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A Clinical Approach to Inherited Hypertrophy

2013; Lippincott Williams & Wilkins; Volume: 6; Issue: 1 Linguagem: Inglês

10.1161/circgenetics.110.959387

1942-325X

Kyla Dunn, Colleen Caleshu, Allison L. Cirino, Carolyn Y. Ho, Euan A. Ashley,

Cardiovascular Effects of Exercise

HomeCirculation: Cardiovascular GeneticsVol. 6, No. 1A Clinical Approach to Inherited Hypertrophy Free AccessResearch ArticlePDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBA Clinical Approach to Inherited HypertrophyThe Use of Family History in Diagnosis, Risk Assessment, and Management Kyla E. Dunn, MS, CGC, Colleen Caleshu, ScM, CGC, Allison L. Cirino, MS, CGC, Carolyn Y. Ho, MD and Euan A. Ashley, MRCP, DPhil Kyla E. DunnKyla E. Dunn From the Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA (K.E.D., C.C., E.A.A.); and Cardiovascular Genetics Center, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (A.L.C., C.Y.H.). , Colleen CaleshuColleen Caleshu From the Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA (K.E.D., C.C., E.A.A.); and Cardiovascular Genetics Center, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (A.L.C., C.Y.H.). , Allison L. CirinoAllison L. Cirino From the Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA (K.E.D., C.C., E.A.A.); and Cardiovascular Genetics Center, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (A.L.C., C.Y.H.). , Carolyn Y. HoCarolyn Y. Ho From the Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA (K.E.D., C.C., E.A.A.); and Cardiovascular Genetics Center, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (A.L.C., C.Y.H.). and Euan A. AshleyEuan A. Ashley From the Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA (K.E.D., C.C., E.A.A.); and Cardiovascular Genetics Center, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (A.L.C., C.Y.H.). Originally published1 Feb 2013https://doi.org/10.1161/CIRCGENETICS.110.959387Circulation: Cardiovascular Genetics. 2013;6:118–131IntroductionLeft-ventricular hypertrophy is a common finding in clinical practice and the end result of a number of different disease processes. As such, distinguishing hypertrophy attributable to athletic training or chronic hypertension from more rare and potentially life-threatening genetic conditions, including hypertrophic cardiomyopathy (HCM), is of utmost clinical importance. This is true not only for the individual patient but also for the patient's family members, who may be at risk when the cause is a heritable disease. We review how family history can be used in identifying inherited cardiac hypertrophy and in guiding ongoing management of the patient and the rest of the family. An in-depth, multigenerational family history has the potential to enhance every aspect of care, from establishing a diagnosis to devising a genetic testing strategy, interpreting genetic test results, and providing ongoing risk assessment for sudden cardiac death (SCD). We review that family history is not simply a static account of preexisting deaths and diagnoses, but a dynamic ongoing process incorporating new and valuable insights from family medical records, clinical cardiology evaluations, genetic testing, and visual analysis of the patient's family tree. Such insights enable comprehensive clinical care for families affected by HCM.Historical ContextScientific understanding of inherited cardiac hypertrophy dates back to 1958, when British forensic pathologist Donald Teare1 published an evocative series of case histories. Several sudden deaths in unrelated young adults had revealed, on autopsy, asymmetrical left-ventricular (LV) hypertrophy accompanied by a bizarre and disorganized myocardium: the disease known today as HCM. In a brief addendum, Teare1 described a family with multiple afflicted members, including a sister and brother who had each died suddenly, one while running for a bus and the other while riding a bicycle. Teare and his colleagues2 would later devote an entire publication to this family, tracing its history for 3 generations and performing cardiology evaluations of living family members. The resulting family pedigree (Figure 1) was the first to reveal HCM as a hereditary disease.Download figureDownload PowerPointFigure 1. Published in 1960, this family pedigree was the first to show autosomal dominant inheritance of hypertrophic cardiomyopathy (HCM). Females are represented by the symbol for Venus (♀), males by the symbol for Mars (♂). Filled shapes indicate verified disease. Adapted with permission from Hollman et al.2At the time, there was little understanding of heredity at a molecular level. By 1958, only 5 years had passed since Watson and Crick3 first revealed the physical structure of DNA, and a family pedigree remained the sole diagnostic tool for inherited disease.Even in the current molecular era, more than 2 decades after the discovery that HCM is caused by genetic changes in