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

3, 2014

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) Classication 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 identies 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 classications 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 stratication, 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;64:30418) 2014 by the American College of Cardiology Foundation.

C ardiomyopathy is the heart muscle disease

sufcient to cause structural and functional
myocardial 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 cardiomyopathies
are inherited, and the recent classication systems
underscore the importance of providing cardiologists
with tools to better describe the patients and families
affected by a morphofunctional cardiomyopathic
phenotype. The American Heart Association (AHA)
classication grouped cardiomyopathies into genetic,
mixed, and acquired forms, and the European Society
of Cardiology classication 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. Lukes 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 Speakers Bureau for Servier; has been a trial committee member for Servier, Cardiorentis, Boston Scientic, 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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JACC VOL. 64, NO. 3, 2014
JULY 22, 2014:30418
each major type of cardiomyopathy into familial or
genetic, and nonfamilial or nongenetic forms (1,2).
The American College of Cardiology (ACC)/AHA stag-
ing of the heart failure (HF) included asymptomatic
patients with a familial history of cardiomyopathy in
the stage A or pre-HF (3).
In the last 20 years, the systematic approach to
family screening has contributed to better assess-
ment of familial cardiomyopathies. This method has
allowed the identication of family members who are
predisposed to disease development, based on the in-
heritance of the cardiomyopathy-associated gene(s).
The electrocardiographic and echocardiographic clues
may show early (subclinical) cardiac involvement
(410). On the other hand, the nongenetic cardiomy-
opathies may be described as associated with specic
etiologies, such as viral infections, autoimmune dis-
eases, and endogenous or exogenous myocardial
toxicity. The contemporary diagnostic algorithms
for work-up of cardiomyopathies are supported by
advanced imaging characterization, disease-specic
biomarkers, and genetic analyses (11). The number of
cardiomyopathies wherein the cause is identied (or
identiable) is increasing, supported by the family
screening and follow up for segregation studies of
genotype with phenotype.
The morphofunctional phenotype-based classi-
cation of cardiomyopathies continues to offer cardi-
ologists the possibility of using a simple and clinically
useful diagnostic language (Table 1). All treatment
protocols are currently based on the phenotype, as
well as signs and symptoms. The phenotype-based
classication (hypertrophic cardiomyopathy [HCM],
dilated cardiomyopathy [DCM], restrictive cardiomy-
opathy [RCM], arrhythmogenic right ventricular car-
diomyopathy [ARVC]/arrhythmogenic ventricular
cardiomyopathy, and left ventricular noncompaction
[LVNC]) describes the major forms of cardiomyopa-
thy, but not their causes. However, cardiomyopathies
are clinically heterogeneous diseases (1217), and
within each subtype of cardiomyopathy there are
differences 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, for
example, there are patients with mildly enlarged
and mildly dysfunctional left ventricle (LV) that
develop life-threatening ventricular arrhythmias;
yet, there may be patients with extremely dilated
and dysfunctional LV but low arrhythmogenic risk.
Similarly, in the HCM group, there are patients with
severe left ventricular hypertrophy who are asymp-
tomatic and do not demonstrate life-threatening ar-
rhythmias. Finally, there are patients who show mild
to moderate hypertrophy but carry a high risk of
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Arbustini et al. 305
MOGE(S) Classication of Cardiomyopathy
arrhythmias. Numerous electrocardiographic ABBREVIATIONS
markers have been shown to be associated AND ACRONYMS
with cardiomyopathy in a subset of the
ACC = American College of
patients, including atrioventricular block Cardiology
(AVB), pre-excitation syndrome (Wolff-Par-
AHA = American Heart
kinson-White syndrome [WPW]), repolariza- Association
tion abnormalities, or low QRS voltage. ARVC = arrhythmogenic right
Echocardiography and cardiac magnetic reso- ventricular cardiomyopathy
nance imaging may reveal variable features AVB = atrioventricular block
within the similar phenotypes, including the DCM = dilated cardiomyopathy
severity, distribution, and extent of myocar- EMF = endomyocardial brosis
dial hypertrophy, thickening of valves, non- HCM = hypertrophic
compaction, ventricular dilation, ventricular cardiomyopathy
dysfunction, myocardial brosis, inltrative LV = left ventricle
or intramyocyte storage, or fatty inltration of LVNC = left ventricular
the myocardium (18,19). Although each sub- noncompaction
type of cardiomyopathy is dened by its major RCM = restrictive
morphofunctional phenotype, a careful clin- cardiomyopathy
ical evaluation demonstrates high phenotype WPW = Wolff-Parkinson-White
syndrome
variability.
Most cardiomyopathies demonstrate an auto-
somal dominant inheritance, but X-linked recessive,
autosomal recessive, or matrilineal inheritance may
occur in a minority of cases. Although elucidation
of family history and comprehensive assessment
of pedigree is the foremost necessity in family
studies (17,20,21), it may not be by itself sufcient
to establish the diagnosis of familial cardiomyo-
pathy. Cascade family screening and monitoring
may 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 the
disease (16,17).
The knowledge of the genetic basis of all kinds
of cardiomyopathies has progressively increased
(1214,22). Linkage analyses (23), genome-wide asso-
ciation studies (GWAS) (24,25), and whole-exome se-
quencing (WES) (26) have incrementally contributed
to the list of disease genes (Online Table 1), which
now includes more than 100 genes. HCM is caused by
the mutations of genes that code for structural and
functional proteins of the sarcomere (15), whereas
DCM is caused by the mutation of genes related to
structure and function of nuclear envelope, cyto-
skeleton, sarcomere, and sarcoplasmic reticulum (27).
ARVC is known as a collection of diseases of the
desmosome (28), and RCM is caused by defects in
genes encoding for sarcomeric proteins (29) or inter-
mediate laments, such as desmin (20).
However, the early assignment of phenotypes to
groups of genes and pathways is no longer conrmed
by recent genetic studies. In fact, genes may cause
similar phenotypes (Fig. 1), most disease genes are not
306 Arbustini et al. JACC VOL. 64, NO. 3, 2014

