cardiology

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.

C

ardiomyopathy is the heart muscle disease

underscore the importance of providing cardiologists

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, most cardiomyopathies

mixed, and acquired forms, and the European Society

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 n 241924 and Italian Ministry of Health “Diagnosis and Treatment of Hypertrophic
Cardiomyopathies” (n RF-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.

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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

ing of the heart failure (HF) included asymptomatic

patients,

patients with a familial history of cardiomyopathy in

(AVB), pre-excitation syndrome (Wolff-Par-

the stage A or pre-HF (3).

including

atrioventricular

block

ACC = American College of
Cardiology

AHA = American Heart

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-

The electrocardiographic and echocardiographic clues

compaction, ventricular dilation, ventricular

cardiomyopathy

may show early (subclinical) cardiac involvement

dysfunction, myocardial fibrosis, infiltrative

LV = left ventricle

(4–10). On the other hand, the nongenetic cardiomy-

or intramyocyte storage, or fatty infiltration of

LVNC = left ventricular

opathies may be described as associated with specific

the myocardium (18,19). Although each sub-

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

for work-up of cardiomyopathies are supported by

variability.

HCM = hypertrophic

WPW = Wolff-Parkinson-White
syndrome

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), it may not be by itself sufficient

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 cardiomyopathy

[ARVC]/arrhythmogenic

The knowledge of the genetic basis of all kinds

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), most disease genes are not

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T A B L E 1 Recapitulation of the Classification Systems for Cardiomyopathies in the

Last 50 Years

nonsarcomeric genes also may cause HCM (33). An
increasing number of cardiomyopathies are being
recognized as associated with complex genetics (34).

Year

1956

Definitions/Classifications

References

Myocardial diseases classified as
myocarditis (inflammatory heart
muscle disease), and myocardiosis
(other heart muscle diseases).

Blankerhorn and Gall (71)

1957

The term cardiomyopathy proposed for
uncommon, noncoronary heart muscle
diseases.

Bridgen (72)

1972

Cardiomyopathy described as myocardial
diseases of unknown origin, and first
classification proposed as dilated,
hypertrophic, and restrictive (or
obliterative) cardiomyopathy.

Goodwin and Oakley (73)

WHO-ISFC adopts Goodwin and Oakley
classification, and defines
cardiomyopathies as myocardial
diseases of unknown etiology. WHOISFC adds specific heart muscle
diseases (cause of myocardial
affliction known) to the classification.

Report of the WHO/ISFC Task Force on
the Definition and Classification of
Cardiomyopathies (74)

WHO-ISFC updates its classification of
cardiomyopathies (diseases of
myocardium associated with
myocardial dysfunction). The update
includes arrhythmogenic right
ventricular cardiomyopathy and
unclassified cardiomyopathy, but
excludes specific heart muscle
disease.

Richardson et al. (75)

1980

1996

eton, sarcomere, or desmosome, or those involved in
calcium-handling and energy production (Online
Table 1). The constantly increasing number of
disease-causing genes suggests that the unresolved
issue of variable penetrance or expression may
represent incomplete genotyping (Fig. 3), or that the
presumptive disease-causing role has erroneously
been assigned to a wrong gene and mutation. Although functional studies are likely to elucidate the
role of the protein mutations, the speed of detection
of mutations will continue to outpace the experiments that are needed to confirm their functional
importance in the animal models or in vitro studies.
The approach to genetic testing could continue to be
either clinically guided, based on the sequencing of
genes selected on the basis of a clinical hypothesis, or
based on sequencing of large panels of diseaseassociated/candidate genes (35–38). However, inter-

ISFC becomes WHF

2006

AHA defines cardiomyopathies as
diseases of myocardium associated
with mechanical and/or electrical
dysfunction, which usually (but not
invariably) exhibit inappropriate
ventricular hypertrophy or dilation,
due to a variety of causes that
frequently are genetic, classified as
primary or secondary. Presents first
visionary attempt to classify primary
cardiomyopathy by genetic origin
(genetic, acquired, or mixed)

Maron et al. (1)

ESC defines cardiomyopathies as
myocardial disorder in which the heart
muscle was structurally and
functionally abnormal. Classified
dilated, hypertrophic, restrictive,
arrhythmogenic right ventricular, or
unclassified cardiomyopathy
subtypes as familial/genetic and
nonfamilial/nongenetic. Maintained
the importance of phenotype
preceding genetic classification for
clinical practice.