the contractile apparatus of heart muscle cells, and with whole-genome sequencing on the clinical horizon, certain aspects of clinical care are guided by a traditional family tree and cannot be accomplished by any other method. Clinical practice guidelines recommend a multigenerational family history as part of the care of all individuals with cardiomyopathy4—and, increasingly, time-saving tools make it easier for clinicians to incorporate a thorough family history into patient care. We now explore the role of family history in a clinical approach to LV hypertrophy.Family History: Distinguishing Genetic Disease From Secondary LV HypertrophyGiven the prevalence of hypertension in the adult population, and the popularity of competitive athletics among adolescents, it is common in cardiology practice to encounter patients with some degree of LV hypertrophy detected on ECG or noninvasive cardiac imaging studies. Most cases of mild hypertrophy can be confidently determined to be secondary. Nonetheless, a well-recognized phenotypic overlap exists with more rare and life-threatening disease processes, including HCM. Such cases can be particularly concerning to the clinician when the patient is a young athlete, at an age when SCD from HCM is most likely to occur.5–7Clinical testing can offer clarity in some instances. Evidence of diastolic dysfunction, for example, can be useful in discriminating HCM from the athletic heart.8,9 As we and others have previously described, this intrinsic feature of HCM can be present in individuals genetically predisposed to the disease even when LV wall thickness is normal.10–15 Other classic features of HCM, but not of physiological hypertrophy, include asymmetrical septal hypertrophy,16,17 small or normal LV cavity size, left atrial enlargement, anatomic abnormalities of the mitral valve or papillary muscles,18 and dynamic LV outflow tract obstruction.6,7,19 LV hypertrophy that regresses after detraining an athlete or controlling blood pressure suggests a secondary cause rather than primary HCM.8,9Despite these potential clues, patients can defy easy categorization. In ambiguous cases of LV hypertrophy, insights from family history may provide important clarity.Illustrative CasesPatients A and B were 18-year-old males referred for evaluation of mild LV hypertrophy. Both had normal mitral valve function and no evidence of LV outflow tract obstruction.Patient A was suspected of having athlete's heart with physiological hypertrophy, as he exercised intensely for up to 7 hours per day, 5 days per week. His ECG was distinctly abnormal, with deep inverted T-waves in the precordial leads and high voltage throughout. However, the specificity of these findings was reduced because substantial QRS voltage and inverted T-waves are more common among Black athletes, such as Patient A.20,21Patient A's maternal family history, however, was notable for 2 premature sudden cardiac deaths (SCDs) as shown in Figure 2A. His grandmother's brother (individual II-7 in the family pedigree) had died suddenly at age 29 and his grandmother's uncle (I-3) at age 35, raising suspicion for inherited cardiomyopathy. Echocardiograms were performed on the patient's immediate family members to look for previously unrecognized disease. Evaluation showed both his teenage sisters (IV-2 and IV-3) to exhibit mild LV hypertrophy in the absence of any other explanation. His mother (III-2), who had hypertension, had LV hypertrophy as well. Furthermore, after a 3-month detraining period, Patient A had no regression of his cardiac hypertrophy. Given the cumulative weight of the evidence, driven by his family history, we diagnosed Patient A with HCM—revising the pedigree as shown in Figure 2B.Download figureDownload PowerPointFigure 2. Strategic clinical assessment of a patient's close family members aids diagnosis by adding valuable information to the family history. A, When 18-year-old Patient A (arrow) presented with mild left-ventricular (LV) hypertrophy, his family history of sudden cardiac death (I-3 and II-7) raised suspicion for hypertrophic cardiomyopathy (HCM). B, Clinical cardiology evaluation of the patient's mother (III-2) and sisters (IV-2 and IV-3) provided the evidence needed for diagnosis. Circles indicate females; squares, males; and slash, deceased.Patient B, by contrast, was not unusually athletic and had no known history of hypertension. He had recently experienced multiple episodes of syncope, one while playing basketball, raising concern that his LV hypertrophy was pathological and a sign of HCM with exercise-induced arrhythmias.Patient B's family history, however, contained no suggestion of SCD or significant cardiovascular disease (Figure 3). Accordingly, our suspicion for inherited cardiomyopathy was decreased. Twenty-four-hour ambulatory blood pressure monitoring was pursued and revealed a substantial burden of labile hypertension. Patient B's family history