MOGE(S) Classication of Cardiomyopathy JULY 22, 2014:30418

nonsarcomeric genes also may cause HCM (33). An

T A B L E 1 Recapitulation of the Classication Systems for Cardiomyopathies in the
Last 50 Years
increasing number of cardiomyopathies are being
recognized as associated with complex genetics (34).
Year Denitions/Classications References
More than 100 nuclear and mitochondrial disease-
1956 Myocardial diseases classied as Blankerhorn and Gall (71)
myocarditis (inammatory heart causing genes have been identied encoding for the
muscle disease), and myocardiosis proteins of nuclear envelope, sarcolemma, cytoskel-
(other heart muscle diseases).
eton, sarcomere, or desmosome, or those involved in
1957 The term cardiomyopathy proposed for Bridgen (72)
uncommon, noncoronary heart muscle calcium-handling and energy production (Online
diseases. Table 1). The constantly increasing number of
1972 Cardiomyopathy described as myocardial Goodwin and Oakley (73)
disease-causing genes suggests that the unresolved
diseases of unknown origin, and rst
classication proposed as dilated, issue of variable penetrance or expression may
hypertrophic, and restrictive (or
represent incomplete genotyping (Fig. 3), or that the
obliterative) cardiomyopathy.
1980 WHO-ISFC adopts Goodwin and Oakley Report of the WHO/ISFC Task Force on presumptive disease-causing role has erroneously
classication, and denes the Denition and Classication of been assigned to a wrong gene and mutation. Al-
cardiomyopathies as myocardial Cardiomyopathies (74)
diseases of unknown etiology. WHO- though functional studies are likely to elucidate the
ISFC adds specic heart muscle role of the protein mutations, the speed of detection
diseases (cause of myocardial
afiction known) to the classication. of mutations will continue to outpace the experi-
1996 WHO-ISFC updates its classication of Richardson et al. (75) ments that are needed to conrm their functional
cardiomyopathies (diseases of importance in the animal models or in vitro studies.
myocardium associated with
myocardial dysfunction). The update The approach to genetic testing could continue to be
includes arrhythmogenic right either clinically guided, based on the sequencing of
ventricular cardiomyopathy and
unclassied cardiomyopathy, but genes selected on the basis of a clinical hypothesis, or
excludes specic heart muscle based on sequencing of large panels of disease-
disease.
associated/candidate genes (3538). However, inter-
1998 ISFC becomes WHF
2006 AHA denes cardiomyopathies as Maron et al. (1) pretation of the results rather than performing the
diseases of myocardium associated test would pose a bigger challenge in the modern era
with mechanical and/or electrical
dysfunction, which usually (but not of next-generation sequencing.
invariably) exhibit inappropriate On the basis of clinical and genetic evidence indi-
ventricular hypertrophy or dilation,
due to a variety of causes that cating that most cardiomyopathies are familial dis-
frequently are genetic, classied as eases and that genetic diagnosis is now reachable in a
primary or secondary. Presents rst
visionary attempt to classify primary high proportion of patients, scientic societies, such
cardiomyopathy by genetic origin as the Heart Rhythm Society, Heart Failure Society of
(genetic, acquired, or mixed)
America, and the European Society of Cardiology,
2008 ESC denes cardiomyopathies as Elliott et al. (2)
myocardial disorder in which the heart have provided guidelines and recommendations for
muscle was structurally and family screening and genetic testing for cardiomy-
functionally abnormal. Classied
dilated, hypertrophic, restrictive, opathies (Table 2).
arrhythmogenic right ventricular, or
unclassied cardiomyopathy
subtypes as familial/genetic and THE MOGE(S) NOMENCLATURE
nonfamilial/nongenetic. Maintained
the importance of phenotype
preceding genetic classication for In the quest for a genetic terminology, nomenclature
clinical practice. such as desmosomalopathy (39), cytoskeletalopathy
2013 WHF-MOGE(S) nosology proposes a Arbustini et al. (54,55)
descriptive genotype-phenotype
(40), sarcomyopathy (39), channelopathy (41), car-
nosology system. diodystrophinopathy (42), cardiolaminopathy (43),
zaspopathy (44), myotilinopathy (45), dystrophin-
AHA American Heart Association; ESC European Society of Cardiology; ISFC International Society and
Federation of Cardiology; WHF World Heart Federation; WHO World Health Organization. opathy (46), alpha-B crystallinopathy (44), desmin-
opathy (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 dene
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 laments, 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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JACC VOL. 64, NO. 3, 2014 Arbustini et al. 307
JULY 22, 2014:30418 MOGE(S) Classication of Cardiomyopathy

