The MOGE(S) Classification of Cardiomyopathy for Clinicians

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 64, NO. 3, 2014

ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jacc.2014.05.027

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW The MOGE(S) Classiﬁcation of Cardiomyopathy for Clinicians

Eloisa Arbustini, MD,* Navneet Narula, MD,y Luigi Tavazzi, MD, PHD,z Alessandra Serio, MD, PHD,*

Maurizia Grasso, BD, PHD,* Valentina Favalli, PHD,* Riccardo Bellazzi, ME, PHD,x Jamil A. Tajik, MD,k

Robert O. Bonow, MD,{ Valentin Fuster, MD, PHD,# Jagat Narula, MD, PHD#

ABSTRACT

Most cardiomyopathies are familial diseases. Cascade family screening identifies asymptomatic patients and family members with early traits of disease. The inheritance is autosomal dominant in a majority of cases, and recessive, X-linked, or matrilinear in the remaining. For the last 50 years, cardiomyopathy classifications have been based on the morphofunctional phenotypes, allowing cardiologists to conveniently group them in broad descriptive categories. However, the phenotype may not always conform to the genetic characteristics, may not allow risk stratification, and may not provide pre-clinical diagnoses in the family members. Because genetic testing is now increasingly becoming a part of clinical work-up, and based on the genetic heterogeneity, numerous new names are being coined for the description of cardiomyopathies associated with mutations in different genes; a comprehensive nosology is needed that could inform the clinical phenotype and involvement of organs other than the heart, as well as the genotype and the mode of inheritance. The recently proposed MOGE(S) nosology system embodies all of these characteristics, and describes the morphofunctional phenotype (M), organ(s) involvement (O), genetic inheritance pattern (G), etiological annotation (E) including genetic defect or underlying disease/substrate, and the functional status (S) of the disease using both the American College of Cardiology/American Heart Association stage and New York Heart Association functional class. The proposed nomenclature is supported by a web-assisted application and assists in the description of cardiomyopathy in symptomatic or asymptomatic patients and family members in the context of genetic testing. It is expected that such a nomenclature would help group cardiomyopathies on their etiological basis, describe complex genetics, and create collaborative registries. (J Am Coll Cardiol 2014;64:304–18) © 2014 by the American College of Cardiology Foundation.

ardiomyopathy is the heart muscle disease underscore the importance of providing cardiologists C sufficient to cause structural and functional with tools to better describe the patients and families myocardial abnormality in the absence of affected by a morphofunctional cardiomyopathic coronary artery disease, hypertension, valvular dis- phenotype. The American Heart Association (AHA) ease, and congenital heart disease. Based on the clin- classification grouped cardiomyopathies into genetic, ical and genetic evidence,mostcardiomyopathies mixed,andacquiredforms,andtheEuropeanSociety are inherited, and the recent classification systems of Cardiology classification proposed subgrouping of

From the *Center for Inherited Cardiovascular Diseases, IRCCS Foundation Policlinico San Matteo, Pavia, Italy; yWeill Cornell Medical College, New York, New York; zGVM Care & Research, E.S. Health Science Foundation, Maria Cecilia Hospital, Cotignola, Italy; xUniversity of Pavia, Pavia, Italy; kSt. Luke’s Medical Center, Milwaukee, Wisconsin; {Northwestern University School of Medicine, Chicago, Illinois; and the #Icahn School of Medicine at Mount Sinai, New York, New York. This study was supported by Grants European Union INHERITANCE project n241924 and Italian Ministry of Health “Diagnosis and Treatment of Hypertrophic Cardiomyopathies” (nRF-PSM-2008-1145809) (to Dr. Arbustini), IRCCS Policlinico San Matteo, Pavia. Dr. Tavazzi has served as a member of the Speaker’s Bureau for Servier; has been a trial committee member for Servier, Cardiorentis, Boston Scientiﬁc, St. Jude Medical, CVIE Therapeutics, Vifor Pharma, and Medtronic. Dr. Narula has received research grants from GE Healthcare & Philips Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. P. K. Shah, MD, served as the Guest Editor for this paper.

Manuscript received April 30, 2014; revised manuscript received May 27, 2014, accepted May 28, 2014. JACC VOL. 64, NO. 3, 2014 Arbustini et al. 305 JULY 22, 2014:304– 18 MOGE(S) Classiﬁcation of Cardiomyopathy

each major type of cardiomyopathy into familial or arrhythmias. Numerous electrocardiographic ABBREVIATIONS genetic, and nonfamilial or nongenetic forms (1,2). markers have been shown to be associated AND ACRONYMS The American College of Cardiology (ACC)/AHA stag- with cardiomyopathy in a subset of the ACC = American College of ing of the heart failure (HF) included asymptomatic patients, including atrioventricular block Cardiology patients with a familial history of cardiomyopathy in (AVB), pre-excitation syndrome (Wolff-Par- AHA = American Heart the stage A or pre-HF (3). kinson-White syndrome [WPW]), repolariza- Association

In the last 20 years, the systematic approach to tion abnormalities, or low QRS voltage. ARVC = arrhythmogenic right family screening has contributed to better assess- Echocardiography and cardiac magnetic reso- ventricular cardiomyopathy ment of familial cardiomyopathies. This method has nance imaging may reveal variable features AVB = atrioventricular block allowed the identification of family members who are within the similar phenotypes, including the DCM = dilated cardiomyopathy predisposed to disease development, based on the in- severity, distribution, and extent of myocar- EMF = endomyocardial fibrosis heritance of the cardiomyopathy-associated gene(s). dial hypertrophy, thickening of valves, non- HCM = hypertrophic The electrocardiographic and echocardiographic clues compaction, ventricular dilation, ventricular cardiomyopathy may show early (subclinical) cardiac involvement dysfunction, myocardial fibrosis, infiltrative LV = left ventricle – fi (4 10). On the other hand, the nongenetic cardiomy- or intramyocyte storage, or fatty in ltration of LVNC = left ventricular opathies may be described as associated with specific the myocardium (18,19).Althougheachsub- noncompaction etiologies, such as viral infections, autoimmune dis- type of cardiomyopathy is defined by its major RCM = restrictive eases, and endogenous or exogenous myocardial morphofunctional phenotype, a careful clin- cardiomyopathy toxicity. The contemporary diagnostic algorithms ical evaluation demonstrates high phenotype WPW = Wolff-Parkinson-White syndrome for work-up of cardiomyopathies are supported by variability. advanced imaging characterization, disease-specific Most cardiomyopathies demonstrate an auto- biomarkers, and genetic analyses (11). The number of somal dominant inheritance, but X-linked recessive, cardiomyopathies wherein the cause is identified (or autosomal recessive, or matrilineal inheritance may identifiable) is increasing, supported by the family occur in a minority of cases. Although elucidation screening and follow up for segregation studies of of family history and comprehensive assessment genotype with phenotype. of pedigree is the foremost necessity in family The morphofunctional phenotype-based classifi- studies (17,20,21),itmaynotbebyitselfsufficient cation of cardiomyopathies continues to offer cardi- to establish the diagnosis of familial cardiomyo- ologists the possibility of using a simple and clinically pathy. Cascade family screening and monitoring useful diagnostic language (Table 1). All treatment may be necessary to identify affected but asymp- protocols are currently based on the phenotype, as tomatic family members unaware of their disease, well as signs and symptoms. The phenotype-based or who display subclinical abnormalities by non- classification (hypertrophic cardiomyopathy [HCM], invasive imaging tests as early markers of the dilated cardiomyopathy [DCM], restrictive cardiomy- disease (16,17). opathy [RCM], arrhythmogenic right ventricular car- The knowledge of the genetic basis of all kinds diomyopathy [ARVC]/arrhythmogenic ventricular of cardiomyopathies has progressively increased cardiomyopathy, and left ventricular noncompaction (12–14,22). Linkage analyses (23), genome-wide asso- [LVNC]) describes the major forms of cardiomyopa- ciation studies (GWAS) (24,25), and whole-exome se- thy, but not their causes. However, cardiomyopathies quencing (WES) (26) have incrementally contributed are clinically heterogeneous diseases (12–17),and to the list of disease genes (Online Table 1), which within each subtype of cardiomyopathy there are now includes more than 100 genes. HCM is caused by differences in sex, age of onset, rate of progression, the mutations of genes that code for structural and risk of development of overt heart failure, and like- functional proteins of the sarcomere (15),whereas lihood of sudden death. In the DCM group, for DCM is caused by the mutation of genes related to example, there are patients with mildly enlarged structure and function of nuclear envelope, cyto- and mildly dysfunctional left ventricle (LV) that skeleton, sarcomere, and sarcoplasmic reticulum (27). develop life-threatening ventricular arrhythmias; ARVC is known as a collection of diseases of the yet, there may be patients with extremely dilated desmosome (28), and RCM is caused by defects in and dysfunctional LV but low arrhythmogenic risk. genes encoding for sarcomeric proteins (29) or inter- Similarly, in the HCM group, there are patients with mediate filaments, such as desmin (20). severe left ventricular hypertrophy who are asymp- However, the early assignment of phenotypes to tomatic and do not demonstrate life-threatening ar- groups of genes and pathways is no longer confirmed rhythmias. Finally, there are patients who show mild by recent genetic studies. In fact, genes may cause to moderate hypertrophy but carry a high risk of similar phenotypes (Fig. 1),mostdiseasegenesarenot 306 Arbustini et al. JACC VOL. 64, NO. 3, 2014 MOGE(S) Classification of Cardiomyopathy JULY 22, 2014:304– 18