had helped to guide us toward the true cause of his hypertrophy: occult hypertension.Download figureDownload PowerPointFigure 3. An uneventful family history lowers suspicion for hypertrophic cardiomyopathy, prompting more thorough investigation of alternative pathogenesis. For 18-year-old Patient B (arrow) with mild left-ventricular (LV) hypertrophy, 24-hour blood pressure monitoring revealed occult hypertension as the underlying cause. Circles indicate females; squares, males; and slash, deceased.It is worth emphasizing that a comprehensive family history was needed to ascertain the informative deaths in Patient A's family. While it is standard practice for clinicians to inquire about a patient's first-degree relatives (parents, siblings, and children), a truly informative assessment of inherited disease risk requires delving deeper into the family tree. Even among members of the same family, the clinical presentation of HCM can vary widely,22,23 and the diagnosis may have been missed in some relatives, particularly those who are asymptomatic with mild or even no associated health problems. What's more, some genetically affected family members never develop LV hypertrophy—a phenomenon known as reduced penetrance. Clinical practice guidelines,4 therefore, recommend a careful 3-generation family history that extends at least to the patient's second-degree relatives (grandparents, aunts, uncles, nieces, and nephews).To get the most from a family history in clinical practice, it may be necessary to go beyond tallying preexisting deaths and diagnoses. Strategic clinical assessment of the patient's close family members, triggered by the proband's diagnosis with HCM or suspicion of familial disease, can add important insights to what is already known from static history (as it did with Patient A). Such directed evaluations serve 2 major purposes: (1) identifying family members with unrecognized clinical disease to initiate appropriate clinical care, and (2) providing key supportive evidence for a diagnosis of HCM in the original patient and, by extension, the family. For example, if an ECG reveals HCM in a patient's parent, sibling, or child, then this shifts the patient's a priori risk for HCM from 1 in 500, based on disease prevalence in the general public,24,25 to 1 in 2, based on the likelihood of inheriting an autosomal dominant disease.Differential Diagnosis: Other Forms of Inherited LV HypertrophyInformative elements of a family history for a patient with LV hypertrophy are presented in Table 1. It is important to ascertain whether relatives have exhibited classic symptoms of HCM, such as shortness of breath, chest pain, presyncope, or syncope—particularly with exertion.6,7 Other key questions involve HCM's more rare and serious consequences, including stroke, end-stage congestive heart failure, or SCD. Asking for details about cardiothoracic surgeries or other procedures family members have undergone can be important in distinguishing HCM from conditions such as coronary artery disease. Another essential line of inquiry involves accidental and unexpected deaths in the family, such as single-car accidents in which the family member was the driver, drownings, or sudden infant death syndrome. These events sometimes indicate a sudden cardiac arrest that has gone unrecognized.Table 1. Patients With Left-ventricular Hypertrophy: Important Elements of a Family HistoryKnown cardiac diagnoses (request records)Hypertrophy may be reported as an enlarged, strong, thick, or even athletic heartAge of onsetSymptoms in a young, athletic person is typical of HCMOnset before puberty suggests multiple genetic variants may be presentChest painParticularly pain that improves during a lengthy exercise warm-upArrhythmia symptomsPalpitations, syncope, or presyncope, particularly with exertionStroke (particularly at unusually young ages), abnormal blood clottingValve problems, heart murmursHeart failure symptomsExercise-induced asthma is a common misdiagnosis, particularly in childrenMedicationsBeta blockers, calcium channel blockers, and antiarrhythmic agents are frequently taken for HCMHeart-related surgeries and procedures (request records)Includes catheterization, endocardial biopsy, myectomy, mitral valve replacement, cardiac transplantCardiac devicesImplantable cardioverter-defibrillators (ICDs), pacemakersSudden cardiac death (request autopsy reports)Particularly concerning < age 35 or in the documented absence of coronary artery diseaseObtain further details regarding deaths labeled as heart attackAccidental/unexpected death, particularly in young individualsSingle-car accidents in which the family member was the driver, drownings, SIDS deathsGenetic testing (request laboratory results to verify interpretation)Screening ECGs and echocardiograms performed on at-risk family members (request records)Features relevant to differential diagnosisLearning disabilities/mental retardationNoonan