Family Matters

HomeCirculation: Genomic and Precision MedicineVol. 11, No. 4Family Matters Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBFamily MattersOutcomes of Hypertrophic Cardiomyopathy Family Screening Jodie Ingles, GradDipGenCouns, PhD, MPH and Christopher Semsarian, MBBS, PhD, MPH Jodie InglesJodie Ingles Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney Medical School, University of Sydney, Department of Cardiology, Royal Prince Alfred Hospital, Australia. and Christopher SemsarianChristopher Semsarian Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney Medical School, University of Sydney, Department of Cardiology, Royal Prince Alfred Hospital, Australia. Originally published16 Apr 2018https://doi.org/10.1161/CIRCGEN.118.002112Circulation: Genomic and Precision Medicine. 2018;11:e002112See Article by van Velzen et alHypertrophic cardiomyopathy (HCM) is a clinically heterogeneous disease affecting up to 1 in 200 of the general population.1 Primarily an autosomal dominantly inherited trait, first-degree relatives have a 50% risk of inheriting the underlying gene variant, though there are many examples of incomplete penetrance and variable expression. The factors that influence disease onset and severity are largely unknown, but it is a well-recognized phenomenon in HCM. Within one family there may be relatives who never develop disease, others who will present with only mild features, and tragically some will suffer the most serious outcomes of heart failure or sudden cardiac death. There is little to guide the discussion with families before a decision to undergo cascade genetic testing, and evidence relating to penetrance and outcomes of relatives remains sparse.In this issue, van Velzen et al2 present their long-term experience of cascade family screening in HCM. Over a 31-year period, a total of 777 relatives from 209 families were seen for family screening in the Erasmus Medical Center. Because of the widespread availability of genetic testing in the Netherlands, there is a unique ability to understand the long-term outcomes to the family. There were 620 relatives (80%) who underwent cascade genetic testing, with 264 (43%) shown to be genotype positive, whereas 356 (57%) were genotype negative and released from ongoing clinical surveillance. A third of the asymptomatic adult relatives were diagnosed with HCM at their first clinical evaluation, and annual cardiac mortality was calculated to be 0.3% per year. For the remainder of relatives, 16% developed disease during the mean 7-year follow-up period. Risk of cardiac events in unaffected gene carriers was very low with annual cardiac mortality of 0.1% per year, after the sudden cardiac death of a 21-year-old relative with no evidence of HCM at postmortem but also found to carry a known pathogenic variant in the long QT syndrome gene, KCNH2.Clinical Screening for HCMBecause of the known age-related penetrance of HCM, clinical screening recommendations suggest more frequent cardiac evaluation including clinical history, physical examination, ECG, and echocardiogram every 1 to 2 years during adolescence, then less frequently after the age of 20 years in the absence of symptoms (Table).3,4 Clinical evaluation of children may be considered or performed less frequently under the age of 10 to 12 years where there is a malignant family history including disease onset in childhood, participation in intense physical activity and investigation of cardiac symptoms. Although an autosomal dominant condition, published studies illustrate that many gene carrier relatives do not develop a phenotype and those that do are often only mildly affected.5 Whether this is because of relatives being diagnosed in an earlier disease phase, or the underlying gene variants having variable effect sizes potentially limiting penetrance,6 remains to be determined though is likely related to a combination of factors.Table. Current Guideline Recommendations About Clinical Screening Frequency for First-Degree Relatives at Risk of HCMAge RangeACCF/AHA HCM Guidelines, 2011ESC HCM Guidelines, 2014<10–12 y<12 y: optional unless evidence of disease onset in the family in childhood, competitive athlete, onset of symptoms, clinical suspicion<10 y: may be considered when there is a malignant family history in childhood or involved in demanding physical activity12–20 yEvery 12–18 moEvery 1–2 y between the ages of 10 to 20 y>20 yEvery 5 y, or at onset of symptoms. May be more frequent where family history suggests malignant clinical courseEvery 2–5 y from 20 y of age onwardsACCF indicates American College of Cardiology Foundation; AHA, American Heart Association; ESC, European Society of Cardiology; and HCM, hypertrophic cardiomyopathy.The authors illustrate that in their experience, current guidelines may not be adequate to identify clinically affected relatives. In their center, 6 children (15%) under the age of 12 years were diagnosed with HCM, with 3/6 having a malignant family history. Furthermore, few adolescents were diagnosed (12–18 years), despite this being widely recognized as the key period for disease conversion. Independent risk factors for a relative being diagnosed with HCM included positive gene variant status, male sex, younger age of the proband at diagnosis, and older age at clinical evaluation. Indeed, the majority of newly