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THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

The MOGE(S) Classification ofCardiomyopathy 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,kRobert O. Bonow, MD,{ Valentin Fuster, MD, PHD,# Jagat Narula, MD, PHD#
ABSTRACT

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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.

C ardiomyopathy is the heart muscle diseasesufficient to cause structural and functionalmyocardial abnormality in the absence of

coronary artery disease, hypertension, valvular dis-ease, and congenital heart disease. Based on the clin-ical and genetic evidence, most cardiomyopathiesare inherited, and the recent classification systems

m the *Center for Inherited Cardiovascular Diseases, IRCCS Foundation

dical College, New York, New York; zGVM Care & Research, E.S. Health Sc

ly; xUniversity of Pavia, Pavia, Italy; kSt. Luke’s Medical Center, Milwauk

dicine, Chicago, Illinois; and the #Icahn School of Medicine at Mount Sina

ants European Union INHERITANCE project n�241924 and Italian Ministry

rdiomyopathies” (n�RF-PSM-2008-1145809) (to Dr. Arbustini), IRCCS Polic

mber of the Speaker’s Bureau for Servier; has been a trial committee me

de Medical, CVIE Therapeutics, Vifor Pharma, and Medtronic. Dr. Narula

ilips Healthcare. All other authors have reported that they have no rela

close. P. K. Shah, MD, served as the Guest Editor for this paper.

nuscript received April 30, 2014; revised manuscript received May 27, 20

nt.onlinejacc.org/ on 12/10/2015

underscore the importance of providing cardiologistswith tools to better describe the patients and familiesaffected by a morphofunctional cardiomyopathicphenotype. The American Heart Association (AHA)classification grouped cardiomyopathies into genetic,mixed, and acquired forms, and the European Societyof Cardiology classification proposed subgrouping of

Policlinico San Matteo, Pavia, Italy; yWeill Cornell

ience Foundation, Maria Cecilia Hospital, Cotignola,

ee, Wisconsin; {Northwestern University School of

i, New York, New York. This study was supported by

of Health “Diagnosis and Treatment of Hypertrophic

linico San Matteo, Pavia. Dr. Tavazzi has served as a

mber for Servier, Cardiorentis, Boston Scientific, St.

has received research grants from GE Healthcare &

tionships relevant to the contents of this paper to

14, accepted May 28, 2014.

http://crossmark.crossref.org/dialog/?doi=10.1016/j.jacc.2014.05.027&domain=pdf

http://dx.doi.org/10.1016/j.jacc.2014.05.027

ABB R E V I A T I O N S

AND ACRONYMS

ACC = American College of

Cardiology

AHA = American Heart

Association

ARVC = arrhythmogenic right

ventricular cardiomyopathy

AVB = atrioventricular block

DCM = dilated cardiomyopathy

EMF = endomyocardial fibrosis

HCM = hypertrophic

cardiomyopathy

LV = left ventricle

LVNC = left ventricular

noncompaction

RCM = restrictive

cardiomyopathy

WPW = Wolff-Parkinson-White

syndrome

J A C C V O L . 6 4 , N O . 3 , 2 0 1 4 Arbustini et al.J U L Y 2 2 , 2 0 1 4 : 3 0 4 – 1 8 MOGE(S) Classification of Cardiomyopathy

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each major type of cardiomyopathy into familial orgenetic, and nonfamilial or nongenetic forms (1,2).The American College of Cardiology (ACC)/AHA stag-ing of the heart failure (HF) included asymptomaticpatients with a familial history of cardiomyopathy inthe stage A or pre-HF (3).

In the last 20 years, the systematic approach tofamily screening has contributed to better assess-ment of familial cardiomyopathies. This method hasallowed the identification of family members who arepredisposed to disease development, based on the in-heritance of the cardiomyopathy-associated gene(s).The electrocardiographic and echocardiographic cluesmay show early (subclinical) cardiac involvement(4–10). On the other hand, the nongenetic cardiomy-opathies may be described as associated with specificetiologies, such as viral infections, autoimmune dis-eases, and endogenous or exogenous myocardialtoxicity. The contemporary diagnostic algorithmsfor work-up of cardiomyopathies are supported byadvanced imaging characterization, disease-specificbiomarkers, and genetic analyses (11). The number ofcardiomyopathies wherein the cause is identified (oridentifiable) is increasing, supported by the familyscreening and follow up for segregation studies ofgenotype with phenotype.

The morphofunctional phenotype-based classifi-cation of cardiomyopathies continues to offer cardi-ologists the possibility of using a simple and clinicallyuseful diagnostic language (Table 1). All treatmentprotocols are currently based on the phenotype, aswell as signs and symptoms. The phenotype-basedclassification (hypertrophic cardiomyopathy [HCM],dilated cardiomyopathy [DCM], restrictive cardiomy-opathy [RCM], arrhythmogenic right ventricular car-diomyopathy [ARVC]/arrhythmogenic ventricularcardiomyopathy, and left ventricular noncompaction[LVNC]) describes the major forms of cardiomyopa-thy, but not their causes. However, cardiomyopathiesare clinically heterogeneous diseases (12–17), andwithin each subtype of cardiomyopathy there aredifferences in sex, age of onset, rate of progression,risk of development of overt heart failure, and like-lihood of sudden death. In the DCM group, forexample, there are patients with mildly enlargedand mildly dysfunctional left ventricle (LV) thatdevelop life-threatening ventricular arrhythmias;yet, there may be patients with extremely dilatedand dysfunctional LV but low arrhythmogenic risk.Similarly, in the HCM group, there are patients withsevere left ventricular hypertrophy who are asymp-tomatic and do not demonstrate life-threatening ar-rhythmias. Finally, there are patients who show mildto moderate hypertrophy but carry a high risk of

ded From: http://content.onlinejacc.org/ on 12/10/2015

arrhythmias. Numerous electrocardiographicmarkers have been shown to be associatedwith cardiomyopathy in a subset of thepatients, including atrioventricular block(AVB), pre-excitation syndrome (Wolff-Par-kinson-White syndrome [WPW]), repolariza-tion abnormalities, or low QRS voltage.Echocardiography and cardiac magnetic reso-nance imaging may reveal variable featureswithin the similar phenotypes, including theseverity, distribution, and extent of myocar-dial hypertrophy, thickening of valves, non-compaction, ventricular dilation, ventriculardysfunction, myocardial fibrosis, infiltrativeor intramyocyte storage, or fatty infiltration ofthe myocardium (18,19). Although each sub-type of cardiomyopathy is defined by its majormorphofunctional phenotype, a careful clin-ical evaluation demonstrates high phenotypevariability.