nonsarcomeric genes also may cause HCM (33).An TABLE 1 Recapitulation of the Classification Systems for Cardiomyopathies in the Last 50 Years increasing number of cardiomyopathies are being recognized as associated with complex genetics (34). Year Definitions/Classifications References More than 100 nuclear and mitochondrial disease- fi 1956 Myocardial diseases classi ed as Blankerhorn and Gall (71) fi myocarditis (inflammatory heart causing genes have been identi ed encoding for the muscle disease), and myocardiosis proteins of nuclear envelope, sarcolemma, cytoskel- (other heart muscle diseases). eton, sarcomere, or desmosome, or those involved in 1957 The term cardiomyopathy proposed for Bridgen (72) uncommon, noncoronary heart muscle calcium-handling and energy production (Online diseases. Table 1). The constantly increasing number of 1972 Cardiomyopathy described as myocardial Goodwin and Oakley (73) disease-causing genes suggests that the unresolved diseases of unknown origin, and first classification proposed as dilated, issueofvariablepenetranceorexpressionmay hypertrophic, and restrictive (or represent incomplete genotyping (Fig. 3), or that the obliterative) cardiomyopathy. 1980 WHO-ISFC adopts Goodwin and Oakley Report of the WHO/ISFC Task Force on presumptive disease-causing role has erroneously classification, and defines the Definition and Classification of been assigned to a wrong gene and mutation. Al- cardiomyopathies as myocardial Cardiomyopathies (74) diseases of unknown etiology. WHO- though functional studies are likely to elucidate the ISFC adds specific heart muscle role of the protein mutations, the speed of detection diseases (cause of myocardial affliction known) to the classification. of mutations will continue to outpace the experi- 1996 WHO-ISFC updates its classification of Richardson et al. (75) ments that are needed to confirm their functional cardiomyopathies (diseases of importance in the animal models or in vitro studies. myocardium associated with myocardial dysfunction). The update The approach to genetic testing could continue to be includes arrhythmogenic right either clinically guided, based on the sequencing of ventricular cardiomyopathy and unclassified cardiomyopathy, but genes selected on the basis of a clinical hypothesis, or excludes specific heart muscle based on sequencing of large panels of disease- disease. associated/candidate genes (35–38). However, inter- 1998 ISFC becomes WHF 2006 AHA defines cardiomyopathies as Maron et al. (1) pretation of the results rather than performing the diseases of myocardium associated test would pose a bigger challenge in the modern era with mechanical and/or electrical dysfunction, which usually (but not of next-generation sequencing. invariably) exhibit inappropriate On the basis of clinical and genetic evidence indi- ventricular hypertrophy or dilation, due to a variety of causes that cating that most cardiomyopathies are familial dis- frequently are genetic, classified as eases and that genetic diagnosis is now reachable in a fi primary or secondary. Presents rst fi visionary attempt to classify primary high proportion of patients, scienti csocieties,such cardiomyopathy by genetic origin as the Heart Rhythm Society, Heart Failure Society of (genetic, acquired, or mixed) America, and the European Society of Cardiology, 2008 ESC defines cardiomyopathies as Elliott et al. (2) myocardial disorder in which the heart have provided guidelines and recommendations for muscle was structurally and family screening and genetic testing for cardiomy- functionally abnormal. Classified dilated, hypertrophic, restrictive, opathies (Table 2). arrhythmogenic right ventricular, or unclassified cardiomyopathy subtypes as familial/genetic and THE MOGE(S) NOMENCLATURE nonfamilial/nongenetic. Maintained the importance of phenotype preceding genetic classification for In the quest for a genetic terminology, nomenclature clinical practice. such as desmosomalopathy (39), cytoskeletalopathy 2013 WHF-MOGE(S) nosology proposes a Arbustini et al. (54,55) (40),sarcomyopathy(39), channelopathy (41),car- descriptive genotype-phenotype nosology system. diodystrophinopathy (42), cardiolaminopathy (43), zaspopathy (44), myotilinopathy (45),dystrophin- AHA ¼ American Heart Association; ESC ¼ European Society of Cardiology; ISFC ¼ International Society and Federation of Cardiology; WHF ¼ World Heart Federation; WHO ¼ World Health Organization. opathy (46), alpha-B crystallinopathy (44),desminopathy (47), caveolinopathy (48),calpainopathy (49), sarcoglycanopathy (50), dysferlinopathy (51), linked to a unique phenotype, and identical gene merosinopathy (52), and emerinopathy (53) are being mutations may result in different phenotypes (Fig. 2). used. Not only would such nosology evolve to be For instance, sarcomeric gene defects associated with unmanageable, the genetic notation would define HCM also may result in DCM (30), and desmosome neither the phenotype nor the extent of systemic genes coupled with ARVC may cause DCM (31). Genes involvement. For instance, labeling an arrhythmo- encoding intermediate filaments, such as nuclear genic cardiomyopathy as desmosomalopathy would lamins, in addition to DCM may cause ARVC (32),and neither describe the clinical phenotype (right-sided, JACC VOL. 64, NO. 3, 2014 Arbustini et al. 307 JULY 22, 2014:304– 18 MOGE(S) Classification of Cardiomyopathy

biventricular, or predominantly left-sided cardio- molecular (disease gene and mutation) genetics in fa- myopathy), nor describe the gene that causes the milial disease. The MOGE(S) classification also aimed cardiomyopathy. The zaspopathy may cause isolated at describing sporadic cardiomyopathies, and speci- LVNC or dilated LVNC and may be associated with fying their etiology when known or unknown (Central skeletal myopathy (44). The troponinopathy may Illustration). Even for a sporadic cardiomyopathy, the result in hypertrophic, restrictive, or dilated pheno- genetic origin of the disease cannot be excluded unless types. Hypertrophic myosinopathy may not distin- a nongenetic cause is proven, and family screening is guish between MYH7 and MYBPC3 or light chain completed to exclude familial inheritance. In the myosin. Even if these gene-specific terms are simply absence of certainty, each cardiomyopathy would be added to the phenotype, the notations would considered a potentially genetic disease, thus, offering become unbearably complex, such as the arrhyth- families the same screening options that would be mogenic plakophillinopathy or desmocollinopathy, offered to an overt familial disease. In the past, pa- dilated desmoplakinopathy or cardiolaminopathy, tients with sporadic cardiomyopathy were frequently hypertrophic myosinopathy or troponinopathy, and labeled as nonfamilial, and diagnosed with chronic restrictive desminopathy or troponinopathy. (viral) myocarditis or peripartum cardiomyopathy. Endorsed by the World Heart Federation, the Their long-term follow-up of families unfortunately MOGE(S) classification (54,55) was developed from the often uncovered a genetic etiology upon manifestation need to describe cardiomyopathies by integrating a of the disease in offspring or siblings of the proband morphofunctional phenotype-based description with withthesamedisease. information regarding extracardiac organ invol- Borrowing from tumor, node, metastases (TNM) vement and clinical (pattern of inheritance) and staging in oncology (56), MOGE(S) nosology of

Dilated cardiolaminopathy Dilated emerinopathy

MD-AVBOHGADEG-LMNA [p.Arg190Trp] S (C-II) MD-AVBOHGX-LREG-EMD [p.Leu15Phe] S(B-II)

FIGURE 1 Similar Phenotypes but Different Inheritance May Inﬂuence Comprehensive Assessment of the Family and Genetic Counseling

Mutations in genes coding for proteins of the nuclear envelope, such as Lamin AC (LMNA) and Emerin (EMD) cause dilated cardiomyopathy (DCM) with conduction disease. The phenotypes look alike (echocardiograms revealed DCM with similar left ventricular dimensions and function in these 2 individuals), and the only distinguishing descriptor is the type of inheritance (shown in blue letters in the MOGE[S] description below the echocardiograms). Both LMNA and EMD mutations are pathologic and appear red in MOGE(S). Serum creatine phosphokinase (sCPK) can be normal in both conditions; EMD mutations are associated with X-linked recessive inheritance and LMNA mutations are associated with Autosomal dominant (AD) inheritance. 308 Arbustini et al. JACC VOL. 64, NO. 3, 2014 MOGE(S) Classiﬁcation of Cardiomyopathy JULY 22, 2014:304– 18