Elliott et al. (2)

WHF-MOGE(S) nosology proposes a
descriptive genotype-phenotype
nosology system.

Arbustini et al. (54,55)

2013

causing genes have been identified encoding for the
proteins of nuclear envelope, sarcolemma, cytoskel-

1998

2008

More than 100 nuclear and mitochondrial disease-

pretation of the results rather than performing the
test would pose a bigger challenge in the modern era
of next-generation sequencing.
On the basis of clinical and genetic evidence indicating that most cardiomyopathies are familial diseases and that genetic diagnosis is now reachable in a
high proportion of patients, scientific societies, such
as the Heart Rhythm Society, Heart Failure Society of
America, and the European Society of Cardiology,
have provided guidelines and recommendations for
family screening and genetic testing for cardiomyopathies (Table 2).

THE MOGE(S) NOMENCLATURE
In the quest for a genetic terminology, nomenclature
such as desmosomalopathy (39), cytoskeletalopathy
(40), sarcomyopathy (39), channelopathy (41), cardiodystrophinopathy (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,

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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), such as in ARVC/
arrhythmogenic

ventricular

cardiomyopathy

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

and

EMF. The diagnostic criteria for ARVC have been
debated and modified, and the M A notation can be
further specified with the help of the major [M] or
minor [m] diagnostic clues that are variably combined

F I G U R E 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

in the Modified 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)

different categories [m4X4] are present; borderline

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

when 1 major and 1 minor [M1þm1] or 3 minor criteria
from different categories [m3X3] are present; and

nificant diastolic dysfunction, mild LV hypertrophy (interventricular septum ¼ 12 mm),
severe biatrial dilation (right > left), mild right ventricular dysfunction, tricuspid regurgitation, 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], M A[M1þm2X2], or MA[m4X4]; a

rhythmias. The MOGE(S) committee is working with

borderline diagnosis as MA[M1þm1] or MA[m3X3]; and a

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).
A recent commentary appropriately emphasized the

MOGE(S) IN DAY-TO-DAY
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). Because EMF can

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

ease as well as the single or double ventricular

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), the classification of arrhyth-

volvement/Genetic

mias is far from the aim of MOGE(S); however, we

flexible

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

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structure

/familial/Etiology/gene)

that

readily

provides

but

several

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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)

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

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

gestive of cardiomyopathy.

ID

Phenotype

Outcome

Age (years)

I:1

HCM

SD

53

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

II:1

HCM

HF

56

II:2

HCM

SD

45

II:3

HCM

SD

60

M:

MORPHO-FUNCTIONAL

PHENOTYPE. The

“M”

M D (DCM), MH (HCM), MA (ARVC), MR (RCM), and M NC
(LVNC). This notation corresponds to the current
clinical classification of cardiomyopathies. The first
and commonly used clinical diagnosis is labeled as a

II:5

HCM

SD

50

II:6

HCM

SD

47

II:7

HCM

HF

69

II:8

HCM

HF

67

nificant restrictive pattern can be described as M HþD

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 M DþNC or M AþNC or MHþNC.

III:5

HCM

SD

8

The “M” notation also carries key clinical red flags

subscript to the “M.” HCM that evolves into dilated
congestive phenotype or HCM presenting with sig-

III:7

HCM

SD

32

such as short PR interval (PR), WPW, or AVB, which

III:8

HCM

SD

32

may be displayed as M H[PR] , M H[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
LVNC are not fulfilled; NS[Hypertrab]). Furthermore,

III:2

RCM

HTX

41

IV:2

HCM

HTX

56

“M” allows for the description of early phenotypes.