Most cardiomyopathies demonstrate an auto-somal dominant inheritance, but X-linked recessive,autosomal recessive, or matrilineal inheritance mayoccur in a minority of cases. Although elucidationof family history and comprehensive assessmentof pedigree is the foremost necessity in familystudies (17,20,21), it may not be by itself sufficientto establish the diagnosis of familial cardiomyo-pathy. Cascade family screening and monitoringmay be necessary to identify affected but asymp-tomatic family members unaware of their disease,or who display subclinical abnormalities by non-invasive imaging tests as early markers of thedisease (16,17).

The knowledge of the genetic basis of all kindsof cardiomyopathies has progressively increased(12–14,22). Linkage analyses (23), genome-wide asso-ciation studies (GWAS) (24,25), and whole-exome se-quencing (WES) (26) have incrementally contributedto the list of disease genes (Online Table 1), whichnow includes more than 100 genes. HCM is caused bythe mutations of genes that code for structural andfunctional proteins of the sarcomere (15), whereasDCM is caused by the mutation of genes related tostructure and function of nuclear envelope, cyto-skeleton, sarcomere, and sarcoplasmic reticulum (27).ARVC is known as a collection of diseases of thedesmosome (28), and RCM is caused by defects ingenes encoding for sarcomeric proteins (29) or inter-mediate filaments, such as desmin (20).

However, the early assignment of phenotypes togroups of genes and pathways is no longer confirmedby recent genetic studies. In fact, genes may causesimilar phenotypes (Fig. 1), most disease genes are not

TABLE 1 Recapitulation of the Classification Systems for Cardiomyopathies in the

Last 50 Years

Year Definitions/Classifications References

1956 Myocardial diseases classified asmyocarditis (inflammatory heartmuscle disease), and myocardiosis(other heart muscle diseases).

Blankerhorn and Gall (71)

1957 The term cardiomyopathy proposed foruncommon, noncoronary heart musclediseases.

Bridgen (72)

1972 Cardiomyopathy described as myocardialdiseases of unknown origin, and firstclassification proposed as dilated,hypertrophic, and restrictive (orobliterative) cardiomyopathy.

Goodwin and Oakley (73)

1980 WHO-ISFC adopts Goodwin and Oakleyclassification, and definescardiomyopathies as myocardialdiseases of unknown etiology. WHO-ISFC adds specific heart musclediseases (cause of myocardialaffliction known) to the classification.

Report of the WHO/ISFC Task Force onthe Definition and Classification ofCardiomyopathies (74)

1996 WHO-ISFC updates its classification ofcardiomyopathies (diseases ofmyocardium associated withmyocardial dysfunction). The updateincludes arrhythmogenic rightventricular cardiomyopathy andunclassified cardiomyopathy, butexcludes specific heart muscledisease.

Richardson et al. (75)

1998 ISFC becomes WHF

2006 AHA defines cardiomyopathies asdiseases of myocardium associatedwith mechanical and/or electricaldysfunction, which usually (but notinvariably) exhibit inappropriateventricular hypertrophy or dilation,due to a variety of causes thatfrequently are genetic, classified asprimary or secondary. Presents firstvisionary attempt to classify primarycardiomyopathy by genetic origin(genetic, acquired, or mixed)

Maron et al. (1)

2008 ESC defines cardiomyopathies asmyocardial disorder in which the heartmuscle was structurally andfunctionally abnormal. Classifieddilated, hypertrophic, restrictive,arrhythmogenic right ventricular, orunclassified cardiomyopathysubtypes as familial/genetic andnonfamilial/nongenetic. Maintainedthe importance of phenotypepreceding genetic classification forclinical practice.

Elliott et al. (2)

2013 WHF-MOGE(S) nosology proposes adescriptive genotype-phenotypenosology system.

Arbustini et al. (54,55)

AHA ¼ American Heart Association; ESC ¼ European Society of Cardiology; ISFC ¼ International Society andFederation of Cardiology; WHF ¼ World Heart Federation; WHO ¼ World Health Organization.

Arbustini et al. J A C C V O L . 6 4 , N O . 3 , 2 0 1 4

MOGE(S) Classification of Cardiomyopathy J U L Y 2 2 , 2 0 1 4 : 3 0 4 – 1 8

306


linked to a unique phenotype, and identical genemutations may result in different phenotypes (Fig. 2).For instance, sarcomeric gene defects associated withHCM also may result in DCM (30), and desmosomegenes coupled with ARVC may cause DCM (31). Genesencoding intermediate filaments, such as nuclearlamins, in addition to DCM may cause ARVC (32), and

ntent.onlinejacc.org/ on 12/10/2015

nonsarcomeric genes also may cause HCM (33). Anincreasing number of cardiomyopathies are beingrecognized as associated with complex genetics (34).More than 100 nuclear and mitochondrial disease-causing genes have been identified encoding for theproteins of nuclear envelope, sarcolemma, cytoskel-eton, sarcomere, or desmosome, or those involved incalcium-handling and energy production (OnlineTable 1). The constantly increasing number ofdisease-causing genes suggests that the unresolvedissue of variable penetrance or expression mayrepresent incomplete genotyping (Fig. 3), or that thepresumptive disease-causing role has erroneouslybeen assigned to a wrong gene and mutation. Al-though functional studies are likely to elucidate therole of the protein mutations, the speed of detectionof mutations will continue to outpace the experi-ments that are needed to confirm their functionalimportance in the animal models or in vitro studies.The approach to genetic testing could continue to beeither clinically guided, based on the sequencing ofgenes selected on the basis of a clinical hypothesis, orbased on sequencing of large panels of disease-associated/candidate genes (35–38). However, inter-pretation of the results rather than performing thetest would pose a bigger challenge in the modern eraof next-generation sequencing.