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

Dilated cardiolaminopathy Dilated emerinopathy

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

F I G U R E 1 Similar Phenotypes but Different Inheritance May Inuence Comprehensive Assessment of the Family and Genetic Counseling

Mutations in genes coding for proteins of the nuclear envelope, such as Lamin AC (LMNA) and Emerin (EMD) cause dilated cardiomyopathy
(DCM) with conduction disease. The phenotypes look alike (echocardiograms revealed DCM with similar left ventricular dimensions and
function in these 2 individuals), and the only distinguishing descriptor is the type of inheritance (shown in blue letters in the MOGE[S]
description below the echocardiograms). Both LMNA and EMD mutations are pathologic and appear red in MOGE(S). Serum creatine
phosphokinase (sCPK) can be normal in both conditions; EMD mutations are associated with X-linked recessive inheritance and LMNA mutations
are associated with Autosomal dominant (AD) inheritance.

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308 Arbustini et al. JACC VOL. 64, NO. 3, 2014

MOGE(S) Classication of Cardiomyopathy JULY 22, 2014:30418

Association (NYHA) (I to IV) functional classes was

also added. The S notation is especially useful
when mutation carriers are healthy, or if they dem-
onstrate imaging-veried early abnormalities sug-
TNNI3 p.(Leu144Gln) gestive of cardiomyopathy.
ID Phenotype Outcome Age (years) M: MORPHO-FUNCTIONAL PHENOTYPE. The M
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
M D (DCM), MH (HCM), MA (ARVC), MR (RCM), and M NC
II:1 HCM HF 56
(LVNC). This notation corresponds to the current
II:2 HCM SD 45
MR OH GAD EG-TNNI3[p. Leu144GIn] SD-IV clinical classication of cardiomyopathies. The rst
II:3 HCM SD 60
and commonly used clinical diagnosis is labeled as a
II:5 HCM SD 50
subscript to the M. HCM that evolves into dilated
II:6 HCM SD 47
congestive phenotype or HCM presenting with sig-
II:7 HCM HF 69
II:8 HCM HF 67
nicant restrictive pattern can be described as M HD
II:10 HCM/RCM HF 64 or MHR (Figs. 2 and 4). Multiple other combinations
III:3 RCM HTX 56 may be possible, such as M DNC or M ANC or MHNC.
III:5 HCM SD 8 The M notation also carries key clinical red ags
III:7 HCM SD 32 such as short PR interval (PR), WPW, or AVB, which
III:8 HCM SD 32 may be displayed as M H[PR] , M H[WPW], or MD[AVB]. It
III:14 HCM SD 14 also may describe a nonspecic or noncoded pheno-
III:15 HCM SD 14 type (such as hypertrabeculation when criteria for
III:2 RCM HTX 41 LVNC are not fullled; NS[Hypertrab]). Furthermore,
IV:2 HCM HTX 56 M allows for the description of early phenotypes.
MH+R OH GAD EG-TNNI3[p. Leu144GIn] SC-III IV:3 HCM SD 28 For instance, conditions where diagnostic criteria for
IV:5 HCM/RCM HTX 41 the suspected clinical phenotype (such as DCM or
IV:9 HCM SD 25 HCM) are not fullled 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 25
childbirth in the family. Clinically-unaffected mutation carriers
V:6 HCM SD 17 are described as M0 . When the information about the
VI:1 HCM ICD 16 cardiac phenotype is not available, such as in the
deceased relatives, the description is MNA . Overall,
the M notation is exible and suitable for any
MH OH GAD EG-TNNI3[p. Leu144GIn] SC-III clinical combination of disease phenotypes and clin-
ical traits.
F I G U R E 2 The Same Genotype May Be Associated With Different
O: THE INVOLVED ORGANS. The second descriptor is
Phenotypic Expressions
the organ involvement, which can either be the heart
Restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM)/RCM, and HCM only (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 HM ), auditory system
(p.Leu144Gln). The table shows the ID (family member), age, phenotype, and outcome of (O HA), kidney (O HK), nervous system (OHN), liver
family members. The echocardiographic gures refer to cardiac phenotypes in 3 family
(O HLi ), gastrointestinal system (OHG ), cutaneous
members indicated by the corresponding colors: RCM red-bordered gure (III:3);
HCM/RCM blue-bordered gure (IV:5); HCM = green-bordered gure (VI:1). HF heart (O HC), ocular or eyes (OHE), respiratory or lung
failure; HTx heart transplantation; ICD implantable cardioverter-debrillator; (O HLu ), or mental retardation (OHMR). Healthy mu-
SD 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 eld of diagnostic hypotheses and can