Association (NYHA) (I to IV) functional classes was also added. The “S” notation is especially useful when mutation carriers are healthy, or if they demonstrate imaging-verified early abnormalities sug- TNNI3 p.(Leu144Gln) gestive of cardiomyopathy. ID Phenotype Outcome Age (years) M: MORPHO-FUNCTIONAL PHENOTYPE. The “M” HCM SD 53 I:1 notation provides the clinical diagnosis, which cor- I:3 HCM SD 32 responds to the description of the phenotype such as I:4 HCM HF 65 MD (DCM), MH (HCM), MA (ARVC), MR (RCM), and MNC II:1 HCM HF 56 (LVNC). This notation corresponds to the current II:2 HCM SD 45 MR OH GAD EG-TNNI3[p. Leu144GIn] SD-IV clinical classification of cardiomyopathies. The first II:3 HCM SD 60 and commonly used clinical diagnosis is labeled as a II:5 HCM SD 50 subscript to the “M.” HCM that evolves into dilated II:6 HCM SD 47 congestive phenotype or HCM presenting with sig- II:7 HCM HF 69 fi II:8 HCM HF 67 ni cant restrictive pattern can be described as MHþD II:10 HCM/RCM HF 64 or MHþR (Figs. 2 and 4). Multiple other combinations III:3 RCM HTX 56 may be possible, such as MDþNC or MAþNC or MHþNC. “ ” fl III:5 HCM SD 8 The M notation also carries key clinical red ags III:7 HCM SD 32 such as short PR interval (PR), WPW, or AVB, which

III:8 HCM SD 32 may be displayed as MH[PR],MH[WPW], or MD[AVB].It III:14 HCM SD 14 also may describe a nonspecific or noncoded pheno- III:15 HCM SD 14 type (such as hypertrabeculation when criteria for III:2 RCM HTX 41 LVNC are not fulfilled; NS[Hypertrab]). Furthermore, IV:2 HCM HTX 56 “M” allows for the description of early phenotypes. M O G E S H+R H AD G-TNNI3[p. Leu144GIn] C-III IV:3 HCM SD 28 For instance, conditions where diagnostic criteria for IV:5 HCM/RCM HTX 41 the suspected clinical phenotype (such as DCM or IV:9 HCM SD 25 HCM) are not fulfilled but the imaging data indicate V:1 HCM SD 17 an increased LV diameter and a borderline LV func- V:2 HCM SD 32 tion (ME[D]), or a possible LV hypertrophy (ME[H])in SD V:3 HCM 14 carriers of the mutation that have caused the disease V:4 HCM Death at 25 childbirth in the family. Clinically-unaffected mutation carriers

V:6 HCM SD 17 are described as M0. When the information about the VI:1 HCM ICD 16 cardiac phenotype is not available, such as in the

deceased relatives, the description is MNA.Overall, the “M” notation is ﬂexible and suitable for any

MH OH GAD EG-TNNI3[p. Leu144GIn] SC-III clinical combination of disease phenotypes and clinical traits. FIGURE 2 The Same Genotype May Be Associated With Different O: THE INVOLVED ORGANS. The second descriptor is Phenotypic Expressions the organ involvement, which can either be the heart

Restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM)/RCM, and HCM only (OH) or in combination with other organ systems,

may occur in different family members who are carriers of the same mutation in TNNI3 such as skeletal muscle (OHþM), auditory system (p.Leu144Gln). The table shows the ID (family member), age, phenotype, and outcome of (OHþA), kidney (OHþK), nervous system (OHþN), liver family members. The echocardiographic figures refer to cardiac phenotypes in 3 family (OHþLi), gastrointestinal system (OHþG), cutaneous members indicated by the corresponding colors: RCM ¼ red-bordered figure (III:3); HCM/RCM ¼ blue-bordered figure (IV:5); HCM = green-bordered figure (VI:1). HF ¼ heart (OHþC), ocular or eyes (OHþE), respiratory or lung failure; HTx ¼ heart transplantation; ICD ¼ implantable cardioverter-defibrillator; (OHþLu), or mental retardation (OHþMR). Healthy mu- ¼ SD sudden death. tation carriers are described as O0, because the heart

is still clinically unaffected; it complements the M0 cardiomyopathies addressed 5 attributes: the mor- notation. The involvement of organs/systems other phofunctional phenotype (M), organ involvement (O), than the heart allows for convenient recognition of genetic or familial inheritance pattern (G), and etio- syndromes (Fig. 5).Thesimplecombinationofdata logical description (E) of genetic defect or non- on cardiac phenotype and involvement of kidney, genetic underlying cause. The functional status (S), liver, lung, or gastrointestinal system can usefully using the ACC/AHA (A to D) stage and New York Heart restrict the ﬁeld of diagnostic hypotheses and can JACC VOL. 64, NO. 3, 2014 Arbustini et al. 309 JULY 22, 2014:304– 18 MOGE(S) Classiﬁcation of Cardiomyopathy

address focused genetic testing. Such combinations also allow for easy recognition of syndromes. G: GENETIC INHERITANCE. The third descriptor represents genetic or familial inheritance as deduced clinically by family pedigree and screening. The inheritance includes autosomal dominant (GAD), autosomal recessive (GAR), X-linked (GXL), X-linked recessive (GXLR), or dominant (GXLD) or matrilineal

(GM) transmission. Patients who are the uniquely affected members of the family with a documented disease mutation are described as de novo (GDN)oras having phenotypically sporadic (GS)cardiomyopathy. MH+D OH GAD EG-MYH7[p.Val606Met]+LMNA[p. Asp254GIy] SC-II The negative or unknown family history (GN or GU) and the family history not investigated so far (G0)also FIGURE 3 The Presence of More Than 1 Genotype May Influence can be specified. the Phenotype E: ETIOLOGY. The notation “E” includes a description in 2 steps. The first step informs the underlying cause The figure shows a 39-year-old male patient who was initially diagnosed with HCM but has evolved to a dilated phenotype while maintaining the left of the cardiomyopathy, which may be of genetic (EG)or ventricular (LV) hypertrophy, in New York Heart Association functional class II. nongenetic cause. The latter needs to be addressed His recent echocardiogram demonstrated an LV end-diastolic volume of 150 individually as in the following paragraph; the non- ml, LV end-diastolic dimension of 55 mm, LV ejection fraction of 50%, LV identifiable cause is also noted (EN). The second nota- hypertrophy (22 mm), left atrial dilation, patent foramen ovale, moderate- tion defines precise etiology. For example, the gene severe pulmonary arterial hypertension, and pericardial effusion. Patient received cardiac resynchronization therapy/ICD implantation after resusci- mutation needs to be specified next to the EG,and tated cardiac arrest. The disease was autosomal dominant and associated with similarly, the cause of the underlying disease in mutations in the MYH7 and in LMNA both coming from the maternal lineage. nongenetic cardiomyopathies also needs to be The LMNA variant, however, is still to be considered a variant of unknown explained. significance. In genetic cardiomyopathies, the disease gene and mutation(s) can be added, such as in the case of HCM

(EG-MYH7[p. Arg403Glu]) or familial amyloidosis (EG-ATTR Universal Mutation Database (62), provide data on

[p.Val122Ile]). The “E” speciﬁcation may describe: family minor allele frequency (MAF). Finally, the studies on members who are noncarriers of the mutation that families provide segregation data, and pathology causes the disease in the family (EG-Neg), the obligate studies (Fig. 7) or in vitro systems may eventually carrier (EG-OC), or the obligate noncarrier (EG-ONC). contribute to document the abnormal expression of

EG-NA indicates nonavailability of the genetic test. the mutated protein. The way of describing complex After completion of the screening of all known dis- genetics in MOGE(S) can take advantage of color ease genes in familial disease, genetically orphan coding (app available online [63]), which provides the patients are labeled as negative: EG-N (genetic defect immediate information about pathologic mutations not identified). EG-0 indicates that genetic testing was (red), genetic variants of unknown significance (VUS) not done or was not feasible for any reason. When (yellow/orange), or a single nucleotide polymorphism all members of a single family are described, the (SNP) with some possible functional effects (green) MOGE(S) system highlights mutations that do not (Central Illustration). fully segregate with the phenotype or are part of In nongenetic cardiomyopathies, the etiology can be incomplete genotyping (Fig. 6). The increasingly described as viral (V) (the first notation) adding the complex genetics (>1mutationinasinglepatient)call virus (e.g., Coxsackie B3 virus [CB3], human cyto- for a comprehensive description of the genetic make- megalovirus [HCMV], or Epstein-Barr virus [EBV] up of the patients and families. The international presented as EV-HCMV,EV-CB3,orEV-EBV) for the second nomenclature of genetic variants may facilitate the notation; the infectious, nonviral diseases (EI)maybe description (57); the in silico evaluation supports the presented with further specification of the infectious interpretation of the significance of each variant (e.g., agent whenever possible. When the myocarditis is the

PolyPhen-2 [58] and SIFT [59]). proven cause of the myocardial disease (EM), the The large public databases, such as the National second notation could specify the origin of myocar-

Heart, Lung, and Blood Institute’sExomeSequencing ditis, such as sarcoidosis (EM-Sarcoid)ornoninfectious Project (60), the 1,000 Genomes Project (61),and giant cell myocarditis. An autoimmune etiology, 310 Arbustini et al. JACC VOL. 64, NO. 3, 2014 MOGE(S) Classiﬁcation of Cardiomyopathy JULY 22, 2014:304– 18