On the basis of clinical and genetic evidence indi-cating that most cardiomyopathies are familial dis-eases and that genetic diagnosis is now reachable in ahigh proportion of patients, scientific societies, suchas the Heart Rhythm Society, Heart Failure Society ofAmerica, and the European Society of Cardiology,have provided guidelines and recommendations forfamily screening and genetic testing for cardiomy-opathies (Table 2).

THE MOGE(S) NOMENCLATURE

In the quest for a genetic terminology, nomenclaturesuch as desmosomalopathy (39), cytoskeletalopathy(40), sarcomyopathy (39), channelopathy (41), car-diodystrophinopathy (42), cardiolaminopathy (43),zaspopathy (44), myotilinopathy (45), dystrophin-opathy (46), alpha-B crystallinopathy (44), desmin-opathy (47), caveolinopathy (48), calpainopathy(49), sarcoglycanopathy (50), dysferlinopathy (51),merosinopathy (52), and emerinopathy (53) are beingused. Not only would such nosology evolve to beunmanageable, the genetic notation would defineneither the phenotype nor the extent of systemicinvolvement. For instance, labeling an arrhythmo-genic cardiomyopathy as desmosomalopathy wouldneither describe the clinical phenotype (right-sided,


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biventricular, or predominantly left-sided cardio-myopathy), nor describe the gene that causes thecardiomyopathy. The zaspopathy may cause isolatedLVNC or dilated LVNC and may be associated withskeletal myopathy (44). The troponinopathy mayresult in hypertrophic, restrictive, or dilated pheno-types. Hypertrophic myosinopathy may not distin-guish between MYH7 and MYBPC3 or light chainmyosin. Even if these gene-specific terms are simplyadded to the phenotype, the notations wouldbecome unbearably complex, such as the arrhyth-mogenic plakophillinopathy or desmocollinopathy,dilated desmoplakinopathy or cardiolaminopathy,hypertrophic myosinopathy or troponinopathy, andrestrictive desminopathy or troponinopathy.

Endorsed by the World Heart Federation, theMOGE(S) classification (54,55) was developed from theneed to describe cardiomyopathies by integrating amorphofunctional phenotype-based description withinformation regarding extracardiac organ invol-vement and clinical (pattern of inheritance) and

MD-AVBOHGADEG-LMNA [p.Arg190Trp] S (C-II)

Dilated cardiolaminopathy

FIGURE 1 Similar Phenotypes but Different Inheritance May Influenc

Mutations in genes coding for proteins of the nuclear envelope, such as

(DCM) with conduction disease. The phenotypes look alike (echocardiog

function in these 2 individuals), and the only distinguishing descriptor is

description below the echocardiograms). Both LMNA and EMD mutation

phosphokinase (sCPK) can be normal in both conditions; EMDmutations a

are associated with Autosomal dominant (AD) inheritance.


molecular (disease gene and mutation) genetics in fa-milial disease. The MOGE(S) classification also aimedat describing sporadic cardiomyopathies, and speci-fying their etiology when known or unknown (CentralIllustration). Even for a sporadic cardiomyopathy, thegenetic origin of the disease cannot be excluded unlessa nongenetic cause is proven, and family screening iscompleted to exclude familial inheritance. In theabsence of certainty, each cardiomyopathy would beconsidered a potentially genetic disease, thus, offeringfamilies the same screening options that would beoffered to an overt familial disease. In the past, pa-tients with sporadic cardiomyopathy were frequentlylabeled as nonfamilial, and diagnosed with chronic(viral) myocarditis or peripartum cardiomyopathy.Their long-term follow-up of families unfortunatelyoften uncovered a genetic etiology uponmanifestationof the disease in offspring or siblings of the probandwith the same disease.

Borrowing from tumor, node, metastases (TNM)staging in oncology (56), MOGE(S) nosology of

MD-AVBOHGX-LREG-EMD [p.Leu15Phe] S(B-II)

Dilated emerinopathy

e Comprehensive Assessment of the Family and Genetic Counseling

Lamin AC (LMNA) and Emerin (EMD) cause dilated cardiomyopathy

rams revealed DCM with similar left ventricular dimensions and

the type of inheritance (shown in blue letters in the MOGE[S]

s are pathologic and appear red in MOGE(S). Serum creatine

re associated with X-linked recessive inheritance and LMNAmutations

TNNI3 p.(Leu144Gln)

ID Phenotype Outcome Age (years)I:1

I:4

II:1II:2II:3II:5

II:6II:7II:8II:10

III:3III:5III:7III:8

III:14III:15III:2IV:2IV:3

IV:5IV:9V:1

V:2

V:3V:4

V:6VI:1

I:3

HCM

HCMHCM

HCMHCMHCMHCM

HCMHCMHCM

HCM/RCM

RCMHCMHCM

HCM

HCMHCMRCMHCMHCM

HCMHCM/RCM

HCM

HCM

HCMHCM

HCMHCM

SD

SD

SDSDSD

SD

HF

HF

HFHF

HF

HTXSDSD

SD

SDSD

HTXHTX

HTX

SD

SDSD

SDSD

SDICD

Death atchildbirth

533265

56

456050

47

696764

56832

32

1414415628

412517

32

1425

1716

MR OH GAD EG-TNNI3[p. Leu144GIn] SD-IV

MH+R OH GAD EG-TNNI3[p. Leu144GIn] SC-III

MH OH GAD EG-TNNI3[p. Leu144GIn] SC-III

FIGURE 2 The Same Genotype May Be Associated With Different

Phenotypic Expressions

Restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM)/RCM, and HCM

may occur in different family members who are carriers of the same mutation in TNNI3

(p.Leu144Gln). The table shows the ID (family member), age, phenotype, and outcome of

family members. The echocardiographic figures refer to cardiac phenotypes in 3 family

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

failure; HTx ¼ heart transplantation; ICD ¼ implantable cardioverter-defibrillator;

SD ¼ sudden death.