syndrome, Danon diseaseParesthesiasFabry disease, transthyretin amyloidosisRenal diseaseFabry disease, immunoglobulin light chain (primary) amyloidosisSkeletal muscle weaknessPompe disease, Danon disease, mitochondrial disordersLiver pathology, skin bronzingHereditary hemochromatosisFacial dysmorphologyNoonan syndromeHCM indicates hypertrophic cardiomyopathy; and SIDS, sudden infant death syndrome.Cardiac hypertrophy can result, too, from a wide range of genetic conditions that affect multiple organ systems (Table 2). A careful family history may, therefore, detect extracardiac features that help to make a diagnosis. Inheritance patterns can provide additional diagnostic clues: Danon disease and Fabry disease are both X-linked conditions, meaning that disease expression in carrier females may be subtle or absent.26 Father-to-son transmission would effectively rule out an X-linked condition.Table 2. Diseases Mimicking Hypertrophic Cardiomyopathy on EchocardiographySyndromeGene(s)Gene SymbolLocusPhenotypeInheritanceAMP kinase diseaseAMP-activated protein kinasePRKAG27q36.1Cardiac hypertrophy, preexcitationAutosomal dominantFamilial amyloid diseaseTransthyretinTTR18q12.1Low voltage, severe cardiac hypertrophy, paresthesiasAutosomal dominantNoonan syndromeProtein tyrosine phosphatase, nonreceptor type 11 (aka tyrosine phosphatase SHP2)PTPN1112q24.1Short stature, facial dysmorphology, congenital heart defects, cardiac hypertrophy, skeletal anomalies, bleeding disorders, learning disabilities (variable)Autosomal dominantSon of sevenless homolog 1SOS12p22.1RAF proto-oncogene serine/threonine-protein kinaseRAF13p25GTPase KRasKRAS12p12.1Fabry diseaseAlpha-galactosidase AGLAXq22Renal disease, paresthesias, cardiac hypertrophy. Females can manifest signs of diseaseX linkedDanon diseaseLysosomal-associated membrane protein 2LAMP2Xq24Males present in childhood with cardiac hypertrophy, skeletal myopathy, mental retardation. Females can manifest signs of cardiomyopathyX linkedHereditary hemochromatosisHereditary hemochromatosis proteinHFE6p21.3Iron overload, cardiomyopathy, hypogonadotropic hypogonadism, arthropathy, hepatic fibrosis or cirrhosis, diabetes mellitus, progressive skin pigmentation/bronzingAutosomal recessivePompe diseaseAcid α-glucosidase (aka acid maltase)GAA17q25Acid maltase deficiency (aka glycogen storage disease type II), infantile and juvenile/adult forms, skeletal myopathy, ventilatory failure, cardiac hypertrophyAutosomal recessiveAccurately distinguishing HCM from its mimics is important, given the significant differences in prognosis and treatment. Enzyme replacement therapy is available for Fabry disease and Pompe disease, for example.27 Anticipation of the likely need for heart transplantation may be warranted for Danon disease, which can progress rapidly to end-stage heart failure, particularly in adolescent males.28 In ambiguous cases, genetic testing can be of assistance. Genes for some of these syndromes are included on clinically available HCM genetic testing panels—facilitating simultaneous genetic testing for primary HCM and for multisystem diseases that include LV hypertrophy.Family History: Managing HCMStratifying Risk for SCDGiven that HCM is the most common form of inherited LV hypertrophy, the remainder of this article will focus on the role of family history in managing HCM. Once a diagnosis has been established, the next important contribution of family history involves assessing a patient's risk for SCD.A family history of SCD is a major consideration when assessing an individual patient's risk to determine whether an implantable cardioverter-defibrillator for primary prevention is appropriate.7,29 It is 1 of 6 major risk factors considered along with previous cardiac arrest, LV thickness of 3 cm or greater, a history of unexplained syncope, nonsustained ventricular tachycardia on 48-hour Holter monitor, and abnormal blood pressure response to exercise.6,7 Although any history of premature SCD is concerning, deaths of greatest concern involve close family members, particularly when multiple family members have died.6,30Careful scrutiny is often needed to determine which events constitute premature SCD attributable to HCM. Such events occur most frequently in adolescents and adults under age 35,7 suggesting that SCD in an elderly relative may be of less clinical concern—particularly given the higher likelihood of confounding comorbidities, most prominently coronary artery disease. Yet the risk for HCM-related cardiac arrest remains elevated throughout life, and published guidelines offer no easy algorithm or well-defined age cut-off for risk stratification. Gathering medical records and autopsy reports for suspicious deaths can be highly informative when available. If family members have been implanted with implantable cardioverter-defibrillators, then events that previously would have resulted in SCD may now register as appropriate