TABLE 2 Genetic Testing: Position of the ScientiﬁcSocieties

Strength of Type of Cardiomyopathy Recommendation Evidence/Class

Heart Failure Society of America, 2009 (76) All patients with Clinical screening for cardiomyopathy is recommended: cardiomyopathy In asymptomatic first-degree relatives A In asymptomatic at-risk relatives who are known to carry the disease-causing mutation A In asymptomatic at-risk relatives when genetic testing has not been performed or has not identified a disease-causing mutation A Clinical screening consists of history, physical examination, ECG, echocardiography, CK-MM, signal averaged ECG in ARVC only, B 24-h Holter monitoring in HCM and ARVC, exercise treadmill testing in HCM, and CMR in ARVC Clinical screening should be considered at scheduled follow-up intervals or at any time that signs and symptoms appear At-risk first-degree relatives with any abnormal clinical screening test (regardless the genotype) should be considered for repeat C clinical screening at 1 year HCM Family history for $3 generations A Clinical screening for cardiomyopathy in asymptomatic first-degree relatives A Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening and A management (MYH7, MYBPC3, TNNT2 TNNI3, TPMI, ACTC1, MYL2, and MYL3). DCM Family history for $3 generations A Clinical screening for cardiomyopathy in asymptomatic first-degree relatives A Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening and B management (LMNA, MYH7, TNNT2, SCN5A, DES, MYBPC3, TNNI3, TPMI, ACTC, PLN, LDB3, and TAZ) RCM Family history for $3 generations B Clinical screening for cardiomyopathy in asymptomatic first-degree relatives B Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening and C management (gene tests: uncertain) ARVC Family history for $3 generations A Clinical screening for cardiomyopathy in asymptomatic first-degree relatives A Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening and A management (DSP, PKP2, DSG2, and DSC2) LVNC Family history for $3 generations A Clinical screening for cardiomyopathy in asymptomatic first-degree relatives B Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening and C management (gene tests: uncertain) CMP with extracardiac Family history for $3 generations A traits Clinical screening for cardiomyopathy in asymptomatic first-degree relatives A Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening and A management

ESC Position Statement on Genetic Counseling and Testing in Cardiomyopathies, 2010 (16) Diagnostic work-up Genetic counseling 1 in patients and Information for patients and families: genetic origin, inheritance pattern and heritability, phenotype and age-dependence, families with CMP benefits of clinical family screening, pregnancy-related risk, available genetic tests, and contacts with charities and referral (the numbers in centers. the right column indicate the steps) Clinical screening in relatives of probands with cardiomyopathy when genetic test is not available 2 First-degree relatives, unless a nongenetic cause of the disease is proven Age for starting the first screening and scheduled monitoring, based on age, type of cardiomyopathy, lifestyles, and symptoms (family-tailored monitoring) Clinical screening in asymptomatic relatives who carry a disease-causing mutation 3 Monitoring including ECG, ECHO, exercise test, 24-h Holter-ECG, and disease-specific clinical evaluations Genetic testing and positive diagnosis 4 Appropriate for the diagnosis in special or atypical forms of cardiomyopathies, in the setting of expert teams after detailed clinical and family assessment Genetic testing and predictive diagnosis 5 Asymptomatic relatives when the disease-causing mutation has been previously identified in the family Appropriate Post-mortem genetic tests: the deceased family member is the only affected in the family; appropriate in HCM and ARVC; To be considered questionable in sporadic DCM and RCM In children, at the age at which cardiac examination is useful To be considered Genetic testing and prognostic testing 6 Cannot be systematically recommended for prognostic stratification Non systematic In selected patients or for selected types of cardiomyopathies; the setting is of expert teams after clinical and family To be considered assessment Genetic testing and pre-natal diagnosis 7 Continued on the next page JACC VOL. 64, NO. 3, 2014 Arbustini et al. 311 JULY 22, 2014:304– 18 MOGE(S) Classification of Cardiomyopathy

TABLE 2 Continued

ESC Position Statement on Genetic Counseling and Testing in Cardiomyopathies, 2010 (16) Legal rules for pre-natal diagnosis vary in different countries No standards

Selected disorders or high-risk situations in the setting of expert teams after detailed clinical and family assessment Appropriate Molecular analyses and appropriate and correct interpretation 8 Should be performed in certiﬁed diagnostic laboratories; requires expert multidisciplinary centers Suggestion Phenotype and family assessment should be available for appropriate tests and correct interpretation Suggestion Post-test genetic counseling 9 Recommended for all patients and families (appropriate) with a cardiomyopathy Recommended Should be performed by speciﬁcally-trained professionals, in a multidisciplinary manner, and in specialized centers Suggestion

HRS/EHRA, 2011 (77) HCM Genetic test should be performed in patients with clinical diagnosis of HCM, either comprehensive or targeted I (MYBPC3, MYH7, TNNI3, TNNT2, TPM1) Mutation-specific genetic testing in relatives of mutated probands I DCM Diagnosis in probands/index patients with DCM with CCD, either comprehensive or targeted (LMNA and SCN5A)I Mutation-specific genetic testing in relatives of mutated probands I Patients with familial DCM: confirm diagnosis; identify patients at risk of arrhythmias; and facilitate family screening IIa and monitoring plans RCM Mutation-specific test in family members after identification of the causative mutation in the index case. I Patients with clinical suspicion for RCM IIb ACM/ARVC Mutation-specific test in family members after identification of the causative mutation in the index case. I Comprehensive and targeted (DSC2, DSG2, DSP, JUP, PKP2, and TMEM43) for patients satisfying task force criteria IIa for ACM/ARVC. Patients with 1 major or 2 minor criteria, according to the 2010 task force criteria IIb Patients with only a single minor criterion III LVNC Mutation-specific test in family members after identification of the causative mutation in the index case. I Patients with an established clinical diagnosis of LVNC IIb

The table summarizes the strength of evidence for genetic testing provided in existing documents from scientiﬁc societies with the caveat that randomized and/or blinded studies do not exist and published data are either from a single institution or multicenter collections or registries. ACM ¼ arrhythmogenic cardiomyopathy; ARVC ¼ arrhythmogenic right ventricular cardiomyopathy; CCD ¼ cardiac conduction disease; CK-MM ¼ creatine kinase-MM; CMR ¼ cardiac magnetic resonance; DCM ¼ dilated cardiomyopathy; ECG ¼ electrocardiogram; ECHO ¼ echocardiogram; EHRA ¼ European Heart Rhythm Association; ESC ¼ European Society of Cardiology; HCM ¼ hypertrophic cardiomyopathy; HRS ¼ Heart Rhythm Society; LVNC ¼ left ventricular noncompaction; RCM ¼ restrictive cardiomyopathy.

S: FUNCTIONAL STATUS. “ ” either suspected or proven (EAI-S or EA-P), may popu- S, in 2 notations, de- late the ﬁrst notation followed by the speciﬁceti- scribes the heart failure ACC/AHA stage (A to D) ology, such as rheumatoid arthritis or systemic coupled with NYHA functional class (I to IV), presented lupus erythematosus. The MOGE(S) app allows the as SA-I or SC-II,andsoon.Thedescriptor“S” is optional, description of each proven diagnosis (e.g., MD but may come in handy for the description of early

OHþCþS G0 EAI-P-Rheumatoid Arthritis SC-II or MD OHþC G0 cardiomyopathy. The ACC/AHA guidelines include

EAI-P-Rheumatoid Arthritis SB-II). Nonheritable amyloid- patients with a family history of cardiomyopathy in osis (EA-K,EA-L,orEA-SAA) represent kappa, lambda, or stage A. In families with known mutation, the diag- serum amyloid A protein characterization, respec- nosis of early cardiomyopathies can be further sup- tively. Toxic cardiomyopathies, either endogenous, ported by the presence of the mutation(s), whereas in such as pheochromocytoma-related cardiomyopathy, genetically orphan familial cardiomyopathy, only the or drug-induced cardiomyopathy, are described early imaging markers of the disease can be high-

(ET-Pheo or ET-Chloroquine). When the former is described lighted. This description could be especially useful for in the context of a syndrome (such as VHL, MEN2A/2B, those individuals seeking a definitive recommenda- or NF1), the description can be implemented by adding tion from the physician about their sport worthiness. thenameofthesyndrome(i.e.,ET-Pheo-VHL). The Although criteria for early diagnosis of cardiomyopa- Loeffler’s eosinophilic endomyocarditis can be de- thy are not systematically described, increasingly, scribed according to the cause as either being id- family screening and monitoring have revealed that iopathic or a part of myeloproliferative disorder the cardiomyopathies likely serve a long pre-clinical or associated with the somatic chromosomal rearrange- subclinical course before the onset of symptoms or the ment of PDGFRa or PDGFRb genes that generate a manifestation of the clinical phenotype (65). fusion gene encoding for constitutively active PDGFR The Central Illustration shows the MOGE(S) tyrosine kinases (64). system notations and modeling. The alphabetical 312 Arbustini et al. JACC VOL. 64, NO. 3, 2014 MOGE(S) Classification of Cardiomyopathy JULY 22, 2014:304– 18