308


cardiomyopathies addressed 5 attributes: the mor-phofunctional phenotype (M), organ involvement (O),genetic or familial inheritance pattern (G), and etio-logical description (E) of genetic defect or non-genetic underlying cause. The functional status (S),using the ACC/AHA (A to D) stage and New York Heart


Association (NYHA) (I to IV) functional classes wasalso added. The “S” notation is especially usefulwhen mutation carriers are healthy, or if they dem-onstrate imaging-verified early abnormalities sug-gestive of cardiomyopathy.

M: MORPHO-FUNCTIONAL PHENOTYPE. The “M”

notation provides the clinical diagnosis, which cor-responds to the description of the phenotype such asMD (DCM), MH (HCM), MA (ARVC), MR (RCM), and MNC

(LVNC). This notation corresponds to the currentclinical classification of cardiomyopathies. The firstand commonly used clinical diagnosis is labeled as asubscript to the “M.” HCM that evolves into dilatedcongestive phenotype or HCM presenting with sig-nificant restrictive pattern can be described as MHþD

or MHþR (Figs. 2 and 4). Multiple other combinationsmay be possible, such as MDþNC or MAþNC or MHþNC.

The “M” notation also carries key clinical red flagssuch as short PR interval (PR), WPW, or AVB, whichmay be displayed as MH[PR], MH[WPW], or MD[AVB]. Italso may describe a nonspecific or noncoded pheno-type (such as hypertrabeculation when criteria forLVNC are not fulfilled; NS[Hypertrab]). Furthermore,“M” allows for the description of early phenotypes.For instance, conditions where diagnostic criteria forthe suspected clinical phenotype (such as DCM orHCM) are not fulfilled but the imaging data indicatean increased LV diameter and a borderline LV func-tion (ME[D]), or a possible LV hypertrophy (ME[H]) incarriers of the mutation that have caused the diseasein the family. Clinically-unaffected mutation carriersare described as M0. When the information about thecardiac phenotype is not available, such as in thedeceased relatives, the description is MNA. Overall,the “M” notation is flexible and suitable for anyclinical combination of disease phenotypes and clin-ical traits.

O: THE INVOLVED ORGANS. The second descriptor isthe organ involvement, which can either be the heartonly (OH) or in combination with other organ systems,such as skeletal muscle (OHþM), auditory system(OHþA), kidney (OHþK), nervous system (OHþN), liver(OHþLi), gastrointestinal system (OHþG), cutaneous(OHþC), ocular or eyes (OHþE), respiratory or lung(OHþLu), or mental retardation (OHþMR). Healthy mu-tation carriers are described as O0, because the heartis still clinically unaffected; it complements the M0

notation. The involvement of organs/systems otherthan the heart allows for convenient recognition ofsyndromes (Fig. 5). The simple combination of dataon cardiac phenotype and involvement of kidney,liver, lung, or gastrointestinal system can usefullyrestrict the field of diagnostic hypotheses and can

MH+D OH GAD EG-MYH7[p.Val606Met]+LMNA[p. Asp254GIy] SC-II

FIGURE 3 The Presence of More Than 1 Genotype May Influence

the Phenotype

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

ventricular (LV) hypertrophy, in New York Heart Association functional class II.

His recent echocardiogram demonstrated an LV end-diastolic volume of 150

ml, LV end-diastolic dimension of 55 mm, LV ejection fraction of 50%, LV

hypertrophy (22 mm), left atrial dilation, patent foramen ovale, moderate-

severe pulmonary arterial hypertension, and pericardial effusion. Patient

received cardiac resynchronization therapy/ICD implantation after resusci-

tated cardiac arrest. The disease was autosomal dominant and associated with

mutations in the MYH7 and in LMNA both coming from the maternal lineage.

The LMNA variant, however, is still to be considered a variant of unknown

significance.


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address focused genetic testing. Such combinationsalso allow for easy recognition of syndromes.

G: GENETIC INHERITANCE. The third descriptor re-presents genetic or familial inheritance as deducedclinically by family pedigree and screening. Theinheritance includes autosomal dominant (GAD),autosomal recessive (GAR), X-linked (GXL), X-linkedrecessive (GXLR), or dominant (GXLD) or matrilineal(GM) transmission. Patients who are the uniquelyaffected members of the family with a documenteddisease mutation are described as de novo (GDN) or ashaving phenotypically sporadic (GS) cardiomyopathy.The negative or unknown family history (GN or GU)and the family history not investigated so far (G0) alsocan be specified.

E: ETIOLOGY. The notation “E” includes a descriptionin 2 steps. The first step informs the underlying causeof the cardiomyopathy, whichmay be of genetic (EG) ornongenetic cause. The latter needs to be addressedindividually as in the following paragraph; the non-identifiable cause is also noted (EN). The second nota-tion defines precise etiology. For example, the genemutation needs to be specified next to the EG, andsimilarly, the cause of the underlying disease innongenetic cardiomyopathies also needs to beexplained.