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JACC VOL. 64, NO. 3, 2014
JULY 22, 2014:30418
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 specied.
E: ETIOLOGY. The notation E includes a description
in 2 steps. The rst step informs the underlying cause
of the cardiomyopathy, which may be of genetic (EG) or
nongenetic cause. The latter needs to be addressed
individually as in the following paragraph; the non-
identiable cause is also noted (EN ). The second nota-
tion denes precise etiology. For example, the gene
mutation needs to be specied next to the E G, and
similarly, the cause of the underlying disease in
nongenetic cardiomyopathies also needs to be
explained.
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
[p.Val122Ile] ). The E specication may describe: family
members who are noncarriers of the mutation that
causes the disease in the family (EG-Neg), the obligate
carrier (E G-OC), or the obligate noncarrier (E G-ONC).
E G-NA indicates nonavailability of the genetic test.
After completion of the screening of all known dis-
ease genes in familial disease, genetically orphan
patients are labeled as negative: E G-N (genetic defect
not identied). E G-0 indicates that genetic testing was
not done or was not feasible for any reason. When
all members of a single family are described, the
MOGE(S) system highlights mutations that do not
fully segregate with the phenotype or are part of
incomplete genotyping (Fig. 6). The increasingly
complex genetics (>1 mutation in a single patient) call
for a comprehensive description of the genetic make-
up of the patients and families. The international
nomenclature of genetic variants may facilitate the
description (57); the in silico evaluation supports the
interpretation of the signicance of each variant (e.g.,
PolyPhen-2 [58] and SIFT [59]).
The large public databases, such as the National
Heart, Lung, and Blood Institutes Exome Sequencing
Project (60), the 1,000 Genomes Project (61), and
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Arbustini et al. 309
MOGE(S) Classication of Cardiomyopathy
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 Inuence
the Phenotype
The gure 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
signicance.
Universal Mutation Database (62), provide data on
minor allele frequency (MAF). Finally, the studies on
families provide segregation data, and pathology
studies (Fig. 7) or in vitro systems may eventually
contribute to document the abnormal expression of
the mutated protein. The way of describing complex
genetics in MOGE(S) can take advantage of color
coding (app available online [63]), which provides the
immediate information about pathologic mutations
(red), genetic variants of unknown signicance (VUS)
(yellow/orange), or a single nucleotide polymorphism
(SNP) with some possible functional effects (green)
(Central Illustration).
In nongenetic cardiomyopathies, the etiology can be
described as viral (V) (the rst notation) adding the
virus (e.g., Coxsackie B3 virus [CB3], human cyto-
megalovirus [HCMV], or Epstein-Barr virus [EBV]
presented as EV-HCMV, E V-CB3, or E V-EBV) for the second
notation; the infectious, nonviral diseases (E I) may be
presented with further specication of the infectious
agent whenever possible. When the myocarditis is the
proven cause of the myocardial disease (EM ), the
second notation could specify the origin of myocar-
ditis, such as sarcoidosis (E M-Sarcoid ) or noninfectious
giant cell myocarditis. An autoimmune etiology,
310 Arbustini et al. JACC VOL. 64, NO. 3, 2014

MOGE(S) Classication of Cardiomyopathy JULY 22, 2014:30418

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

Strength of
Type of Cardiomyopathy Recommendation Evidence/Class

Heart Failure Society of America, 2009 (76)