diagnosed relatives were in the age ranges 36 to 50 years (36%) and >50 years (44%).Genetic Screening for HCMWhere a genetic diagnosis has been made in the proband, cascade genetic testing can be a very useful tool in clarifying risk for relatives.7,8 There are challenges in knowing with sufficient certainty that a genetic variant is the cause of disease and for this reason specialized expertise is strongly advocated.9,10 The greatest utility of a genetic test in HCM is for the relatives.11 The ability to release ≈50% from the need for further clinical surveillance and worry drives the favorable health economic modeling that has been previously performed in this setting.12,13 It is important to note the approach to family screening described by the authors in this study, where it is common practice to perform cascade genetic testing before any cardiac evaluation. This means gene negative relatives are released without knowing for certain that the phenotype is absent. An important consideration in understanding this approach is the high prevalence of founder variants in MYBPC3 that exist in the Netherlands. Almost half of the probands had a clearly pathogenic founder variant identified, explaining the overall genetic yield in this population of 72%, which is far greater than more recent reports in other populations of 30% to 40%.10,14 In this setting where there is greater certainty in the genetic diagnosis, this approach of releasing relatives without clinical evaluation may be feasible, however, should not be widely advocated in other populations. Discordance in variant classification is problematic, with different centers9 and clinicians15 commonly disagreeing on the same genetic change. Reclassification of genetic variants occurs frequently,16 and can lead to serious harm in the family. In the general setting, clinical evaluation as an initial first step for asymptomatic relatives (before cascade genetic testing) would likely minimize the risk of inappropriately releasing family members from screening.Risk to Unaffected HCM Gene CarriersOver the last decade, feeding back a positive gene result to an unaffected relative has evolved significantly. There is a growing awareness of the potential harms that can be caused by imposing a disease label on an otherwise healthy person.7 As we begin to better elucidate the genetic architecture of HCM, we can have a more informed discussion with the relatives about their likely risk of developing disease and risk of cardiac events during their lifetime. The authors of this study reported 30% risk of a diagnosis on first cardiac evaluation, and a 15% risk thereafter. Similarly, Christiaans et al17 reported 30% risk of gene positive relatives being diagnosed with HCM. Importantly, those who suffered cardiac events had manifest disease and clinical risk factors, reassuring clinically unaffected gene carriers of a very low risk of cardiac events. Evidence from studies such as these allows more informed discussion with the family and a greater level of certainty about future risks.Factors Contributing to Variable Presentation in RelativesIt is increasingly clear that the underlying genetics of HCM is not straightforward Mendelian inheritance.18 Certainly, many families will have multiple affected individuals demonstrating autosomal dominant inheritance, but increasingly we see smaller families with less extensive familial patterns of disease. We and others,18,19 have most recently proposed an important subgroup of HCM cases, so-called nonfamilial HCM. These individuals have no family history of disease and no identifiable genetic variant, with better event-free survival from major cardiac events, potentially representing a distinct underlying cause.19 van Velzen et al2 however demonstrated nonfamilial HCM only represents a very small minority of probands (12%) in their center, perhaps again because of the large founder mutation experience. Understanding HCM disease subgroups is important because at present our family screening approach makes the assumption 50% of at-risk relatives will develop disease, most likely during adolescence. A greater understanding of the factors influencing disease expression will allow us to give more tailored and precise risk information to families, targeting clinical resources at those most likely to develop a phenotype. We recently showed cumulative rare variants in sarcomere genes led to a younger age at diagnosis in HCM patients compared with those with a single variant. This effect existed despite the clinical classification of the variants, that is, uncertain and causative variants,10 demonstrating there may be ways to understand other factors that modulate disease expression.We are living through an exciting period of discovery and remarkable advances in genetic technologies. Providing greater certainty and potentially finding a path to more precision-based management of relatives will have immeasurable benefit to the families. Key to this will be better phenotype subclassification of HCM, and understanding the true risk to relatives. The longstanding experience of specialized clinics such as these are critical to this, though with acknowledgment of the nuances of the population the data are drawn from. The greatest beneficiaries will most certainly be the families we care for.AcknowledgmentsDr Ingles is the recipient of a National Heart Foundation of Australia Future Leader Fellowship (No. 100833). Dr Semsarian is the recipient of a National Health and Medical Research Council Practitioner Fellowship (No. 1059156).