In genetic cardiomyopathies, the disease gene andmutation(s) can be added, such as in the case of HCM(EG-MYH7[p. Arg403Glu]) or familial amyloidosis (EG-ATTR

[p.Val122Ile]). The “E” specification may describe: familymembers who are noncarriers of the mutation thatcauses the disease in the family (EG-Neg), the obligatecarrier (EG-OC), or the obligate noncarrier (EG-ONC).EG-NA indicates nonavailability of the genetic test.After completion of the screening of all known dis-ease genes in familial disease, genetically orphanpatients are labeled as negative: EG-N (genetic defectnot identified). EG-0 indicates that genetic testing wasnot done or was not feasible for any reason. Whenall members of a single family are described, theMOGE(S) system highlights mutations that do notfully segregate with the phenotype or are part ofincomplete genotyping (Fig. 6). The increasinglycomplex genetics (>1 mutation in a single patient) callfor a comprehensive description of the genetic make-up of the patients and families. The internationalnomenclature of genetic variants may facilitate thedescription (57); the in silico evaluation supports theinterpretation of the significance of each variant (e.g.,PolyPhen-2 [58] and SIFT [59]).

The large public databases, such as the NationalHeart, Lung, and Blood Institute’s Exome SequencingProject (60), the 1,000 Genomes Project (61), and


Universal Mutation Database (62), provide data onminor allele frequency (MAF). Finally, the studies onfamilies provide segregation data, and pathologystudies (Fig. 7) or in vitro systems may eventuallycontribute to document the abnormal expression ofthe mutated protein. The way of describing complexgenetics in MOGE(S) can take advantage of colorcoding (app available online [63]), which provides theimmediate information about pathologic mutations(red), genetic variants of unknown significance (VUS)(yellow/orange), or a single nucleotide polymorphism(SNP) with some possible functional effects (green)(Central Illustration).

In nongenetic cardiomyopathies, the etiology can bedescribed as viral (V) (the first notation) adding thevirus (e.g., Coxsackie B3 virus [CB3], human cyto-megalovirus [HCMV], or Epstein-Barr virus [EBV]presented as EV-HCMV, EV-CB3, or EV-EBV) for the secondnotation; the infectious, nonviral diseases (EI) may bepresented with further specification of the infectiousagent whenever possible. When the myocarditis is theproven cause of the myocardial disease (EM), thesecond notation could specify the origin of myocar-ditis, such as sarcoidosis (EM-Sarcoid) or noninfectiousgiant cell myocarditis. An autoimmune etiology,

TABLE 2 Genetic Testing: Position of the Scientific Societies

Type of Cardiomyopathy RecommendationStrength of

Evidence/Class

Heart Failure Society of America, 2009 (76)

All patients withcardiomyopathy

Clinical screening for cardiomyopathy is recommended:

� 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,24-h Holter monitoring in HCM and ARVC, exercise treadmill testing in HCM, and CMR in ARVC

B

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 repeatclinical screening at 1 year

C

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 andmanagement (MYH7, MYBPC3, TNNT2 TNNI3, TPMI, ACTC1, MYL2, and MYL3).

A

DCM Family history for $3 generations A


Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening andmanagement (LMNA, MYH7, TNNT2, SCN5A, DES, MYBPC3, TNNI3, TPMI, ACTC, PLN, LDB3, and TAZ)

B

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 andmanagement (gene tests: uncertain)

C

ARVC Family history for $3 generations A


Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening andmanagement (DSP, PKP2, DSG2, and DSC2)

A

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 andmanagement (gene tests: uncertain)

C

CMP with extracardiactraits

Family history for $3 generations A


Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening andmanagement

A

ESC Position Statement on Genetic Counseling and Testing in Cardiomyopathies, 2010 (16)

Diagnostic work-upin patients andfamilies with CMP(the numbers inthe right columnindicate the steps)

Genetic counseling 1

Information for patients and families: genetic origin, inheritance pattern and heritability, phenotype and age-dependence,benefits of clinical family screening, pregnancy-related risk, available genetic tests, and contacts with charities and referralcenters.

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 detailedclinical 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;questionable in sporadic DCM and RCM

To be considered

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 familyassessment

To be considered

Genetic testing and pre-natal diagnosis 7

Continued on the next page



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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(MYBPC3, MYH7, TNNI3, TNNT2, TPM1)

I

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 screeningand monitoring plans

IIa

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 criteriafor ACM/ARVC.

IIa

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 publisheddata 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 cardio-myopathy; HRS ¼ Heart Rhythm Society; LVNC ¼ left ventricular noncompaction; RCM ¼ restrictive cardiomyopathy.


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either suspected or proven (EAI-S or EA-P), may popu-late the first notation followed by the specific eti-ology, such as rheumatoid arthritis or systemiclupus erythematosus. The MOGE(S) app allows thedescription of each proven diagnosis (e.g., MD

OHþCþS G0 EAI-P-Rheumatoid Arthritis SC-II or MD OHþC G0

EAI-P-Rheumatoid Arthritis SB-II). Nonheritable amyloid-osis (EA-K, EA-L, or EA-SAA) represent kappa, lambda, orserum amyloid A protein characterization, respec-tively. Toxic cardiomyopathies, either endogenous,such as pheochromocytoma-related cardiomyopathy,or drug-induced cardiomyopathy, are described(ET-Pheo or ET-Chloroquine). When the former is describedin the context of a syndrome (such as VHL, MEN2A/2B,or NF1), the description can be implemented by addingthe name of the syndrome (i.e., ET-Pheo-VHL). TheLoeffler’s eosinophilic endomyocarditis can be de-scribed according to the cause as either being id-iopathic or a part of myeloproliferative disorderassociated with the somatic chromosomal rearrange-ment of PDGFRa or PDGFRb genes that generate afusion gene encoding for constitutively active PDGFRtyrosine kinases (64).