All patients with Clinical screening for cardiomyopathy is recommended:

cardiomyopathy  In asymptomatic rst-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 identied a disease-causing mutation A
Clinical screening consists of history, physical examination, ECG, echocardiography, CK-MM, signal averaged ECG in ARVC only, B
24-h Holter monitoring in HCM and ARVC, exercise treadmill testing in HCM, and CMR in ARVC
Clinical screening should be considered at scheduled follow-up intervals or at any time that signs and symptoms appear
At-risk rst-degree relatives with any abnormal clinical screening test (regardless the genotype) should be considered for repeat C
clinical screening at 1 year
HCM Family history for $3 generations A
Clinical screening for cardiomyopathy in asymptomatic rst-degree relatives A
Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening and A
management (MYH7, MYBPC3, TNNT2 TNNI3, TPMI, ACTC1, MYL2, and MYL3).
DCM Family history for $3 generations A
Clinical screening for cardiomyopathy in asymptomatic rst-degree relatives A
Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening and B
management (LMNA, MYH7, TNNT2, SCN5A, DES, MYBPC3, TNNI3, TPMI, ACTC, PLN, LDB3, and TAZ)
RCM Family history for $3 generations B
Clinical screening for cardiomyopathy in asymptomatic rst-degree relatives B
Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening and C
management (gene tests: uncertain)
ARVC Family history for $3 generations A
Clinical screening for cardiomyopathy in asymptomatic rst-degree relatives A
Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening and A
management (DSP, PKP2, DSG2, and DSC2)
LVNC Family history for $3 generations A
Clinical screening for cardiomyopathy in asymptomatic rst-degree relatives B
Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening and C
management (gene tests: uncertain)
CMP with extracardiac Family history for $3 generations A
traits Clinical screening for cardiomyopathy in asymptomatic rst-degree relatives A
Genetic testing should be considered for the 1 most clearly affected person in a family to facilitate family screening and A
management

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

Diagnostic work-up Genetic counseling 1

in patients and Information for patients and families: genetic origin, inheritance pattern and heritability, phenotype and age-dependence,
families with CMP benets of clinical family screening, pregnancy-related risk, available genetic tests, and contacts with charities and referral
(the numbers in centers.
the right column
indicate the steps) Clinical screening in relatives of probands with cardiomyopathy when genetic test is not available 2
First-degree relatives, unless a nongenetic cause of the disease is proven
Age for starting the rst 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-specic 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 identied in the family Appropriate
Post-mortem genetic tests: the deceased family member is the only affected in the family; appropriate in HCM and ARVC; To be considered
questionable in sporadic DCM and RCM
In children, at the age at which cardiac examination is useful To be considered
Genetic testing and prognostic testing 6
Cannot be systematically recommended for prognostic stratication Non systematic
In selected patients or for selected types of cardiomyopathies; the setting is of expert teams after clinical and family To be considered
assessment
Genetic testing and pre-natal diagnosis 7
Continued on the next page

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JACC VOL. 64, NO. 3, 2014 Arbustini et al. 311
JULY 22, 2014:30418 MOGE(S) Classication 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 certied 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 specically-trained professionals, in a multidisciplinary manner, and in specialized centers Suggestion

HRS/EHRA, 2011 (77)

HCM Genetic test should be performed in patients with clinical diagnosis of HCM, either comprehensive or targeted I
(MYBPC3, MYH7, TNNI3, TNNT2, TPM1)
Mutation-specic 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-specic genetic testing in relatives of mutated probands I
Patients with familial DCM: conrm diagnosis; identify patients at risk of arrhythmias; and facilitate family screening IIa
and monitoring plans
RCM Mutation-specic test in family members after identication of the causative mutation in the index case. I
Patients with clinical suspicion for RCM IIb
ACM/ARVC Mutation-specic test in family members after identication of the causative mutation in the index case. I
Comprehensive and targeted (DSC2, DSG2, DSP, JUP, PKP2, and TMEM43) for patients satisfying task force criteria IIa
for ACM/ARVC.
Patients with 1 major or 2 minor criteria, according to the 2010 task force criteria IIb
Patients with only a single minor criterion III
LVNC Mutation-specic test in family members after identication 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 scientic 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 arrhythmogenic cardiomyopathy; ARVC arrhythmogenic right ventricular cardiomyopathy; CCD cardiac conduction disease; CK-MM creatine kinase-MM; CMR cardiac magnetic resonance;
DCM dilated cardiomyopathy; ECG electrocardiogram; ECHO echocardiogram; EHRA European Heart Rhythm Association; ESC European Society of Cardiology; HCM hypertrophic cardio-
myopathy; HRS Heart Rhythm Society; LVNC left ventricular noncompaction; RCM restrictive cardiomyopathy.