M O G E S MORPHO-FUNCTIONAL ORGAN/SYSTEM GENETIC INHERITANCE ETIOLOGY STAGE PHENOTYPE INVOLVEMENT PATTERN NOTATION

Proband’s Clinical history Genetic counseling Clinical Genetic testing Functional cardiomyopathy and evaluation with pedigree family screening in the proband status (CM) diagnosis ACC/AHA, (DCM, HCM, RCM, Organ NYHA ARVC/D, LVNC) involvement: asymptomatic Extracardiac Familial Non-familial; relative Positive Negative organs/tissues Phenotypically unaware of CHARACTERISTICS sporadic the disease

Multidisciplinary Inheritance Informative Relatives Cascade New tests evaluation AD, AR XL and non- with ECG genetic novel according per (R or D) or informative and/or Echo testing in genes clinical needs Matrilineal families abnormalities relatives or diagnostic hypothesis Consultant Healthy family Regular non-informed members monitoring about family with normal in relatives history ECG and ECHO

D Dilated H Heart N Family history negative G Genetic cause ACC-AHA LV=left ventricle stage H Hypertrophic U Family history unknown OC Obligate carrier RV=right ventricle represented R Restrictive RLV=biventricular AD Autosomal dominant ONC Obligate non-carrier as letter SUBSCRIPT A, B, C, D R EMF M Muscle (skeletal) AR Autosomal recessive DN De novo Endomyocardial Neg Genetic test negative for NA N Nervous XLD X-linked dominant the known familial mutation not applicable LV=left ventricle C Cutaneous XLR X-linked recessive N NU RV=right ventricle E Eye, Ocular XL X-linked not used RLV=biventricular 0 No genetic test, any reason* A Auditory M Matrilineal A ARVC G-A-TTR Genetic amyloidosis followed by M=major K Kidney 0 Family history not investigated* G-HFE Hemochromatosis NYHA class m=minor G Gastrointestinal Undet Inheritance still undetermined Non-genetic etiologies: represented c=category as Roman LV= left ventricle Li Liver S Phenotypically Sporadic M Myocarditis numeral RV=right ventricle (apparent or real) Lu Lung V Viral infection (add the virus I, II, III, IV RLV=biventricular S Skeletal NC LVNC AI Autoimmune/immune- 0 Absence of E Early, with type mediate; suspected (AI-S), organ/system in parentheses proven (AI-P) involvement*, NS e.g. in family A Amyloidosis (add type: phenotype members who A-K, A-L, A-SAA) are healthy I Infectious, non viral NA Information mutation carriers; (add the infectious agent) non available the mutation is T Toxicity (add cause/drug) 0 inheritance in G Eo Hypereosinophilic heart disease O Other

CENTRAL ILLUSTRATION The MOGE(S) Nosology System for Classifying CM Patients

Evaluation of cardiomyopathy patients and development of MOGE(S) nosology. (M) The morphofunctional phenotype description may contain more information using standard abbreviations: AVB ¼ atrioventricular block; LQT ¼ prolongation of the QT interval; YPR ¼ short PR interval; YR ¼ low electrocardiographic voltages; WPW ¼ Wolf Parkinson White syndrome; and other clinical red flags. These red flags are to be placed in parentheses after the notation of morphofunctional phenotype. Overlapping (HþR), (DþA), (NCþH), (HþD), (DþNC) or more complex combinations such as (HþRþNC). *Notation is zero (0) not the letter “O.” (E) The etiologic annotation provides the description of the specific disease gene and mutation, as well as a description of nongenetic etiology. Even when genetic analysis is not available, the (G) may inform about a genetic disease, supporting family monitoring strategies. #According to the Human Genome Variation Society, genetic variants should be classified based on their effects on gene function as: affecting function, probably affecting function, unknown (variants of unknown significance [VUS]), probably not affecting function, and not affecting function. A color code assigned to each variant can provide information about the potential role of the identified variant: affects function or probably affects function (red); Variant of Unknown Significance (VUS) (yellow); and probably does not affect function (or probably no functional effect) or does not affect function (no functional effect) (green). The compilation is guided by the MOGES app (63). ACC ¼ American College of Cardiology; AHA ¼ American Heart Association; ARVC/D ¼ arrhythmogenic right ventricular cardiomyopathy/dysplasia; DCM ¼ dilated cardiomyopathy; ECG ¼ electrocardiogram; ECHO ¼ echocardiogram; HCM ¼ hypertrophic cardiomyopathy; LVNC ¼ left ventricular noncompaction; NYHA ¼ New York Heart Association; RCM ¼ restrictive cardiomyopathy.

components are likely going to change in parallel the Sanger and post-Sanger era. To facilitate the with new scientific information. The proposed application and to provide a simple summary for nomenclature reflects the current diagnostic work- the patient’s clinical record by the MOGE(S) system, up of cardiomyopathies for evaluation of the we encourage the use of the web-assisted app (63), phenotype, family screening, and genetic testing in which can be downloaded for smartphones and JACC VOL. 64, NO. 3, 2014 Arbustini et al. 313 JULY 22, 2014:304– 18 MOGE(S) Classification of Cardiomyopathy

tablets and can be ﬂexibly edited, expanded, or modiﬁed.

FLEXIBILITY AND EXPANDIBILITY OF MOGE(S) SYSTEM

Similar to the TNM staging system, MOGE(S) allows flexibility and can be expanded when needed. The authors believe that the nomenclature will evolve to become more comprehensive and user-friendly as clinicians begin to apply it in practice. Investigators from around the world have suggested modifications in MOGE(S) nosology (66,67),suchasinARVC/ M O G E -MYL6 S arrhythmogenic ventricular cardiomyopathy and H+R H DN G [p.Gly162Arg] D-IV EMF. The diagnostic criteria for ARVC have been FIGURE 4 debated and modified, and the MA notation can be Variation in Phenotypic Expression further specified with the help of the major [M] or The hypertrophic cardiomyopathy (HCM) phenotype with restrictive pattern may be caused minor [m] diagnostic clues that are variably combined by defects of sarcomere genes, including less common genes, such as MYL6, that code the fi in the Modi ed Task Force Criteria (68). These criteria myosin light chain 6 protein. The echocardiogram is from a 12-year-old girl waiting for define ARVC as definite when 2 major [M2], 1 major heart transplantation, in New York Heart Association functional class IV, who genetically and 2 minor [M1þm2], or 4 minor criteria from 4 showed a de novo mutation. The echocardiogram shows normal left ventricular (LV) ¼ different categories [m4X4] are present; borderline end-diastolic volume, borderline systolic LV dysfunction (ejection fraction 50%), sig- nificant diastolic dysfunction, mild LV hypertrophy (interventricular septum ¼ 12 mm), when 1 major and 1 minor [M1þm1] or 3 minor criteria severe biatrial dilation (right > left), mild right ventricular dysfunction, tricuspid regur- from different categories [m3X3] are present; and gitation, mild pulmonary hypertension (40 mm Hg), and pericardial effusion. possible when 1 major or 2 minor criteria from different categories [M1þm2X2] are present. The number of the major and minor criteria can be added to the main MA notation. A definite diagnosis may be patients deserving of a device implantation for ar- described as MA[M2],MA[M1þm2X2],orMA[m4X4];a rhythmias. The MOGE(S) committee is working with borderline diagnosis as MA[M1þm1] or MA[m3X3];anda electrophysiologists to develop a clinically-useful fast possible diagnosis as MA[M1] or MA[m2x2]. The “M” rhythm disturbances description as a third “S” notation can therefore summarize not only the diag- notation. nosis or diagnostic hypothesis but also the strength of the diagnosis (69). MOGE(S) IN DAY-TO-DAY A recent commentary appropriately emphasized the CLINICAL PRACTICE need for morphological notation for important cardiomyopathies from low- and middle-income coun- Upon the first reading, MOGE(S) may appear to be a tries, such as tropical endomyocardial fibrosis (EMF) complex nosology system that further complicates (67), which is one of the most prevalent causes of the description of cardiomyopathies. However, in restrictive cardiomyopathy (70).BecauseEMFcan practice, it is rather simple to apply and the use of the manifest as isolated or dominant LV EMF, isolated or app provides a guided step-by-step compilation. The dominant right ventricular EMF, or biventricular (right use of MOGE(S) does not obligate a clinician to ventricular þ LV) EMF, MOGE(S) can describe the dis- include genetic testing. As presented in the Central easeaswellasthesingleordoubleventricular Illustration, the genetic tests may not be available or involvement (64). feasible. However, it behooves clinicians to make an A possible limitation of the MOGE(S) nosology is effort to elicit family history, especially about sudden the lack of information about 1 of the most important death, and document familial patterns. MOGE(S) clinical issues in cardiomyopathies: arrhythmias. offers a hierarchical (Phenotype/Organ/tissue In- As anticipated (54,55),theclassification of arrhyth- volvement/Genetic /familial/Etiology/gene) but mias is far from the aim of MOGE(S); however, we flexible structure that readily provides several have received overwhelming suggestions for expan- descriptors in a standardized language. This system sion of the “S” notation to include the information also necessitates the routine diagnostic work-up about rhythm disturbances in cardiomyopathies that for cardiomyopathies in probands and relatives. would give the clinical advantage of highlighting Whether or not all information queried by MOGE(S) is 314 Arbustini et al. JACC VOL. 64, NO. 3, 2014 MOGE(S) Classification of Cardiomyopathy JULY 22, 2014:304– 18