S: FUNCTIONAL STATUS. “S,” in 2 notations, de-scribes the heart failure ACC/AHA stage (A to D)coupledwith NYHA functional class (I to IV), presentedas SA-I or SC-II, and so on. The descriptor “S” is optional,but may come in handy for the description of earlycardiomyopathy. The ACC/AHA guidelines includepatients with a family history of cardiomyopathy instage A. In families with known mutation, the diag-nosis of early cardiomyopathies can be further sup-ported by the presence of the mutation(s), whereas ingenetically orphan familial cardiomyopathy, only theearly imaging markers of the disease can be high-lighted. This description could be especially useful forthose individuals seeking a definitive recommenda-tion from the physician about their sport worthiness.Although criteria for early diagnosis of cardiomyopa-thy are not systematically described, increasingly,family screening and monitoring have revealed thatthe cardiomyopathies likely serve a long pre-clinical orsubclinical course before the onset of symptoms or themanifestation of the clinical phenotype (65).

The Central Illustration shows the MOGE(S)system notations and modeling. The alphabetical

Proband’s cardiomyopathy(CM) diagnosis

(DCM, HCM, RCM,ARVC/D, LVNC)

Clinical history and evaluation

Functionalstatus

ACC/AHA,NYHA

Multidisciplinary evaluationaccording perclinical needsor diagnostichypothesis

Organ involvement:Extracardiac organs/tissues

OORGAN/SYSTEMINVOLVEMENT

GGENETIC INHERITANCE

PATTERN

EETIOLOGY

SSTAGE

D Dilated H Hypertrophic R RestrictiveR EMF

Endomyocardial

LV=left ventricle RV=right ventricleRLV=biventricular

A ARVC M=majorm=minorc=categoryLV= left ventricle RV=right ventricleRLV=biventricular

NC LVNCE Early, with type

in parenthesesNS

phenotypeNA Information

non available0

H HeartLV=left ventricle RV=right ventricleRLV=biventricular

M Muscle (skeletal) N Nervous C CutaneousE Eye, Ocular A AuditoryK KidneyG Gastrointestinal Li LiverLu LungS Skeletal0 Absence of

organ/system involvement*, e.g. in family members who are healthy mutation carriers; the mutation is

inheritance in G

G Genetic causeOC Obligate carrierONC Obligate non-carrierDN De novoNeg Genetic test negative for

the known familial mutationN0 No genetic test, any reason* G-A-TTR Genetic amyloidosis G-HFE Hemochromatosis

Non-genetic etiologies:M MyocarditisV Viral infection (add the virus

AI Autoimmune/immune-mediate; suspected (AI-S), proven (AI-P)

A Amyloidosis (add type: A-K, A-L, A-SAA)

I Infectious, non viral (add the infectious agent)

T Toxicity (add cause/drug)Eo Hypereosinophilic

heart diseaseO Other

N Family history negativeU Family history unknownAD Autosomal dominantAR Autosomal recessiveXLD X-linked dominantXLR X-linked recessiveXL X-linkedM Matrilineal0 Family history not investigated*Undet Inheritance still undeterminedS Phenotypically Sporadic

(apparent or real)

ACC-AHAstagerepresented as letterA, B, C, DNA not applicableNU not used

followed byNYHA classrepresentedas RomannumeralI, II, III, IV

CHAR

ACTE

RIST

ICS

SUBS

CRIP

TClinical family screening

asymptomatic relativeunaware ofthe disease

Relativeswith ECGand/or Echoabnormalities

Healthy family members with normal ECG and ECHO

Familial Non-familial;Phenotypicallysporadic

InheritanceAD, AR XL(R or D) orMatrilineal

Informative and non-informative families

Consultant non-informedabout familyhistory

Genetic counselingwith pedigree

Genetic testingin the proband

Positive

Cascadegenetic

testing inrelatives

Negative

Regularmonitoringin relatives

New testsnovel genes

MMORPHO-FUNCTIONAL

PHENOTYPENOTA

TION

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.



312


components are likely going to change in parallelwith new scientific information. The proposednomenclature reflects the current diagnostic work-up of cardiomyopathies for evaluation of thephenotype, family screening, and genetic testing in


the Sanger and post-Sanger era. To facilitate theapplication and to provide a simple summary forthe patient’s clinical record by the MOGE(S) system,we encourage the use of the web-assisted app (63),which can be downloaded for smartphones and

MH+R OH GDN EG-MYL6[p.Gly162Arg] SD-IV

FIGURE 4 Variation in Phenotypic Expression

The hypertrophic cardiomyopathy (HCM) phenotype with restrictive pattern may be caused

by defects of sarcomere genes, including less common genes, such as MYL6, that code the

myosin light chain 6 protein. The echocardiogram is from a 12-year-old girl waiting for

heart transplantation, in New York Heart Association functional class IV, who genetically

showed a de novo mutation. The echocardiogram shows normal left ventricular (LV)

end-diastolic volume, borderline systolic LV dysfunction (ejection fraction ¼ 50%), sig-

nificant diastolic dysfunction, mild LV hypertrophy (interventricular septum ¼ 12 mm),

severe biatrial dilation (right > left), mild right ventricular dysfunction, tricuspid regur-

gitation, mild pulmonary hypertension (40 mm Hg), and pericardial effusion.


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tablets and can be flexibly edited, expanded, ormodified.

FLEXIBILITY AND EXPANDIBILITY

OF MOGE(S) SYSTEM

Similar to the TNM staging system, MOGE(S) allowsflexibility and can be expanded when needed. Theauthors believe that the nomenclature will evolve tobecome more comprehensive and user-friendly asclinicians begin to apply it in practice. Investigatorsfrom around the world have suggested modificationsin MOGE(S) nosology (66,67), such as in ARVC/arrhythmogenic ventricular cardiomyopathy andEMF. The diagnostic criteria for ARVC have beendebated and modified, and the MA notation can befurther specified with the help of the major [M] orminor [m] diagnostic clues that are variably combinedin the Modified Task Force Criteria (68). These criteriadefine ARVC as definite when 2 major [M2], 1 majorand 2 minor [M1þm2], or 4 minor criteria from 4different categories [m4X4] are present; borderlinewhen 1 major and 1 minor [M1þm1] or 3 minor criteriafrom different categories [m3X3] are present; andpossible when 1 major or 2 minor criteria fromdifferent categories [M1þm2X2] are present. Thenumber of the major and minor criteria can be addedto the main MA notation. A definite diagnosis may bedescribed as MA[M2], MA[M1þm2X2], or MA[m4X4]; aborderline diagnosis as MA[M1þm1] or MA[m3X3]; and apossible diagnosis as MA[M1] or MA[m2x2]. The “M”

notation can therefore summarize not only the diag-nosis or diagnostic hypothesis but also the strength ofthe diagnosis (69).