shocks.None of the risk factors for SCD is static—including family history. Family history should be updated at intervals, and patients are urged to contact the clinic with reports of new deaths, cardiac events, or diagnoses.Managing Family MembersHCM is typically inherited in an autosomal dominant fashion, meaning that just 1 altered copy of a gene, inherited from just 1 parent, causes the disease. Although de novo genetic variants (brand new in the patient, not inherited from either parent) have been reported,31,32 the majority of HCM seems to be familial. A patient's diagnosis, therefore, implies risk to other family members even in the absence of a clear family history, and clinical screening of relatives is appropriate. Immediate family members—parents, siblings, and children—each share half of the patient's genes, creating a 50% chance that they carry the same disease-causing variant. A de novo genetic change initiates new familial disease, placing the patient's children, but not the patient's siblings or parents, at risk.Guidelines for the clinical management of these at-risk first-degree family members (Figure 4) include physical examination by a cardiologist familiar with HCM, echocardiography, and 12-lead ECG.4,7 Cardiac MRI, Holter monitoring, and exercise testing may also be beneficial in certain situations. Any family member involved in competitive sports and any family member experiencing symptoms also need evaluation—even if more distantly related to the patient with HCM.Download figureDownload PowerPointFigure 4. Screening recommendations for families with hypertrophic cardiomyopathy (HCM). The frequency of screening is based on the age of the at-risk family member, attributable to the age-dependent penetrance of left-ventricular (LV) hypertrophy. Adapted with permission from Ho.33 Data from Gersh et al.7Moreover, HCM shows age-dependent penetrance, meaning its features may emerge with time in someone previously without signs or symptoms. Cardiac evaluation should, therefore, be repeated at regular intervals over time. Evaluations should occur annually throughout puberty, when the first signs of HCM are most likely to appear, and every 3 to 5 years thereafter. The risk of developing HCM persists even past middle age,34 so unless genetic testing confirms that an at-risk relative has not inherited the family's pathogenic variant, cardiac evaluation should be ongoing as outlined in Figure 4.Family history can play an important role in individualizing these screening recommendations. Someone from a high-risk family with consistent development of heart failure or SCD may warrant more frequent monitoring because it is clear that his or her specific genetic milieu results in particularly grave consequences when an HCM-causing variant is present. Adult relatives who participate in competitive or high-intensity athletics may also warrant more frequent screening. For a family with early onset LV hypertrophy, childhood screening should start earlier than puberty.4,7,35Family History: Pedigree AnalysisSuccessfully identifying at-risk individuals within a family tree requires integration of clinical history with basic laws of inheritance and probability.Illustrative CaseThe family of a 15-year-old patient with HCM is depicted in Figure 5. Figure 5A indicates the immediate family members at 50% risk for HCM based only on the patient's diagnosis. In constructing a detailed, 3-generation pedigree, however, we discovered a family history of the disease that had previously been unrecognized: the patient's mother's cousin (II-6) had died suddenly in his 30s and was diagnosed with HCM on autopsy. Based on this new information, Figure 5B indicates additional at-risk family members who require ongoing cardiology screening because they are first-degree relatives of an affected patient.Download figureDownload PowerPointFigure 5. An evolving hypertrophic cardiomyopathy (HCM) family history and careful pedigree assessment shift cardiology screening needs. A, Relatives needing screening based on initial diagnosis. Diagnosis of this 15-year-old patient (III-5, thick arrow) with HCM means his first-degree relatives (father II-3, mother II-4, and brother III-6; thin arrows) are each at 50% risk. B, Relatives needing screening based on initial plus a second diagnosis. When a second HCM diagnosis (II-6) is discovered in the patient's maternal family history, this individual's first-degree relatives (I-5, II-7, III-7, III-8, and III-9) also require cardiac screening. The patient's father (II-3), not on the affected side of the family, is no longer considered at risk. C, Additional relatives need screening based on obligate carriers. Pedigree analysis identifies 3 obligate carriers (I-3, I-5, and II-4; marked with vertical line) connecting the individuals with HCM, including the patient's mother. Each is at known risk for disease. Immediate family members of an obligate carrier are at 50% risk