cascade genetic counseling and testing was offered to B.J.'s parents; his mother reported the death of her parent—who took prescription barbiturates—during sleep aged mid-40s. B.J.'s mother tested positive for the variant. She is asymptomatic and has a normal resting ECG. Further clinical investigations and cascade testing in other relatives are ongoing.Psychological, Behavioral, and Financial ImpactsAfter disclosure, a semistructured interview was undertaken exploring understanding, perception, and behaviors (consent under MGAC protocol). The interview guide was based on psychosocial literature on genetic risk19 and clinical experience. The interview was audiorecorded and transcribed verbatim. The transcript was analyzed thematically.20B.J.'s initial reaction to the disclosure was disbelief. The suggestion of a cardiac condition was incompatible with his perception of self and conflicted with his level of fitness and lack of symptoms. B.J. described an episode of acute distress between disclosure and specialist clinic appointment. Although his recall of electing to receive SF was partial, he had clear recall of the disclosure conversation and subsequent discussions in the specialist clinic. While acknowledging that sudden cardiac death can occur in young individuals, he was sceptical of his own potential risk. He considered that the SF had impacted him primarily through the implication that training and competitive cycling presented additional, yet unquantifiable, risk. He feared a sudden unheralded collapse while cycling, comparing that with the perceived controllability of avoiding a collision.B.J. did not regret his decision to receive SF and appreciated that the disclosure had occurred after he had already enjoyed many years' competing. Throughout the interview, B.J. displayed reiterative, personally inconclusive evaluation of his risk; he described contacting sports scientists and visiting online forums. This was apparently driven by a sense of responsibility to his family. His provisional acceptance of his risk of LQTS manifested in selective adherence to clinical recommendations: he had moderated cycling but, despite intentions at the time of interview, had not started taking protective medication.Subsequent to cardiac evaluation, B.J. was unable to obtain critical illness cover; attempts to purchase life cover for an increased mortgage were ultimately successful.DiscussionThis case represents an early example of evaluating a genomic SF. The variant and gene in question were anticipated to be relatively straightforward within the spectrum of inherited heart condition SF as the variant was well characterized and LQT1 is relatively easy to diagnose and treat. However, the case generated significant diagnostic and psychosocial challenges. Initial clinical assessment by resting ECG was reassuring; a phenotype consistent with the variant was discovered only through subsequent specialist assessment. Similarly, initial family history elicitation was reassuring; the grandparent's death—suspicious for LQTS—only came to light on cascade screening. Interventions that might ordinarily be well tolerated, avoidance of extreme exertion and taking β-blockers, proved problematic.Genomic variant interpretation is typically informed by phenotype and family history in the context of a clinical diagnosis10; evidence to inform interpretation in unselected populations is awaited. Furthermore, at present, there are no guidelines on workup that should follow identification of a potentially pathogenic SF. Several large-scale projects are beginning to generate SF with consent or considering approaches to disclosure where no specific consent exists, with the result that return of SF will become frequent. The clinical utility of genetic testing depends on positive clinical, psychosocial, and behavioral outcomes.21 If clinical utility underlies the rationale for search and disclosure of SF, a relationship with clinical risk of ICC must be established. Examination of electronic medical records found no excess of disease expression (by ECG) in individuals harboring a putatively pathogenic cardiac arrhythmia gene variant,12 but further data are required, specifically specialist cardiac evaluation and family history collection.For realization of clinical utility, ascertainment of risk must be followed by consistent risk reduction actions: adherence to screening and clinical recommendations, and informing relatives. The Health Belief Model22 conceptualizes factors involved in taking action to mitigate disease risk: personal susceptibility, severity of disease consequence and wider life impacts, benefit of taking action, and perceived or experienced barriers to that action. It appears that B.J. perceives the seriousness of his diagnosis to be high but remained, at interview, unsure about his