Mitochondrial Cardiomyopathy

MH+D (WPW) OH+M+N+E+A GM EG-MTDNA[A3243G]

FIGURE 5 HCM Phenocopy

The figure shows an LV hypertrophy associated with a mitochondrial DNA mutation that evolves into dilated phenotype. The multiorgan involvement clarifies the syndrome. MOGE(S) describes the type of cardiomyopathy (HþD) and the involvement of skeletal muscle, ocular, and auditory systems, as well as the nervous system. The figure shows the electrocardiographic and echocardiographic features of a typical mitochondrial cardiomyopathy. Electrocardiogram and echocardiogram both show evidence of LV hypertrophy; electrocardiogram also shows Wolff-Parkinson-White syndrome pre-excitation. HCM evolves though LV dilation and dysfunction; in the present case the ejection fraction was 30%. The cryptogenic stroke was the cause of death in this patient.

immediately available does not hamper its applica- App 2 includes the possibility of selecting “ACC-AHA tion. In day-to-day practice, MOGE(S) can be applied not used” when not applied or applicable. at the bedside, and collected data can be easily sub- The following are a few examples from our data- mitted to repositories. In a discharge summary, the base pertaining to the application of MOGE(S):

concluding diagnosis “Dilated Cardiomyopathy (MD “MD OHþM GAD EG-NA SC-III” represents a baseline OH GAD EG-MYH7[Ile533Asn] SB-II)” may provide compre- description of the patient (II:1) who was diagnosed hensive information about the patient. For instance, with DCM, presenting with both cardiac and mus- after a family screening, the mutation does not cle involvement. He was a member of a family with segregate or a second mutation is identified. In that the autosomal dominant DCM, but the genetic case, MOGE(S) allows the description of new infor- testing was not available. The functional status mation (MD OH GAD EG-MYH7[Ile533Asn]þMYBPC3[Arg326Gln]). was described as ACC/AHA stage C and NYHA (S) is a dynamic notation that may modify during functional class III. Subsequently, when the ge- follow-up, and its use can provide information about netic information became available, the notation change in the functional status and evolution of was changed to “MD OHþM GAD EG-LMNA[p.Arg190Trp] remodeling status. Although NYHA functional class is SC-III.” During follow-up, after starting the treat- universally used, ACC/AHA stage has been less ment with an improvement in the NYHA functional commonly applied in clinics. It can be difficult to class, the functional status changed to “MD OHþM apply to cardiomyopathies, such as classical ARVC, GAD EG-LMNA[p.Arg190Trp] SC-I.” At echocardiographic especially when diagnosed on 2 major criteria such as evaluation a brother (II:3) of the proband showed majorECGchanges(e.g.,negativeTwavesinv1 to v3) LV dilation, and borderline LV ejection fraction: he and sudden cardiac death or a first-degree relative or was described as “ME[D] OH GAD EG-NA SB.” Further a known pathologic mutation. MOGE(S), however, in the course of the follow-up, the description was does not obligate us to fill all fields, and the MOGE(S) JACC VOL. 64, NO. 3, 2014 Arbustini et al. 315 JULY 22, 2014:304– 18 MOGE(S) Classification of Cardiomyopathy

I:1 I:2 AF, stroke Age: 59 years Genetic test: not done AF Age: 90 years II:1 II:2 II:3 II:4 II:5 Genetic test: negative

HCM, LVT=18mm HCM LVT=16mm LVT=9mm Onset: 30 years Onset: 52 yrs Age: 56 Death:37 years Age=56 years III:1years III:2 III:3 Genetic test: NA Genetic test: Positive Genetic test: LVT=8mm Negative LVT=8mm Age=36 years Age=24 years Genetic test: IV:1 IV:2 IV:3 IV:4 Genetic test: positive negative

V:1

Family member MOGES

I:1 MOOOGUEG-O

I:2 MOOOGUEG-O

II:1 MOOOGUEG-O

II:2 MOOOGUEG-O

II:3 M0O0GUEG-0

II:4 M0O0GUEG-(OC)

II:5 M0O0GUEG-NegSA-I

III:1 MHOHGUEG-(OC)

III:2 M0O0GUEG-NegSA-I

III:3 MHOHGUEG-MYBPC3 [IVS16-1G>A]SA-I

IV:1 MOOOGADEG-MYBPC3 [IVS16-1G>A]SA-I

IV:2 M0O0GUEG-O

IV:4 M0O0GADEG-NegSA-I

V:1 M0O0GADEG-OSA-I

FIGURE 6 Variable Penetrance and Mutation Segregation With Phenotype

The proband (arrow) is a carrier of a MYBPC3 (IVS16-1A>G) mutation that is known to be associated with hypertrophic cardiomyopathy (HCM). Her brother (obligate carrier) was affected by the age of 30 years. The niece (daughter of the brother) is a carrier of the mutation and healthy at the age of 36 years, with a maximal left ventricular thickness (LVT) of 8 mm. Although the penetrance can be variable and late, the mutation does not seem to segregate with the phenotype by age. AF ¼ atrial ﬁbrillation.

completed as “ME[D] OH GAD EG-LMNA[p.Arg190Trp] maternal family history for loss of hearing, and

SB-I.” He was classiﬁedasstageB-Iduetoasymp- diabetes. The “O” notation in this case offers an tomatic myocardial involvement. Another brother instant suspicion of a known pathologic mutation in (II:2) underwent genetic testing and an echocar- mitochondrial deoxyribonucleic acid (MtDNA). diographic examination and tested positive to She also was a carrier of the heterozygous GJB2 the genetic screening but echocardiogram was del30G that, when homozygous, causes hearing

entirely normal. He was described as “M0 O0 GAD loss.Twosistersshowedhearinglossanddiabetes.

EG-LMNA[p.Arg190Trp] SA-I.” (Online Fig. 1 shows the The phenotype of the proband was severe, as family pedigree at the end of the family screening.) described by the functional status (ACC/AHA stage

“MD OHþMþNþA GM EG-MtDNA [tRNALeu A3243G] þ GJB2 C, NYHA functional class IV). We could not trace

[del30G hetero] SD-IV” describes a patient (II:3) admitted reports of the early phase of the cardiomyopathy with severe DCM, with involvement of the skeletal that could theoretically have been HCM in origin muscle, prior stroke, hearing loss, a positive (Online Fig. 2). 316 Arbustini et al. JACC VOL. 64, NO. 3, 2014 MOGE(S) Classiﬁcation of Cardiomyopathy JULY 22, 2014:304– 18

is the only affected member of the family; the young daughter also carries the 2 variants and is healthy, only showing increased trabeculation of the LV apex. The phenotype in the proband is severe as described by the functional status (ACC/ AHA stage C, NYHA functional class II to III) (Online Fig. 3).

“MH OH GAD EG-MYBPC3[IVS16-1G>A] SB-II” describes a patient (III:3) diagnosed with HCM, exclusive involvement of the heart, with a positive family A B history in which the disease is inherited as an autosomal dominant trait, and caused by a known MD(AVB)OHGADEG-LMNA[p.Arg190Trp] SB-I mutation in MYBPC3.Thefunctionalstatusis described by the ACC/AHA stage B, NYHA functional class II. After family screening, her daughter was found to be unaffected and to not be a carrier

of the mutation identiﬁed in the proband (M0 O0

GAD EG-Neg). The sister also was not affected, but was a carrier of the mutation identiﬁed in the

proband (M0 O0 GAD EG-MYBPC3[IVS16-1G>A] SA-I). Her niece, daughter of the affected brother (who died without genetic testing), was not affected but was a carrier of the mutation identiﬁed in the proband. C D This simple information describes her father as the obligate carrier of the mutation. The evaluation of M O G E -DYS S D(>sCPK) H+M X-LR G [Del45-48] C-II the niece, however, presented the problem of nonsegregation of the genotype with the phenotype FIGURE 7 Genotypic Expression May Play a Role in Arrhythmogenicity by age. She showed a maximal LV thickness of 8 mm