either suspected or proven (EAI-S or EA-P), may popu-
late the rst notation followed by the specic eti-
ology, such as rheumatoid arthritis or systemic
lupus erythematosus. The MOGE(S) app allows the
description of each proven diagnosis (e.g., M D
O HCS G 0 EAI-P-Rheumatoid Arthritis S C-II or M D O HC G 0
E AI-P-Rheumatoid Arthritis SB-II). Nonheritable amyloid-
osis (E A-K, EA-L , or EA-SAA) represent kappa, lambda, or
serum amyloid A protein characterization, respec-
tively. Toxic cardiomyopathies, either endogenous,
such as pheochromocytoma-related cardiomyopathy,
or drug-induced cardiomyopathy, are described
(E T-Pheo or ET-Chloroquine ). When the former is described
in the context of a syndrome (such as VHL, MEN2A/2B,
or NF1), the description can be implemented by adding
the name of the syndrome (i.e., E T-Pheo-VHL ). The
Loefers eosinophilic endomyocarditis can be de-
scribed according to the cause as either being id-
iopathic or a part of myeloproliferative disorder
associated with the somatic chromosomal rearrange-
ment of PDGFR a or PDGFR b genes that generate a
fusion gene encoding for constitutively active PDGFR
tyrosine kinases (64).
S: FUNCTIONAL STATUS. S, in 2 notations, de-
scribes the heart failure ACC/AHA stage (A to D)
coupled with NYHA functional class (I to IV), presented
as S A-I or SC-II, and so on. The descriptor S is optional,
but may come in handy for the description of early
cardiomyopathy. The ACC/AHA guidelines include
patients with a family history of cardiomyopathy in
stage 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 in
genetically orphan familial cardiomyopathy, only the
early imaging markers of the disease can be high-
lighted. This description could be especially useful for
those individuals seeking a denitive 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 that
the cardiomyopathies likely serve a long pre-clinical or
subclinical course before the onset of symptoms or the
manifestation of the clinical phenotype (65).
The Central Illustration shows the MOGE(S)
system notations and modeling. The alphabetical

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312 Arbustini et al. JACC VOL. 64, NO. 3, 2014

MOGE(S) Classication of Cardiomyopathy JULY 22, 2014:30418

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

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

Multidisciplinary Inheritance Informative Relatives Cascade New tests

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

D Dilated H Heart N Family history negative G Genetic cause ACC-AHA

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

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 atrioventricular block; LQT prolongation of the QT interval; YPR short PR interval;
YR low electrocardiographic voltages; WPW Wolf Parkinson White syndrome; and other clinical red ags. These red ags are to be placed
in parentheses after the notation of morphofunctional phenotype. Overlapping (HR), (DA), (NCH), (HD), (DNC) or more complex
combinations such as (HRNC). *Notation is zero (0) not the letter O. (E) The etiologic annotation provides the description of the specic
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 classied based on their effects on gene function as: affecting function, probably affecting function, unknown (variants of unknown
signicance [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 identied variant: affects function or probably affects function (red); Variant of Unknown Signicance (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 American College of Cardiology; AHA American Heart Association;
ARVC/D arrhythmogenic right ventricular cardiomyopathy/dysplasia; DCM dilated cardiomyopathy; ECG electrocardiogram;
ECHO echocardiogram; HCM hypertrophic cardiomyopathy; LVNC left ventricular noncompaction; NYHA New York Heart Association;
RCM restrictive cardiomyopathy.

components are likely going to change in parallel the Sanger and post-Sanger era. To facilitate the
with new scientic information. The proposed application and to provide a simple summary for
nomenclature reects the current diagnostic work- the patients clinical record by the MOGE(S) system,
up of cardiomyopathies for evaluation of the we encourage the use of the web-assisted app (63),
phenotype, family screening, and genetic testing in which can be downloaded for smartphones and