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Jodie Ingles, MBBS, PhD, MPH, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, NSW 2042, Australia. E-mail [email protected]References1. Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy.J Am Coll Cardiol. 2015; 65:1249–1254. doi: 10.1016/j.jacc.2015.01.019.CrossrefMedlineGoogle Scholar2. van Velzen HG, Schinkel AFL, Baart SJ, Oldenburg RA, Frohn-Mulder IME, va , n Slegtenhorst MA, et al. Outcomes of contempory family screening in hypertrophic cardiomyopathy.Circ Genom Precis Med. 2018; 11:e001896. doi: 10.1161/CIRCGEN.117.001896.LinkGoogle Scholar3. 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Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).Eur Heart J. 2014; 35:2733–2779.CrossrefMedlineGoogle Scholar5. Gray B, Ingles J, Semsarian C. Natural history of genotype positive-phenotype negative patients with hypertrophic cardiomyopathy.Int J Cardiol. 2011; 152:258–259. doi: 10.1016/j.ijcard.2011.07.095.CrossrefMedlineGoogle Scholar6. Marian AJ, Braunwald E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy.Circ Res. 2017; 121:749–770. doi: 10.1161/CIRCRESAHA.117.311059.LinkGoogle Scholar7. Ingles J, Burns C, Barratt A, Semsarian C. Application of genetic testing in hypertrophic cardiomyopathy for preclinical disease detection.Circ Cardiovasc Genet. 2015; 8:852–859. doi: 10.1161/CIRCGENETICS.115.001093.LinkGoogle Scholar8. Cirino AL, Harris S, Lakdawala NK, Michels M, Olivotto I, Day SM, et al. Role of genetic testing in inherited cardiovascular disease: a review.JAMA Cardiol. 2017; 2:1153–1160. doi: 10.1001/jamacardio.2017.2352.CrossrefMedlineGoogle Scholar9. Furqan A, Arscott P, Girolami F, Cirino AL, Michels M, Day S, et al. Care in specialized centers and data sharing increase agreement in hypertrophic cardiomyopathy genetic test interpretation.Circ Cardiovasc Genet. 2017; 10:e001700. doi: 10.1161/CIRCGENETICS.116.001700.LinkGoogle Scholar10. Burns C, Bagnall RD, Lam L, Semsarian C, Ingles J. Multiple gene variants in hypertrophic cardiomyopathy in the era of next- generation sequencing.Circ Cardiovasc Genet. 2017; 10:e001666. doi: 10.1161/CIRCGENETICS.116.001666.LinkGoogle Scholar11. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA).Heart Rhythm. 2011; 8:1308–1339. doi: 10.1016/j.hrthm.2011.05.020.CrossrefMedlineGoogle Scholar12. Ingles J, McGaughran J, Scuffham PA, Atherton J, Semsarian C. A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy.Heart. 2012; 98:625–630. doi: 10.1136/heartjnl-2011-300368.CrossrefMedlineGoogle Scholar13. Wordsworth S, Leal J, Blair E, Legood R, Thomson K, Seller A, et al. DNA testing for hypertrophic cardiomyopathy: a cost-effectiveness model.Eur Heart J. 2010; 31:926–935. doi: 10.1093/eurheartj/ehq067.CrossrefMedlineGoogle Scholar14. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, et al. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.Genet Med. 2015; 17:880–888. doi: 10.1038/gim.2014.205.CrossrefMedlineGoogle Scholar15. Bland A, Harrington EA, Dunn K, Pariani M, Platt JCK, Grove ME, et al. Clinically impactful differences in variant interpretation between clinicians and testing laboratories: a single-center experience [published online ahead of print December 14, 2017].Genet Med. doi: 10.1038/gim.2017.212.Google Scholar16. Das K J, Ingles J, Bagnall RD, Semsarian C. Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment.Genet Med. 2014; 16:286–293. doi: 10.1038/gim.2013.138.CrossrefMedlineGoogle Scholar17. Christiaans I, Birnie E, Bonsel GJ, Mannens MM, Michels M, Majoor-Krakauer D, et al. Manifest disease, risk factors for sudden cardiac death, and cardiac events in a large nationwide cohort of predictively tested hypertrophic cardiomyopathy mutation carriers: determining the best cardiological screening strategy.Eur Heart J. 2011; 32:1161–1170. doi: 10.1093/eurheartj/ehr092.CrossrefMedlineGoogle Scholar18. Ko C, Arscott P, Concannon M, Saberi S, Day SM, Yashar BM, et al. Genetic testing impacts the utility of prospective familial screening in hypertrophic cardiomyopathy through identification of a nonfamilial subgroup.Genet Med. 2018; 20:69–75. doi: 10.1038/gim.2017.79.CrossrefMedlineGoogle Scholar19. Ingles J, Burns C, Bagnall RD, Lam L, Yeates L, Sarina T, et al. Non familial hypertrophic cardiomyopathy: prevalence, natural history, and clinical implications.Circ Cardiovasc Genet. 2017; 10:e001620.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Qin X, Li P, Qu H, Liu Y, Xia Y, Chen S, Yang Y, Huang S, Wen P, Zhou X, Li X, Wang Y, Tian L, Hakonarson H, Wu Y and Zhuang J (2021) FLNC and MYLK2 Gene Mutations in a Chinese Family with Different Phenotypes of Cardiomyopathy, International Heart Journal, 10.1536/ihj.20-351, 62:1, (127-134), Online publication date: 30-Jan-2021. April 2018Vol 11, Issue 4 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.118.002112PMID: 29661764 Manuscript receivedFebruary 23, 2018Manuscript acceptedMarch 1, 2018Originally publishedApril 16, 2018 Keywordslong QT syndromeheart failuregenetic testingEditorialspenetrancerisk factorsPDF download Advertisement SubjectsCardiomyopathyGeneticsHypertrophyPrecision Medicine