IV:3

HCM

SD

28

For instance, conditions where diagnostic criteria for
the suspected clinical phenotype (such as DCM or

IV:5

HCM/RCM

HTX

41

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

V:3

HCM

SD

14

carriers of the mutation that have caused the disease

V:4

HCM

Death at
childbirth

25

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.

F I G U R E 2 The Same Genotype May Be Associated With Different

Phenotypic Expressions

O: THE INVOLVED ORGANS. The second descriptor is

the organ involvement, which can either be the heart

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

only (O H) 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 (O HþM ), auditory system

(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);

(O HþA), kidney (O HþK), nervous system (OHþN), liver
(O HþLi ), gastrointestinal system (OHþG ), cutaneous

HCM/RCM ¼ blue-bordered figure (IV:5); HCM = green-bordered figure (VI:1). HF ¼ heart

(O HþC), ocular or eyes (OHþE), respiratory or lung

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

(O HþLu ), or mental retardation (OHþMR). Healthy mu-

SD ¼ sudden death.

tation carriers are described as O0 , because the heart
is still clinically unaffected; it complements the M 0
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). The simple combination of data

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

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address focused genetic testing. Such combinations
also allow for easy recognition of syndromes.
G: GENETIC INHERITANCE. The third descriptor re-

presents genetic or familial inheritance as deduced
clinically by family pedigree and screening. The
inheritance includes autosomal dominant (G AD ),
autosomal recessive (G AR), X-linked (G XL ), X-linked
recessive (G XLR), or dominant (G XLD) or matrilineal
(G M) transmission. Patients who are the uniquely
affected members of the family with a documented
disease mutation are described as de novo (G DN ) or as
having phenotypically sporadic (G S ) cardiomyopathy.
The negative or unknown family history (G N or GU )
and the family history not investigated so far (G0 ) also
can be specified.

MH+D OH GAD EG-MYH7[p.Val606Met]+LMNA[p. Asp254GIy] SC-II
F I G U R E 3 The Presence of More Than 1 Genotype May Influence

the Phenotype

E: ETIOLOGY. The notation “E” includes a description

in 2 steps. The first step informs the underlying cause
of the cardiomyopathy, which may be of genetic (EG) or
nongenetic cause. The latter needs to be addressed

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

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

mutation needs to be specified next to the E G, and
similarly, the cause of the underlying disease in
nongenetic

cardiomyopathies

also

needs

to

be

explained.

received cardiac resynchronization therapy/ICD implantation after resuscitated 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.

In genetic cardiomyopathies, the disease gene and
mutation(s) can be added, such as in the case of HCM
(E G-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 (E G-OC), or the obligate noncarrier (E G-ONC).

contribute to document the abnormal expression of

E G-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: E G-N (genetic defect

immediate information about pathologic mutations

not identified). E G-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 (>1 mutation in a single patient) 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, E V-CB3, or E V-EBV) for the second

nomenclature of genetic variants may facilitate the

notation; the infectious, nonviral diseases (E I) may be

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’s Exome Sequencing

ditis, such as sarcoidosis (E M-Sarcoid ) or noninfectious

Project (60), the 1,000 Genomes Project (61), and

giant cell myocarditis. An autoimmune etiology,

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T A B L E 2 Genetic Testing: Position of the Scientific Societies

Type of Cardiomyopathy

Strength of
Evidence/Class

Recommendation
Heart Failure Society of America, 2009 (76)

All patients with
cardiomyopathy

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

HCM

DCM

RCM

ARVC

LVNC

CMP with extracardiac
traits

At-risk first-degree relatives with any abnormal clinical screening test (regardless the genotype) should be considered for repeat
clinical screening at 1 year

C

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

A

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
management (LMNA, MYH7, TNNT2, SCN5A, DES, MYBPC3, TNNI3, TPMI, ACTC, PLN, LDB3, and TAZ)

B

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
management (gene tests: uncertain)

C

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
management (DSP, PKP2, DSG2, and DSC2)