When tissue samples are available, such as in endomyocardial biopsies or from hearts excised by the age of 36 years, whereas her father was during transplantation, the expression of the mutated proteins can be investigated either affected by the age of 30 years (Fig. 6). for diagnosis (Dystrophin) or for supporting the diagnostic hypothesis and investigating “MR OHþMþNþLi GN EGDN-LAMP2 [p.His260Pro fs22] SC-II” the effects of the mutations (i.e., Lamin AC). The 2 sets of the immunohistochemically- describes a patient diagnosed with RCM, along stained histomicrographs refer to patients with either dilated cardiolaminopathy (top) with associated myopathy, cognitive impairment, or dilated cardiodystrophinopathy (bottom). The endomyocardial biopsy above shows decreased expression of the protein (B) compared with the normal control sample (A). and liver disease. The patient had a negative family The MOGE(S) describes the clinical and genetic status. Below, the endomyocardial biopsy history and screening. He was found to carry a from the patient with dilated cardiodystrophinopathy (D) with multifocal loss of frame-shift mutation in the LAMP2 gene; the protein expression as typically observed in heart of patients with dystrophin defects, mutation was absent in both parents. The car- versus normal control sample (C). The MOGE(S) describes the clinical and genetic diomyopathy was rather severe at onset, with ar- status of the patient. The cardiolaminopathy patient with mildly-normal left ventricular (LV) systolic function has demonstrated life-threatening tachyarrhythmias. However, rhythmias and advanced LV function impairment the dystrophinopathy patient with large LV dimensions and severely depressed LV (Online Fig. 4). ejection fraction did not require implantable cardioverter-deﬁbrillator intervention for 2 years. CONCLUSIONS

A substantial increase in the knowledge of the genetic bases of cardiomyopathy calls for a standardized, ﬁ “MAþHypertrab OH GUndet EG-LDB3 [p.Thr507Asn] þ DSG2 universally acceptable classi cation/nosology system

[p.Lys479Glu] SB-II-III” describes a patient (II:1) diag- that integrates phenotype description as well as nosed with ARVC and hypertrabeculation, exclu- genetic information. The flexible MOGE(S) system sive involvement of the heart, without a positive facilitates the transition of description of cardiomy- family history; likely, but still not proven, a opathies from the pre-genetic to the genetic era and recessive disease. In this patient, we identified 2 ensures the capture of an enormous amount of variants of uncertain significance (VUS, yellow- data that could be lost if not systematically regis- orange color in the MOGES app) of biparental tered.TheuseoftheMOGESappobligatesdescrip- origin in 2 different genes. To date, the proband tion of the results achieved in all diagnostic steps, JACC VOL. 64, NO. 3, 2014 Arbustini et al. 317 JULY 22, 2014:304– 18 MOGE(S) Classification of Cardiomyopathy

including clinical cardiologic evaluation, extra- REPRINT REQUESTS AND CORRESPONDENCE: cardiac evaluation, clinical genetics, family screen- Dr. ing, molecular genetics when possible, and functional Jagat Narula, Icahn School of Medicine at Mount status. This exercise provides uniform language and Sinai, Division of Cardiology, One Gustave L. Levy easy-to-capture identical information for data mining Place, Box 1030, New York, New York. E-mail: queries. [email protected].

REFERENCES

1. Maron BJ, Towbin JA, Thiene G, et al. Contem- statement of the European Society of Cardiology 23. Hershberger RE, Siegfried JD. Update 2011: porary definitions and classification of the cardio- Working Group on Myocardial and Pericardial clinical and genetic issues in familial dilated car- myopathies: an American Heart Association Diseases. Eur Heart J 2013;34:2636–48, 2648a– diomyopathy. J Am Coll Cardiol 2011;57:1641–9. Scientific Statement from the Council on Clinical 2648d. 24. Jarcho JA, McKenna W, Pare JA, et al. Mapping Cardiology, Heart Failure and Transplantation 12. Jacoby D, McKenna WJ. Genetics of inherited a gene for familial hypertrophic cardiomyopathy Committee; Quality of Care and Outcomes cardiomyopathy. Eur Heart J 2012;33:296–304. to chromosome 14q1. N Engl J Med 1989;321: Research and Functional Genomics and Trans- 1372–8. lational Biology Interdisciplinary Working Groups; 13. Watkins H, Ashrafian H, Redwood C. Inheri- and Council on Epidemiology and Prevention. ted cardiomyopathies. N Engl J Med 2011;364: 25. Meder B, Rühle F, Weis T, et al. A genome- Circulation 2006;113:1807–16. 1643–56. wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy. Eur Heart J 2. Elliott P, Andersson B, Arbustini E, et al. 14. Maron BJ, Maron MS, Semsarian C. Genetics of 2014;35:1069–77. Classification of the cardiomyopathies: a position hypertrophic cardiomyopathy after 20 years: statement from the European Society of Car- clinical perspectives. J Am Coll Cardiol 2012;60: 26. Villard E, Perret C, Gary F, et al. A genome-wide diology Working Group on Myocardial and Peri- 705–15. association study identifies two loci associated with cardial Diseases. Eur Heart J 2008;29:270–6. heart failure due to dilated cardiomyopathy. Eur 15. Lopes LR, Rahman MS, Elliott PM. A systematic Heart J 2011;32:1065–76. 3. United Healthcare. Available at: http://www.acc. review and meta-analysis of genotype-phenotype org/clinical/statements.html.AccessedJune5,2014. associations in patients with hypertrophic cardio- 27. Hershberger RE, Hedges DJ, Morales A. myopathy caused by sarcomeric protein muta- Dilated cardiomyopathy: the complexity of a 4. Baig MK, Goldman JH, Caforio AL, et al. Familial tions. Heart 2013;99:1800–11. diverse genetic architecture. Nature Rev Cardiol dilated cardiomyopathy: cardiac abnormalities are 2013;10:531. common in asymptomatic relatives and may 16. Charron P, Arad M, Arbustini E, et al. Genetic represent early disease. J Am Coll Cardiol 1998;31: counselling and testing in cardiomyopathies: a 28. Romero J, Mejia-Lopez E, Manrique C, et al. 195–201. position statement of the European Society of Arrhythmogenic right ventricular cardiomyopathy Cardiology Working Group on Myocardial and 5. Gavazzi A, Repetto A, Scelsi L, et al. Evidence- (ARVC/D): a systematic literature review. Clin Med Pericardial Diseases. Eur Heart J 2010;3:2715–26. – based diagnosis of familial non-X-linked dilated Insights Cardiol 2013;7:97 114. cardiomyopathy. Prevalence, inheritance and 17. Rapezzi C, Arbustini E, Caforio APL, et al. 29. Mogensen J, Arbustini E. Restrictive cardio- characteristics. Eur Heart J 2001;22:73–81. Diagnostic work-up in cardiomyopathies: bridging myopathy. Curr Opin Cardiol 2009;24:214–20. the gap between clinical phenotypes and final 6. Murphy RT, Thaman R, Blanes JG, et al. Natural 30. Merlo M, Sinagra G, Carniel E, et al. Sarcomeric diagnosis. A position statement from the ESC history and familial characteristics of isolated left gene causing DCM: poor prognosis of rare sarco- Working Group on Myocardial and Pericardial ventricular non-compaction. Eur Heart J 2005;26: meric gene variants in patients with dilated car- – Diseases. Eur Heart J 2013;34:1448–58. 187 92. diomyopathy. Clin Transl Sci 2013;6:424–8. 18. Karamitsos TD, Neubauer S. The prognostic 7. Mahon NG, Murphy RT, MacRae CA, et al. 31. Zhang M, Tavora F, Burke A. Desmosomal value of late gadolinium enhancement CMR in Echocardiographic evaluation in asymptomatic protein gene mutations in patients with idiopathic nonischemic cardiomyopathies. Curr Cardiol Rep relatives of patients with dilated cardiomyopathy DCM. Heart 2011;97:2090. reveals preclinical disease. Ann Intern Med 2005; 2013;15:326. – 32. Quarta G, Syrris P, Ashworth M, et al. Muta- 143:108 15. 19. Quarta G, Sado DM, Moon JC. Cardiomyopa- tions in the Lamin A/C gene mimic arrhythmogenic 8. McKenna WJ, Spirito P, Desnos M, et al. Expe- thies: focus on cardiovascular magnetic resonance. right ventricular cardiomyopathy. Eur Heart J rience from clinical genetics in hypertrophic car- Br J Radiol 2011;84:S296–305. 2012;33:1128–36. diomyopathy: proposal for new diagnostic criteria 20. Arbustini E, Pasotti M, Pilotto A, et al. Desmin 33. Friedrich FW, Wilding BR, Reischmann S, et al. in adult members of affected families. Heart 1997; accumulation restrictive cardiomyopathy and – Non sarcomeric genes cause HCM: evidence for 77:130 2. atrioventricular block associated with desmin gene FHL1 as a novel disease gene for isolated hyper- 9. Nava A, Bauce B, Basso C, et al. Clinical profile defects. Eur J Heart Fail 2006;8:477–83. trophic cardiomyopathy. Hum Mol Genet 2012;21: and long-term follow-up of 37 families with 21. Arbustini E, Cecchi F, Dubourg O, et al. 3237–54. arrhythmogenic right ventricular cardiomyopathy. Myocardial and Pericardial Working Group of the – 34. Girolami F, Ho CY, Semsarian C, et al. Clin- J Am Coll Cardiol 2000;36:2226 33. European Society of Cardiology. The need for ical features and outcome of hypertrophic car- 10. Hamid MS, Norman M, Quraishi A, et al. Pro- European Registries in inherited cardiomyopathies. diomyopathy associated with triple sarcomere spective evaluation of relatives for familial Eur Heart J 2002;23:1972–4. protein gene mutations. J Am Coll Cardiol 2010; arrhythmogenic right ventricular cardiomyopathy/ 22. Norton N, Li D, Rampersaud E, et al. National 55:1444–53. dysplasia reveals a need to broaden diagnostic Heart, Lung, and Blood Institute GO Exome criteria. J Am Coll Cardiol 2002;40:1445–50. 35. Lopes LR, Elliott PM. New approaches to the Sequencing Project and the Exome Sequencing clinical diagnosis of inherited heart muscle dis- 11. Caforio AL, Pankuweit S, Arbustini E, et al. Project Family Studies Project Team. Exome ease. Heart 2013;99:1451–61. European Society of Cardiology Working Group on sequencing and genome-wide linkage analysis in Myocardial and Pericardial Diseases. Current state 17 families illustrate the complex contribution of 36. Sturm AC. Genetic testing in the contemporary of knowledge on aetiology, diagnosis, manage- TTN truncating variants to dilated cardiomyopa- diagnosis of cardiomyopathy. Curr Heart Fail Rep ment, and therapy of myocarditis: a position thy. Circ Cardiovasc Genet 2013;6:144–53. 2013;10:63–72. 318 Arbustini et al. JACC VOL. 64, NO. 3, 2014 MOGE(S) Classification of Cardiomyopathy JULY 22, 2014:304– 18