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JACC VOL. 64, NO. 3, 2014
JULY 22, 2014:30418
tablets and can be exibly edited, expanded, or
modied.
FLEXIBILITY AND EXPANDIBILITY
OF MOGE(S) SYSTEM
Similar to the TNM staging system, MOGE(S) allows
exibility 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 modications
in MOGE(S) nosology (66,67), such as in ARVC/
arrhythmogenic ventricular cardiomyopathy
EMF. The diagnostic criteria for ARVC have been
debated and modied, and the M A notation can be
further specied with the help of the major [M] or
minor [m] diagnostic clues that are variably combined
in the Modied Task Force Criteria (68). These criteria
dene ARVC as denite when 2 major [M2], 1 major
and 2 minor [M1m2], or 4 minor criteria from 4
different categories [m4X4] are present; borderline
when 1 major and 1 minor [M1m1] or 3 minor criteria
from different categories [m3X3] are present; and
possible when 1 major or 2 minor criteria from
different categories [M1m2X2] are present. The
number of the major and minor criteria can be added
to the main MA notation. A denite diagnosis may be
described as MA[M2], M A[M1m2X2], or MA[m4X4]; a
borderline diagnosis as MA[M1m1] or MA[m3X3]; and a
possible 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 of
the diagnosis (69).
A recent commentary appropriately emphasized the
need for morphological notation for important car-
diomyopathies from low- and middle-income coun-
tries, such as tropical endomyocardial brosis (EMF)
(67), which is one of the most prevalent causes of
restrictive cardiomyopathy (70). Because EMF can
manifest as isolated or dominant LV EMF, isolated or
dominant right ventricular EMF, or biventricular (right
ventricular LV) EMF, MOGE(S) can describe the dis-
ease as well as the single or double ventricular
involvement (64).
A possible limitation of the MOGE(S) nosology is
the lack of information about 1 of the most important
clinical issues in cardiomyopathies: arrhythmias.
As anticipated (54,55), the classication of arrhyth-
mias is far from the aim of MOGE(S); however, we
have received overwhelming suggestions for expan-
sion of the S notation to include the information
about rhythm disturbances in cardiomyopathies that
would give the clinical advantage of highlighting
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Arbustini et al. 313
MOGE(S) Classication of Cardiomyopathy
MH+R OH GDN EG-MYL6[p.Gly162Arg] SD-IV
and
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
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 50%), sig-
nicant diastolic dysfunction, mild LV hypertrophy (interventricular septum 12 mm),
severe biatrial dilation (right > left), mild right ventricular dysfunction, tricuspid regur-
gitation, mild pulmonary hypertension (40 mm Hg), and pericardial effusion.
patients deserving of a device implantation for ar-
rhythmias. The MOGE(S) committee is working with
electrophysiologists to develop a clinically-useful fast
rhythm disturbances description as a third S
notation.
MOGE(S) IN DAY-TO-DAY
CLINICAL PRACTICE
Upon the rst reading, MOGE(S) may appear to be a
complex nosology system that further complicates
the description of cardiomyopathies. However, in
practice, it is rather simple to apply and the use of the
app provides a guided step-by-step compilation. The
use of MOGE(S) does not obligate a clinician to
include genetic testing. As presented in the Central
Illustration, the genetic tests may not be available or
feasible. However, it behooves clinicians to make an
effort to elicit family history, especially about sudden
death, and document familial patterns. MOGE(S)
offers a hierarchical (Phenotype/Organ/tissue In-
volvement/Genetic /familial/Etiology/gene) but
exible structure that readily provides several
descriptors in a standardized language. This system
also necessitates the routine diagnostic work-up
for cardiomyopathies in probands and relatives.
Whether or not all information queried by MOGE(S) is
314 Arbustini et al. JACC VOL. 64, NO. 3, 2014

MOGE(S) Classication of Cardiomyopathy JULY 22, 2014:30418

Mitochondrial Cardiomyopathy

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

F I G U R E 5 HCM Phenocopy

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

immediately available does not hamper its applica- App 2 includes the possibility of selecting ACC-AHA
tion. In day-to-day practice, MOGE(S) can be applied not used when not applied or applicable.
at the bedside, and collected data can be easily sub- The following are a few examples from our data-
mitted to repositories. In a discharge summary, the base pertaining to the application of MOGE(S):
concluding diagnosis Dilated Cardiomyopathy (MD
 M D O HM G AD E G-NA SC-III represents a baseline
O H G AD EG-MYH7[Ile533Asn] SB-II) may provide compre-
description of the patient (II:1) who was diagnosed
hensive information about the patient. For instance,
with DCM, presenting with both cardiac and mus-
after a family screening, the mutation does not
cle involvement. He was a member of a family with
segregate or a second mutation is identied. In that
the autosomal dominant DCM, but the genetic
case, MOGE(S) allows the description of new infor-
testing was not available. The functional status
mation (M D O H G AD EG-MYH7[Ile533Asn]MYBPC3[Arg326Gln]).
was described as ACC/AHA stage C and NYHA
(S) is a dynamic notation that may modify during
functional class III. Subsequently, when the ge-
follow-up, and its use can provide information about
netic information became available, the notation
change in the functional status and evolution of
was changed to M D O HM G AD E G-LMNA[p.Arg190Trp]
remodeling status. Although NYHA functional class is
S C-III. During follow-up, after starting the treat-
universally used, ACC/AHA stage has been less
ment with an improvement in the NYHA functional
commonly applied in clinics. It can be difcult to
class, the functional status changed to MD O HM
apply to cardiomyopathies, such as classical ARVC,
G AD EG-LMNA[p.Arg190Trp] SC-I. At echocardiographic
especially when diagnosed on 2 major criteria such as
evaluation a brother (II:3) of the proband showed
major ECG changes (e.g., negative T waves in v 1 to v3 )
LV dilation, and borderline LV ejection fraction: he
and sudden cardiac death or a rst-degree relative or
was described as ME[D] O H G AD E G-NA S B. Further
a known pathologic mutation. MOGE(S), however,
in the course of the follow-up, the description was
does not obligate us to ll all elds, and the MOGE(S)