A

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
management (gene tests: uncertain)

C

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
management

A

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

Diagnostic work-up
in patients and
families with CMP
(the numbers in
the right column
indicate 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 referral
centers.
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;
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 family
assessment

To be considered

Genetic testing and pre-natal diagnosis

7
Continued on the next page

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MOGE(S) Classification of Cardiomyopathy

T A B L E 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)

DCM

RCM
ACM/ARVC

LVNC

I

Mutation-specific genetic testing in relatives of mutated probands

I

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
and monitoring plans

IIa

Mutation-specific test in family members after identification of the causative mutation in the index case.

I

Patients with clinical suspicion for RCM

IIb

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
for 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

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.

either suspected or proven (EAI-S or EA-P), may popu-

S: FUNCTIONAL STATUS. “S,” in 2 notations, de-

late the first notation followed by the specific eti-

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 S A-I or SC-II, and so on. The descriptor “S” is optional,

description of each proven diagnosis (e.g., M D

but may come in handy for the description of early

O HþCþS G 0 EAI-P-Rheumatoid

S C-II or M D O HþC G 0

cardiomyopathy. The ACC/AHA guidelines include

SB-II). Nonheritable amyloid-

patients with a family history of cardiomyopathy in

osis (E A-K, EA-L , or EA-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

described

early imaging markers of the disease can be high-

(E T-Pheo or ET-Chloroquine ). When the former is described

lighted. This description could be especially useful for

E AI-P-Rheumatoid

Arthritis

drug-induced

Arthritis

cardiomyopathy,

are

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.

the name of the syndrome (i.e., E T-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 PDGFR a or PDGFR b genes that generate a

manifestation of the clinical phenotype (65).

fusion gene encoding for constitutively active PDGFR
tyrosine kinases (64).

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The

Central

Illustration

shows

the

MOGE(S)

system notations and modeling. The alphabetical

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M

O

G

E

S

MORPHO-FUNCTIONAL
PHENOTYPE

ORGAN/SYSTEM
INVOLVEMENT

GENETIC INHERITANCE
PATTERN

ETIOLOGY

STAGE

CHARACTERISTICS

NOTATION

MOGE(S) Classification of Cardiomyopathy

Proband’s
cardiomyopathy
(CM) diagnosis
(DCM, HCM, RCM,
ARVC/D, LVNC)

Genetic counseling
with pedigree

Clinical history
and evaluation
Organ
involvement:
Extracardiac
organs/tissues

Familial

SUBSCRIPT

Multidisciplinary
evaluation
according per
clinical needs
or diagnostic
hypothesis

D

Dilated

H

Hypertrophic

R

Restrictive

R EMF
Endomyocardial
LV=left ventricle
RV=right ventricle
RLV=biventricular
A

ARVC
M=major
m=minor
c=category
LV= left ventricle
RV=right ventricle
RLV=biventricular

E

Early, with type
in parentheses

NS
phenotype
NA Information
non available

Positive

Informative
and noninformative
families

Relatives
with ECG
and/or Echo
abnormalities

Cascade
genetic
testing in
relatives

Consultant
non-informed
about family
history

Healthy family
members
with normal
ECG and ECHO

Functional
status
ACC/AHA,
NYHA

Negative

New tests
novel
genes

Regular
monitoring
in relatives

H Heart
LV=left ventricle
RV=right ventricle
RLV=biventricular

N

Family history negative

G

Genetic cause

U

Family history unknown

OC

Obligate carrier

AD Autosomal dominant

ONC Obligate non-carrier

M Muscle (skeletal)