37. Morales A, Hershberger RE. Genetic evaluation blind, placebo-controlled clinical trial. Orphanet 67. Mayosi BM. Cardiomyopathies: MOGE(S): a of dilated cardiomyopathy. Curr Cardiol Rep 2013; J Rare Dis 2013;8:26. standardized classification of cardiomyopathies? 15:375. Nat Rev Cardiol 2014;11:134–5. 52. Hoffman EP, Clemens PR. HyperCKemic, prox- 38. Frese KS, Katus HA, Meder B. Next-generation imal muscular dystrophies and the dystrophin 68. Marcus FI, McKenna WJ, Sherrill D, et al. sequencing: from understanding biology to membrane cytoskeleton, including dystrophino- Diagnosis of arrhythmogenic right ventricular personalized medicine. Biology 2013;2:378–98. pathies, sarcoglycanopathies, and merosinopathies. cardiomyopathy/dysplasia: proposed modification – of the Task Force Criteria. Eur Heart J 2010;31: 39. Corrado D, Basso C, Thiene G. Is it time to Curr Opin Rheumatol 1996;8:528 38. 806–14. include ion channel diseases among cardiomyop- 53. Wehnert MS, Bonne G. The nuclear muscular – athies? J Electrocardiol 2005;38 Suppl 4:81 7. dystrophies. Semin Pediatr Neurol 2002;9:100–7. 69. Arbustini E, Narula N, Dec WG, et al. The MOGE(S) classification for a phenotype-genotype 40. Pankuweit S, Richter A, Ruppert V, et al. 54. Arbustini E, Narula N, Dec WG, et al. The nomenclature of cardiomyopathy: more ques- Classification of cardiomyopathies and indication fi – MOGE(S) Classi cation for a phenotype genotype tions than answers? (letter). J Am Coll Cardiol for endomyocardial biopsy revisited. Herz 2009; nomenclature of cardiomyopathy. Endorsed by the – – 2014;63:2584 6. 34:55 62. World Heart Federation. J Am Coll Cardiol 2013; 70. Sliwa K, Mocumbi AO. Forgotten cardiovas- 41. Webster G, Berul CI. An update on channelo- 62:2046–72. cular diseases in Africa. Clin Res Cardiol 2010;99: pathies: from mechanisms to management. Cir- 55. Arbustini E, Narula N, Dec WG, et al. The 65–74. culation 2013;127:126–40. MOGE(S) classification for a phenotype–genotype 71. Blankerhorn MA, Gall EA. Myocarditis and 42. Diegoli M, Grasso M, Favalli V, et al. Diagnostic nomenclature of cardiomyopathy. endorsed by the myocardosis: a clinicopathologic appraisal. Circu- work-up and risk stratification in X-linked dilated World Heart Federation. G Heart 2013;8:355–82. lation 1956;13:217–23. cardiomyopathies caused by dystrophin defects. 56. Sobin LH, Gospodarowicz MK, Wittekind Ch, J Am Coll Cardiol 2011;58:925–34. 72. Bridgen W. Uncommon myocardial diseases: editors. TNM Classification of Malignant Tumors. the non-coronary cardiomyopathies. Lancet 1957; 43. Pasotti M, Klersy C, Pilotto A, et al. Long-term 7th edition. Oxford: Wiley-Blackwell, 2009. 273:1179–84. outcome and risk stratification in dilated car- 57. Human Genome Variation Society. Available diolaminopathies. J Am Coll Cardiol 2008;52: 73. Goodwin JF, Oakley CM. The cardiomyopa- at: http://www.hgvs.org/mutnomen/. Accessed 1250–60. thies. Br Heart J 1972;34:545–52. June 5, 2014. 44. Claeys KG, van der Ven PF, Behin A, et al. 74. Report of the WHO/ISFC Task Force on the Differential involvement of sarcomeric proteins in 58. Adzhubei IA, Schmidt S, Peshkin L, et al. definition and classification of cardiomyopathies. myofibrillar myopathies: a morphological and A method and server for predicting damaging Br Heart J 1980;44:672–3. – immunohistochemical study. Acta Neuropathol missense mutations. Nat Methods 2010;7:248 9. 75. Richardson P, McKenna W, Bristow M, et al. 2009;117:293–307. 59. Kumar P, Henikoff S, Ng PC. Predicting the Report of the 1995 World Health Organization/ 45. von Nandelstadh P, Soliymani R, Baumann M, effects of coding non-synonymous variants on International Society and Federation of Cardiol- et al. Analysis of myotilin turnover provides mech- protein function using the SIFT algorithm. Nat ogy Task Force on the Definition and Classifica- anistic insight into the role of myotilinopathy- Protoc 2009;4:1073–81. tion of cardiomyopathies. Circulation 1996;93: causing mutations. Biochem J 2011;436:113–21. 841–2. 60. National Heart, Lung, and Blood Institute. 46. Ferlini A, Neri M, Gualandi F. The medical Exome Sequencing Project. Hosted by the Uni- 76. Hershberger RE, Lindenfeld J, Mestroni L, genetics of dystrophinopathies: molecular genetic versity of Washington. Available at: http://evs.gs. Seidman CE, Taylor MR, Towbin JA, et al. Heart diagnosis and its impact on clinical practice. Neu- washington.edu/EVS/. Accessed June 5, 2014. Failure Society of America. Genetic evaluation romuscul Disord 2013;23:4. of cardiomyopathy—a Heart Failure Society of 61. 1,000 Genome Project. Available at: http:// America practice guideline. J Cardiol Fail 2009;15: 47. Clemen CS, Herrmann H, Strelkov SV, et al. www.1000genomes.org/about. Accessed June 5, 83–97. Desminopathies: pathology and mechanisms. Acta 2014. Neuropathol 2013;125:47–75. 77. Ackerman MJ, Priori SG, Willems S, et al. HRS/ 62. Universal Mutation Database. Available at: EHRA expert consensus statement on the state of 48. Bruno C, Sotgia F, Gazzerro E, et al. Cav- http://www.umd.be/HSF/. Accessed June 5, 2014. genetic testing for the channelopathies and car- eolinopathies. In: Pagon RA, Bird TD, Dolan CR, diomyopathies: this document was developed as a Stephens K, Adam MP, editors. GeneReviews. 63. MOGES. Available at: http://moges.biomeris. partnership between the Heart Rhythm Society [Internet]. Seattle, WA: University of Washington com/. Accessed June 5, 2014. (HRS) and the European Heart Rhythm Association Seattle, 2012. 64. Arbustini E, Narula N, Dec GW, et al. MOGE(S) (EHRA). Europace 2011;13:1077–109. 49. Lo HP, Cooper ST, Evesson FJ, et al. Limb- nosology in low-to-middle-income countries. Nat girdle muscular dystrophy: diagnostic evaluation, Rev Cardiol 2014;11:307. frequency and clues to pathogenesis. Neuro- 65. Brodt C, Siegfried JD, Hofmeyer M, et al. – KEY WORDS cardiomyopathy, muscul Disord 2008;18:34 44. Temporal relationship of conduction system dis- classification, genetics 50. Ceravolo F, Messina S, Rodolico C, et al. D. ease and ventricular dysfunction in LMNA cardio- Myoglobinuriaas first clinicalsign ofa primary alpha- myopathy. J Card Fail 2013;19:233–9. sarcoglycanopathy. Eur J Pediatr 2014;173:239–42. 66. Elliott PM. Classification of cardiomyopathies: APPENDIX For supplemental tables and 51. Walter MC, Reilich P, Thiele S, et al. Treatment evolution or revolution? J Am Coll Cardiol 2013; figures, please see the online version of this of dysferlinopathy with deflazacort: a double- 62:2073–4. article.