A recent commentary appropriately emphasized theneed for morphological notation for important car-diomyopathies from low- and middle-income coun-tries, such as tropical endomyocardial fibrosis (EMF)(67), which is one of the most prevalent causes ofrestrictive cardiomyopathy (70). Because EMF canmanifest as isolated or dominant LV EMF, isolated ordominant right ventricular EMF, or biventricular (rightventricular þ LV) EMF, MOGE(S) can describe the dis-ease as well as the single or double ventricularinvolvement (64).

A possible limitation of the MOGE(S) nosology isthe lack of information about 1 of the most importantclinical issues in cardiomyopathies: arrhythmias.As anticipated (54,55), the classification of arrhyth-mias is far from the aim of MOGE(S); however, wehave received overwhelming suggestions for expan-sion of the “S” notation to include the informationabout rhythm disturbances in cardiomyopathies thatwould give the clinical advantage of highlighting


patients deserving of a device implantation for ar-rhythmias. The MOGE(S) committee is working withelectrophysiologists to develop a clinically-useful fastrhythm disturbances description as a third “S”notation.

MOGE(S) IN DAY-TO-DAY

CLINICAL PRACTICE

Upon the first reading, MOGE(S) may appear to be acomplex nosology system that further complicatesthe description of cardiomyopathies. However, inpractice, it is rather simple to apply and the use of theapp provides a guided step-by-step compilation. Theuse of MOGE(S) does not obligate a clinician toinclude genetic testing. As presented in the CentralIllustration, the genetic tests may not be available orfeasible. However, it behooves clinicians to make aneffort to elicit family history, especially about suddendeath, and document familial patterns. MOGE(S)offers a hierarchical (Phenotype/Organ/tissue In-volvement/Genetic /familial/Etiology/gene) butflexible structure that readily provides severaldescriptors in a standardized language. This systemalso necessitates the routine diagnostic work-upfor cardiomyopathies in probands and relatives.Whether or not all information queried by MOGE(S) is

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.



314


immediately available does not hamper its applica-tion. In day-to-day practice, MOGE(S) can be appliedat the bedside, and collected data can be easily sub-mitted to repositories. In a discharge summary, theconcluding diagnosis “Dilated Cardiomyopathy (MD

OH GAD EG-MYH7[Ile533Asn] SB-II)” may provide compre-hensive information about the patient. For instance,after a family screening, the mutation does notsegregate or a second mutation is identified. In thatcase, MOGE(S) allows the description of new infor-mation (MD OH GAD EG-MYH7[Ile533Asn]þMYBPC3[Arg326Gln]).(S) is a dynamic notation that may modify duringfollow-up, and its use can provide information aboutchange in the functional status and evolution ofremodeling status. Although NYHA functional class isuniversally used, ACC/AHA stage has been lesscommonly applied in clinics. It can be difficult toapply to cardiomyopathies, such as classical ARVC,especially when diagnosed on 2 major criteria such asmajor ECG changes (e.g., negative T waves in v1 to v3)and sudden cardiac death or a first-degree relative ora known pathologic mutation. MOGE(S), however,does not obligate us to fill all fields, and the MOGE(S)


App 2 includes the possibility of selecting “ACC-AHAnot used” when not applied or applicable.

The following are a few examples from our data-base pertaining to the application of MOGE(S):

� “MD OHþM GAD EG-NA SC-III” represents a baselinedescription of the patient (II:1) who was diagnosedwith DCM, presenting with both cardiac and mus-cle involvement. He was a member of a family withthe autosomal dominant DCM, but the genetictesting was not available. The functional statuswas described as ACC/AHA stage C and NYHAfunctional class III. Subsequently, when the ge-netic information became available, the notationwas changed to “MD OHþM GAD EG-LMNA[p.Arg190Trp]

SC-III.” During follow-up, after starting the treat-ment with an improvement in the NYHA functionalclass, the functional status changed to “MD OHþM

GAD EG-LMNA[p.Arg190Trp] SC-I.” At echocardiographicevaluation a brother (II:3) of the proband showedLV dilation, and borderline LV ejection fraction: hewas described as “ME[D] OH GAD EG-NA SB.” Furtherin the course of the follow-up, the description was

Family member

I:2

I:1

II:1

II:2

II:3

II:4

II:5

III:1

III:2

III:3

IV:1

IV:2

IV:4

V:1

MOGES

MOOOGUEG-O

MOOOGUEG-O

MOOOGUEG-O

MOOOGUEG-O

M0O0GUEG-0

M0O0GUEG-(OC)

M0O0GUEG-NegSA-I

M0O0GUEG-NegSA-I

M0O0GADEG-NegSA-I

M0O0GADEG-OSA-I

M0O0GUEG-O

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

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

MHOHGUEG-(OC)

I:1

II:1 II:2 II:3 II:4 II:5

III:1 III:2 III:3

V:1

IV:2 IV:3 IV:4

AF, strokeAge: 59 yearsGenetic test: not done

AFAge: 90 yearsGenetic test: negative

HCM, LVT=18mmOnset: 30 yearsDeath:37 yearsGenetic test: NA

HCM LVT=16mmOnset: 52 yrsAge=56 yearsGenetic test: Positive

LVT=8mmAge=36 yearsGenetic test: IV:1positive

LVT=8mmAge=24 yearsGenetic test:negative

LVT=9mmAge: 56yearsGenetic test:Negative

I:2

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.