susceptibility given his prolonged endurance training and lack of symptoms. For B.J., barriers include reluctance to take β-blockers and moderation of participation in sport from which he derives multiple benefits. Reassuringly, emerging data on psychological impacts of SF disclosure,23 including LQTS-associated variants,24 suggest that recipients do not experience distress and anxiety; however, it will be important to understand factors affecting adherence in SF recipients. Rosenstock22 suggests that conflicting motives of avoidance may result when the factors outlined in the Health Belief Model are finely balanced. The individual may then vacillate between options or experience fear and anxiety. Thus, the absence of an unambiguous disease phenotype might complicate assimilation of SF and may result in requirement for psychosocial support.ConclusionsA genotype-driven approach to identification of patients with ICC may detect at-risk individuals and allow clinical or lifestyle management that is potentially lifesaving. However, this approach presents new challenges for clinical management and genetic counseling, as well as for patients. To inform guidelines and practice, systematic collection and curation of data from the return of SF are required. Gene- and variant-specific evidence from unselected populations is needed to inform estimates of penetrance and understand the phenotypic spectrum of variants discovered as SF. The immediate impact of disclosure on the recipient highlights the need to provide timely clinical review and specialist genetic counseling; wider exploration of the impact of disclosure on recipients should be undertaken. This case highlights some challenges of realizing improved health outcomes after disclosure of SF and provides insights into reasons for which clinical recommendations may not always be followed after disclosure of genomic SF.AcknowledgmentsWe thank B.J. and his family for their participation, Dr Andrea Nemeth, Dr John Taylor, and other members of the Oxford University Hospitals National Health Service Foundation Trust/University of Oxford Genomic Medicine Multidisciplinary Team and the Oxford University Hospitals NHS Foundation Trust cardiac MDT.Sources of FundingM. Mackley was funded by the Rhodes Trust and the Radcliffe Department of Medicine. Dr Ormondroyd and Dr J. Taylor are funded by National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. Dr Watkins acknowledges support from an NIHR Senior Investigator Award. The study is funded in part by the Wellcome Trust/Department of Health as part of the Health Innovation Challenge Fund (R6-388 and WT 100127). The views expressed in this manuscript are those of the authors and not necessarily of the Wellcome Trust or Department of Health.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circgenElizabeth Ormondroyd, PhD, MSc, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Level 6, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU United Kingdom. Email liz.[email protected]ox.ac.ukReferences1. Gonzaga-Jauregui C,et al. Human genome sequencing in health and disease.Annu Rev Med. 2012; 63:35–61. doi: 10.1146/annurev-med-051010-162644CrossrefMedlineGoogle Scholar2. Ormondroyd E, et al. 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The return of unexpected research results in a biobank study and referral to health care for heritable long QT syndrome.Public Health Genomics. 2013; 16:241–250. doi: 10.1159/000354105CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByTomar S, Klinzing D, Chen C, Gan L, Moscarello T, Reuter C, Ashley E and Foo R (2022) Causative Variants for Inherited Cardiac Conditions in a Southeast Asian Population Cohort, Circulation: Genomic and Precision Medicine, 15:2, (e003536), Online publication date: 1-Apr-2022. Graham M, Hallowell N, Solberg B, Haukkala A, Holliday J, Kerasidou A, Littlejohns T, Ormondroyd E, Skolbekken J and Vornanen M (2021) Taking it to the bank: the ethical management of individual findings arising in secondary research, Journal of Medical Ethics, 10.1136/medethics-2020-106941, 47:10, (689-696), Online publication date: 1-Oct-2021. Ormondroyd E, Harper A, Thomson K, Mackley M, Martin J, Penkett C, Salatino S, Stark H, Stephens J and Watkins H (2020) Secondary findings in inherited heart conditions: a genotype-first feasibility study to assess phenotype, behavioural and psychosocial outcomes, European Journal of Human Genetics, 10.1038/s41431-020-0694-9, 28:11, (1486-1496), Online publication date: 1-Nov-2020. October 2018Vol 11, Issue 10 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.118.002316PMID: 30354302 Originally publishedOctober 15, 2018 Keywordspublic policygenotypeethicsphenotypelong QT syndromePDF download Advertisement SubjectsArrhythmiasEthics and Policy
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