and also require screening (arrows added to I-6 and II-5). D, Genetic testing helps target screening to relatives definitively predisposed to HCM. In this family, several family members at 50% risk (II-7, III-6, III-7, and III-9) did not inherit the disease-causing variant; they and their descendants can be excused from further screening. By contrast, II-5 and I-6 test positive, newly revealing their children (II-8 and II-9) to be at 50% risk. Circles indicate females; squares, males; slash, deceased; +, genetic variant present; and –, genetic variant absent.The next level of analysis involves identifying obligate carriers: individuals who logically must carry the family's HCM-causing genetic variant to explain the overall disease pattern within the family. Simple visual inspection of the pedigree reveals these at-risk individuals. In this case, the chain of family members that connects our patient to his mother's affected cousin includes 3 obligate carriers (I-3, I-5, and II-4), each marked with a vertical bar in Figure 5C. Without each of these individuals having inherited and then passing on the disease-causing variant, the 2 known cases of HCM could not have occurred. These carrier individuals may have undiagnosed cardiomyopathy or, if they do not, are at risk to develop HCM in the future.Immediate family members of an obligate carrier are at 50% risk to carry the predisposition to HCM, just like the brother of our initial patient (III-6); they too require ongoing cardiology screening. In Figure 5C, arrows indicate 2 such family members (I-6 and II-5) whose at-risk status we may not have recognized had we not drawn out and analyzed the pedigree.Family History: Genetic Testing StrategyGiven the screening recommendations outlined above, a child at 50% risk of being predisposed to HCM will undergo up to 20 cardiology evaluations between the ages of 12 and 75. It would be ideal if these evaluations could be focused only on the family members who inherited a disease-causing genetic variant and are predisposed to develop HCM, instead of screening everyone at 50% risk. Genetic testing can help to provide this focus.Two decades ago, a key role in the pathophysiology of HCM was attributed to the sarcomere: the assembly of proteins in each cardiac muscle cell that enables contraction (Figure 6). The first disease-causing variant to be discovered was in MYH7, the β-myosin heavy chain gene37; since then the list of sarcomere-associated genes known to cause HCM has grown to more than a dozen, with MYH7 and MYBPC3 (myosin-binding protein C) most frequently involved.36 Multigene panels containing the major genes associated with HCM are clinically available and used when the first affected family member undergoes genetic testing.Download figureDownload PowerPointFigure 6. The cardiac sarcomere, highlighting protein products of genes involved in hypertrophic cardiomyopathy. Disease-causing variants in cardiac myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) are most common, accounting for 20% to 45% and 15% to 20% of the disease, respectively. Cardiac troponin T type 2 (TNNT2) and troponin I type 3 (TNNI3) each account for ≈5%. Variation in other sarcomere genes is less frequent. Data from Ackerman et al.36Family history is an important guide when deciding which family member should be tested first. In general, the best candidate is the person whose HCM was diagnosed at the youngest age or whose disease features are the most classic and severe.4 Notably, this may not be the patient who first presents to clinic. Testing the most affected family member is a well-established principle of medical genetics: it helps to minimize the chance of testing a phenocopy (someone whose LV hypertrophy is attributable solely to hypertension or intense athletic activity) and to maximize the chance that the person tested actually carries the familial predisposition to HCM.What's more, the approach increases the likelihood of detecting all disease-causing genetic variants present in the family, as there may not be just 1. Approximately 5% of patients with HCM have been reported to carry 2 or more sarcomere gene variants38,39 (in the gene panels explored to date), and our appreciation of multigenic contribution is only likely to increase as new DNA sequencing technologies reach the clinic.40 Individuals with this higher genetic dosage may have earlier disease onset and worse prognosis,39,41–44 although it has been difficult to fully understand the impact of multiple variants attributable to phenotypic heterogeneity and the limited scale of previous studies. Notably, when a patient carries 2 disease-causing changes, it is possible that 1 was inherited from each parent. This emphasizes the importance of withholding judgment about which side of the family may be affected by HCM.4,45 The reality is, it may be both.Initial genetic testing with a multigene panel will yield 1 of 3 results: negativ