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JACC VOL. 64, NO. 3, 2014 Arbustini et al. 315
JULY 22, 2014:30418 MOGE(S) Classication of Cardiomyopathy

I:1 I:2 AF, stroke

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

HCM, LVT=18mm HCM LVT=16mm

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

V:1

Family member MOGES

I:1 MOOOGUEG-O
I:2 MOOOGUEG-O
II:1 MOOOGUEG-O
II:2 MOOOGUEG-O
II:3 M0O0GUEG-0
II:4 M0O0GUEG-(OC)
II:5 M0O0GUEG-NegSA-I

III:1 MHOHGUEG-(OC)

III:2 M0O0GUEG-NegSA-I

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

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

IV:2 M0O0GUEG-O

IV:4 M0O0GADEG-NegSA-I
V:1 M0O0GADEG-OSA-I

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 atrial brillation.

completed as ME[D] OH G AD E G-LMNA[p.Arg190Trp]
SB-I. He was classied 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 to
the genetic screening but echocardiogram was
entirely normal. He was described as M0 O0 GAD
E G-LMNA[p.Arg190Trp] S A-I. (Online Fig. 1 shows the
family pedigree at the end of the family screening.)
 MD O HMNA G M EG-MtDNA [tRNALeu A3243G] GJB2
[del30G hetero] S D-IV describes a patient (II:3) admitted
with severe DCM, with involvement of the skeletal
muscle, prior stroke, hearing loss, a positive
maternal family history for loss of hearing, and
diabetes. The O notation in this case offers an
instant suspicion of a known pathologic mutation in
mitochondrial deoxyribonucleic acid (MtDNA).
She also was a carrier of the heterozygous GJB2
del30G that, when homozygous, causes hearing
loss. Two sisters showed hearing loss and diabetes.
The phenotype of the proband was severe, as
described by the functional status (ACC/AHA stage
C, NYHA functional class IV). We could not trace
reports of the early phase of the cardiomyopathy
that could theoretically have been HCM in origin
(Online Fig. 2).

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316 Arbustini et al.
MOGE(S) Classication of Cardiomyopathy
A B
MD(AVB)OHGADEG-LMNA[p.Arg190Trp] SB-I
C D
MD(>sCPK)OH+MGX-LREG-DYS[Del45-48] SC-II
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 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-debrillator intervention
for 2 years.
 MAHypertrab O H G Undet EG-LDB3 [p.Thr507Asn] DSG2 universally acceptable classication/nosology system
[p.Lys479Glu] SB-II-III describes a patient (II:1) diag-
nosed with ARVC and hypertrabeculation, exclu-
sive involvement of the heart, without a positive
family history; likely, but still not proven, a
recessive disease. In this patient, we identied 2
variants of uncertain signicance (VUS, yellow-
orange color in the MOGES app) of biparental
origin in 2 different genes. To date, the proband
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JACC VOL. 64, NO. 3, 2014
JULY 22, 2014:30418
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
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 func-
tional class II. After family screening, her daughter
was found to be unaffected and to not be a carrier
of the mutation identied in the proband (M0 O 0
G AD E G-Neg). The sister also was not affected, but
was a carrier of the mutation identied 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 identied in the proband.
This simple information describes her father as the
obligate carrier of the mutation. The evaluation of
the niece, however, presented the problem of
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 HMNLi GN E G DN-LAMP2 [p.His260Pro fs22] S C-II
describes a patient diagnosed with RCM, along
with associated myopathy, cognitive impairment,
and liver disease. The patient had a negative family
history and screening. He was found to carry a
frame-shift mutation in the LAMP2 gene; the
mutation 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 genetic
bases of cardiomyopathy calls for a standardized,
that integrates phenotype description as well as
genetic information. The exible MOGE(S) system
facilitates the transition of description of cardiomy-
opathies from the pre-genetic to the genetic era and
ensures the capture of an enormous amount of
data 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,
JACC VOL. 64, NO. 3, 2014
JULY 22, 2014:30418
including clinical cardiologic evaluation,
cardiac evaluation, clinical genetics, family screen-
ing, molecular genetics when possible, and functional
status. This exercise provides uniform language and
easy-to-capture identical information for data mining
queries.
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KEY WORDS cardiomyopathy,
classication, genetics
A PPE NDI X For supplemental tables and
gures, please see the online version of this
article.