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completed as “ME[D] OH GAD EG-LMNA[p.Arg190Trp]

SB-I.” He was classified as stage B-I due to asymp-tomatic myocardial involvement. Another brother(II:2) underwent genetic testing and an echocar-diographic examination and tested positive tothe genetic screening but echocardiogram wasentirely normal. He was described as “M0 O0 GAD

EG-LMNA[p.Arg190Trp] SA-I.” (Online Fig. 1 shows thefamily pedigree at the end of the family screening.)

� “MD OHþMþNþA GM EG-MtDNA [tRNALeu A3243G] þ GJB2

[del30G hetero] SD-IV” describes a patient (II:3) admittedwith severe DCM, with involvement of the skeletalmuscle, prior stroke, hearing loss, a positive


maternal family history for loss of hearing, anddiabetes. The “O” notation in this case offers aninstant suspicion of a known pathologic mutation inmitochondrial deoxyribonucleic acid (MtDNA).She also was a carrier of the heterozygous GJB2del30G that, when homozygous, causes hearingloss. Two sisters showed hearing loss and diabetes.The phenotype of the proband was severe, asdescribed by the functional status (ACC/AHA stageC, NYHA functional class IV). We could not tracereports of the early phase of the cardiomyopathythat could theoretically have been HCM in origin(Online Fig. 2).

A

C

B

DMD(>sCPK)OH+MGX-LREG-DYS[Del45-48] SC-II

MD(AVB)OHGADEG-LMNA[p.Arg190Trp] SB-I

FIGURE 7 Genotypic Expression May Play a Role in Arrhythmogenicity

When tissue samples are available, such as in endomyocardial biopsies or fromhearts excised

during transplantation, the expression of the mutated proteins can be investigated either

for diagnosis (Dystrophin) or for supporting the diagnostic hypothesis and investigating

the effects of the mutations (i.e., Lamin AC). The 2 sets of the immunohistochemically-

stained histomicrographs refer to patients with either dilated cardiolaminopathy (top)

or dilated cardiodystrophinopathy (bottom). The endomyocardial biopsy above shows

decreased expression of the protein (B) compared with the normal control sample (A).

The MOGE(S) describes the clinical and genetic status. Below, the endomyocardial biopsy

from the patient with dilated cardiodystrophinopathy (D) with multifocal loss of

protein expression as typically observed in heart of patients with dystrophin defects,

versus normal control sample (C). The MOGE(S) describes the clinical and genetic

status of the patient. The cardiolaminopathy patient with mildly-normal left ventricular

(LV) systolic function has demonstrated life-threatening tachyarrhythmias. However,

the dystrophinopathy patient with large LV dimensions and severely depressed LV

ejection fraction did not require implantable cardioverter-defibrillator intervention

for 2 years.



316


� “MAþHypertrab OH GUndet EG-LDB3 [p.Thr507Asn] þ DSG2

[p.Lys479Glu] SB-II-III” describes a patient (II:1) diag-nosed with ARVC and hypertrabeculation, exclu-sive involvement of the heart, without a positivefamily history; likely, but still not proven, arecessive disease. In this patient, we identified 2variants of uncertain significance (VUS, yellow-orange color in the MOGES app) of biparentalorigin in 2 different genes. To date, the proband


is the only affected member of the family; theyoung daughter also carries the 2 variants and ishealthy, only showing increased trabeculation ofthe LV apex. The phenotype in the proband issevere 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 apatient (III:3) diagnosed with HCM, exclusiveinvolvement of the heart, with a positive familyhistory in which the disease is inherited as anautosomal dominant trait, and caused by a knownmutation in MYBPC3. The functional status isdescribed by the ACC/AHA stage B, NYHA func-tional class II. After family screening, her daughterwas found to be unaffected and to not be a carrierof the mutation identified in the proband (M0 O0

GAD EG-Neg). The sister also was not affected, butwas a carrier of the mutation identified in theproband (M0 O0 GAD EG-MYBPC3[IVS16-1G>A] SA-I). Herniece, daughter of the affected brother (who diedwithout genetic testing), was not affected but wasa carrier of the mutation identified in the proband.This simple information describes her father as theobligate carrier of the mutation. The evaluation ofthe niece, however, presented the problem ofnonsegregation of the genotype with the phenotypeby age. She showed amaximal LV thickness of 8 mmby the age of 36 years, whereas her father wasaffected by the age of 30 years (Fig. 6).

� “MR OHþMþNþLi GN EG DN-LAMP2 [p.His260Pro fs22] SC-II”describes a patient diagnosed with RCM, alongwith associated myopathy, cognitive impairment,and liver disease. The patient had a negative familyhistory and screening. He was found to carry aframe-shift mutation in the LAMP2 gene; themutation was absent in both parents. The car-diomyopathy was rather severe at onset, with ar-rhythmias and advanced LV function impairment(Online Fig. 4).

CONCLUSIONS

A substantial increase in the knowledge of the geneticbases of cardiomyopathy calls for a standardized,universally acceptable classification/nosology systemthat integrates phenotype description as well asgenetic information. The flexible MOGE(S) systemfacilitates the transition of description of cardiomy-opathies from the pre-genetic to the genetic era andensures the capture of an enormous amount ofdata that could be lost if not systematically regis-tered. The use of the MOGES app obligates descrip-tion of the results achieved in all diagnostic steps,


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including clinical cardiologic evaluation, extra-cardiac evaluation, clinical genetics, family screen-ing, molecular genetics when possible, and functionalstatus. This exercise provides uniform language andeasy-to-capture identical information for data miningqueries.


REPRINT REQUESTS AND CORRESPONDENCE: Dr.Jagat Narula, Icahn School of Medicine at MountSinai, Division of Cardiology, One Gustave L. LevyPlace, Box 1030, New York, New York. E-mail:[email protected].

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KEY WORDS cardiomyopathy,classification, genetics

APPENDIX For supplemental tables andfigures, please see the online version of thisarticle.












































































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