AR Autosomal recessive

DN De novo

N Nervous

XLD X-linked dominant

Neg Genetic test negative for
NA
the known familial mutation not applicable

C

Cutaneous

XLR X-linked recessive

E

Eye, Ocular

XL X-linked

N
NU
0 No genetic test, any reason* not used

A

Auditory

M

Matrilineal

G-A-TTR Genetic amyloidosis

K

Kidney

0

Family history not investigated*

G-HFE Hemochromatosis

G Gastrointestinal

Undet Inheritance still undetermined

Li Liver

S

Lu Lung
S

NC LVNC

asymptomatic
relative
unaware of
the disease

Non-familial;
Phenotypically
sporadic

Inheritance
AD, AR XL
(R or D) or
Matrilineal

Genetic testing
in the proband

Clinical
family screening

Phenotypically Sporadic
(apparent or real)

Skeletal

ACC-AHA
stage
represented
as letter
A, B, C, D

followed by

NYHA class
represented
as Roman
M Myocarditis
numeral
V Viral infection (add the virus I, II, III, IV
Non-genetic etiologies:

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

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

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

Infectious, non viral
(add the infectious agent)

T Toxicity (add cause/drug)

0

Eo Hypereosinophilic
heart disease
O Other

inheritance in G

C E N T R A L I L L U S T R A T I O N 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

application and to provide a simple summary for

new

scientific

information.

The

proposed

nomenclature reflects the current diagnostic work-

the patient’s clinical record by the MOGE(S) system,

up

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

of

cardiomyopathies

for

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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), such as in ARVC/
arrhythmogenic

ventricular

cardiomyopathy

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

and

EMF. The diagnostic criteria for ARVC have been
debated and modified, and the M A notation can be
further specified with the help of the major [M] or
minor [m] diagnostic clues that are variably combined

F I G U R E 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

in the Modified 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)

different categories [m4X4] are present; borderline

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

when 1 major and 1 minor [M1þm1] or 3 minor criteria
from different categories [m3X3] are present; and

nificant diastolic dysfunction, mild LV hypertrophy (interventricular septum ¼ 12 mm),
severe biatrial dilation (right > left), mild right ventricular dysfunction, tricuspid regurgitation, 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], M A[M1þm2X2], or MA[m4X4]; a

rhythmias. The MOGE(S) committee is working with

borderline diagnosis as MA[M1þm1] or MA[m3X3]; and a

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).
A recent commentary appropriately emphasized the

MOGE(S) IN DAY-TO-DAY
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). Because EMF can

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

ease as well as the single or double ventricular

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), the classification of arrhyth-

volvement/Genetic

mias is far from the aim of MOGE(S); however, we

flexible

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

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structure

/familial/Etiology/gene)

that

readily

provides

but

several

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Mitochondrial Cardiomyopathy

MH+D (WPW) OH+M+N+E+A GM EG-MTDNA[A3243G]
F I G U R E 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 submitted to repositories. In a discharge summary, the
concluding diagnosis “Dilated Cardiomyopathy (MD
O H G AD EG-MYH7[Ile533Asn] SB-II)” may provide comprehensive information about the patient. For instance,
after a family screening, the mutation does not
segregate or a second mutation is identified. In that
case, MOGE(S) allows the description of new information (M D O H G AD EG-MYH7[Ile533Asn]þMYBPC3[Arg326Gln]).
(S) is a dynamic notation that may modify during
follow-up, and its use can provide information about
change in the functional status and evolution of
remodeling status. Although NYHA functional class is
universally used, ACC/AHA stage has been less
commonly applied in clinics. It can be difficult to
apply to cardiomyopathies, such as classical ARVC,
especially when diagnosed on 2 major criteria such as
major ECG changes (e.g., negative T waves in v 1 to v3 )
and sudden cardiac death or a first-degree relative or
a known pathologic mutation. MOGE(S), however,
does not obligate us to fill all fields, and the MOGE(S)

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The following are a few examples from our database pertaining to the application of MOGE(S):
 “M D O HþM G AD E G-NA SC-III” represents a baseline
description of the patient (II:1) who was diagnosed
with DCM, presenting with both cardiac and muscle involvement. He was a member of a family with
the autosomal dominant DCM, but the genetic
testing was not available. The functional status
was described as ACC/AHA stage C and NYHA
functional class III. Subsequently, when the genetic information became available, the notation
was changed to “M D O HþM G AD E G-LMNA[p.Arg190Trp]
S C-III.” During follow-up, after starting the treatment with an improvement in the NYHA functional
class, the functional status changed to “MD O HþM
G AD EG-LMNA[p.Arg190Trp] SC-I.” At echocardiographic
evaluation a brother (II:3) of the proband showed
LV dilation, and borderline LV ejection fraction: he
was described as “ME[D] O H G AD E G-NA S B.” Further
in the course of the follow-up, the description was

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MOGE(S) Classification of Cardiomyopathy

I:1

II:1

AF, stroke
Age: 59 years
Genetic test: not done

I:2

II:2

II:3

AF
Age: 90 years
II:5 Genetic test: negative

II:4

HCM, LVT=18mm
Onset: 30 years
Death:37 years III:1
Genetic test: NA
LVT=8mm
Age=36 years
Genetic test: IV:1
positive

LVT=9mm
Age: 56
years III:2
Genetic test:
Negative

IV:2

III:3

HCM LVT=16mm
Onset: 52 yrs
Age=56 years
Genetic test: Positive
LVT=8mm
Age=24 years

IV:3

IV:4 Genetic test:
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

F I G U R E 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 G AD E G-LMNA[p.Arg190Trp]

maternal family history for loss of hearing, and

SB-I.” He was classified as stage B-I due to asymp-

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

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. Two sisters showed hearing loss and diabetes.

E G-LMNA[p.Arg190Trp] S A-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 O HþMþNþA G M EG-MtDNA

deoxyribonucleic

acid

(MtDNA).

[tRNALeu A3243G] þ GJB2

C, NYHA functional class IV). We could not trace

[del30G hetero] S D-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).

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315

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MOGE(S) Classification of Cardiomyopathy

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).
 “M H O H G AD E G-MYBPC3[IVS16-1G>A] S B-II” describes a
patient (III:3) diagnosed with HCM, exclusive
involvement of the heart, with a positive family

A

B

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

history in which the disease is inherited as an
autosomal dominant trait, and caused by a known
mutation in MYBPC3. The functional status is
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 O 0
G AD E G-Neg). The sister also was not affected, but
was a carrier of the mutation identified in the
proband (M0 O 0 GAD E G-MYBPC3[IVS16-1G>A] S A-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

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

This simple information describes her father as the
obligate carrier of the mutation. The evaluation of
the niece, however, presented the problem of

F I G U R E 7 Genotypic Expression May Play a Role in Arrhythmogenicity

When tissue samples are available, such as in endomyocardial biopsies or from hearts 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 immunohistochemicallystained histomicrographs refer to patients with either dilated cardiolaminopathy (top)
or dilated cardiodystrophinopathy (bottom). The endomyocardial biopsy above shows

nonsegregation of the genotype with the phenotype
by age. She showed a maximal LV thickness of 8 mm
by the age of 36 years, whereas her father was
affected by the age of 30 years (Fig. 6).
 “M R O HþMþNþLi GN E G

DN-LAMP2 [p.His260Pro fs22]

S C-II”

describes a patient diagnosed with RCM, along
with associated myopathy, cognitive impairment,

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

diomyopathy was rather severe at onset, with ar-

(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,
 “MAþHypertrab O H G Undet EG-LDB3

[p.Thr507Asn] þ DSG2

universally acceptable classification/nosology system

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. The use of the MOGES app obligates descrip-

origin in 2 different genes. To date, the proband

tion of the results achieved in all diagnostic steps,

[p.Lys479Glu]

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Arbustini et al.

JACC VOL. 64, NO. 3, 2014
JULY 22, 2014:304–18

including

clinical

MOGE(S) Classification of Cardiomyopathy

cardiologic

evaluation,

extra-

cardiac evaluation, clinical genetics, family screen-

REPRINT REQUESTS AND CORRESPONDENCE: 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].

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KEY WORDS cardiomyopathy,
classification, genetics

A PPE NDI X For supplemental tables and
figures, please see the online version of this
article.