New phenotype of familial dilated cardiomyopathy and conduction disorders

New phenotype of familial dilated cardiomyopathy and conduction disorders Elsa Silva Oropeza, MD,a and Carmen Navarrete Cadena, MDb Mexico City, Mexico

Background Familial dilated cardiomyopathy (FDCM) is attributed to defects in cytoskeletal proteins, and different patterns of inheritance and phenotypic expressions according to assorted-protein modifications have been identified to date. We describe a clinical family study with 24 individuals in 3 generations affected by dilated cardiomyopathy (DCM) and cardiac conduction abnormalities.

Methods and Results After a follow-up period of 25 ⫾ 14 months, DCM developed in 7 male adults, 6 with associated arterioventricular block (AVB); and 10 female and 7 male adults had several degrees of isolated AVB. This particular clinical expression, with a strong predominance of dilation of the heart developing in the male population and the vertical distribution of patients affected with AVB, is consistent with autosomal dominant inheritance involving both cardiac abnormalities.

Conclusions The presence of isolated AVB or that associated with DCM in a large number of individuals in the same family, in which members of the male sex seems to be predominantly affected by cardiac dilatation, differs from other FDCMs that have been described previously. This FDCM has an autosomal dominant pattern of inheritance with variable phenotypic expressivity, in which AVB may constitute in itself the only manifestation of this entity. To date, we have been unable to identify the mechanism of inheritance, and we advance some theoretical considerations about possible mechanisms. (Am Heart J 2003;145:317-23.) Dilated cardiomyopathy (DCM) is a severe myocardial disease responsible for congestive heart failure and death resulting from progressive cardiac dilatation and impairment of systolic contraction. The annual incidence of idiopathic DCM is estimated in the United States and Europe to be approximately 8 cases per 100,000 inhabitants.1 Although idiopathic DCM is the most frequent clinical form, familial etiology is currently recognized in approximately 30% of idiopathic cases.2 Familial DCM (FDCM) is attributed to defects in cytoskeletal proteins, and currently, several disease loci gene mutations for inheritable DCM have been identified by chromosome mapping.2-5 FDCM has different patterns of inheritance and phenotypic expressions according to assorted-protein modifications: 1) autosomal dominant, the prevailing trait, with isolated DCM, which could be preceded by electric conduction disorders or associated with myopathy; 2) autosomal reces-

From the aDepartment of Cardiac Electrophysiology, Hospital de Cardiologı´a, Centro Me´dico Nacional Siglo XXI, IMSS, Mexico and bDepartment of Medical Investigation in Human Genetics, Coordinacio´n de Investigacio´n Me´dica, Centro Me´dico Nacional Siglo XXI, IMSS, Mexico. Submitted October 18, 2001; accepted May 6, 2002. Reprint requests: Eje´rcito Nacional 475, 3er piso, Col. Granada, Me´xico, D.F., C.P. 11520, Mexico. E-mail: [email protected] Copyright 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1067/mhj.2003.141

sive; 3) X-linked DCM with muscular dystrophy; and 4) mitochondrial.6,7 We present a family study of 24 individuals affected with FDCM, with the clinical spectrum of DCM and/or isolated cardiac conduction abnormalities. In this study population, DCM with cardiac conduction disorders was predominantly present in the males, whereas isolated cardiac electrical disorders affected both the males and females. This particular clinical behavior has never been described, and we present some theoretical considerations concerning possible mechanisms of this phenotypic diversity.

Methods This family study was performed at the Department of Electrophysiology, Hospital de Cardiologı´a, and genetic counseling was obtained from the Department of Medical Investigation in Human Genetics, Coordinacio ´ n de Investigacio ´n Me´dica, Centro Me´dico Nacional, IMSS, in Mexico City. Written informed consent was obtained from all participants in accordance with local requirements. Patient clinical evaluation was divided into 3 stages; phase I included medical history, physical examination, electrocardiography (ECG), and chest radiographs. When any abnormality was found, left ventricular (LV) function was evaluated by echocardiography (ECHO) or radionuclide scanning and Holter monitoring for ECG abnormalities (phase II). In cases in which data were not sufficiently conclusive, affected individuals (phase III) underwent Holter monitoring, stress testing, and/or a cardiac electrophysiological study (EPS); and whenever the patient

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Figure 1

Pedigree of a family showing inheritance of FDCM. Filled symbols indicate patients with DCM, clear symbols indicate unaffected family members, and a slash mark indicates deceased family members. Presence indicates AVB (⫹) and LBBB (⫺); patients with PM (}) and cases studied prospectively (ⱊ), or some medical information could be obtained.

agreed, an endomyocardial biopsy (EMB) was performed. This stage also included laboratory tests: complete blood count, glucose, electrolytes, creatine kinase (CK), lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, and cholesterol levels; when a thyroid problem was suspected, in vitro T3, T4, and thyroid-stimulating hormone level determinations were carried out. Index cases were followed prospectively, and abnormal studies were repeated during the follow-up period. A structural heart abnormality was defined as the presence of radiographic cardiomegaly and LV dysfunction by ECHO or radionuclide scanning with an ejection fraction (EF) ⬍0.45, fractional shortening (FS) ⬍25%, or both. Additional causes of ventricular dysfunction were investigated and discarded, mainly before a familial etiology was revealed by the pedigree analysis: coronary artery disease, valvular or congenital heart disease, moderate or severe long-standing hypertension, active myocarditis, and infiltrative or hypertrophic cardiomyopathy with dilative course. In particular, cases involving thyroid abnormalities and excessive alcohol consumption were studied, and no relationship was found with LV dysfunction. Diagnosis of FDCM was defined by applying the proposal guidelines of the European Collaborative Group6: unknown causes of ventricular dysfunction and major and minor criteria are fulfilled in ⱖ2 affected individuals in a single family, or first-degree relatives with unexplained sudden death at ⬍35 years of age. Evidence of DCM, a major criterion, or LV dilation plus the following minor criteria identified other affected members: 1) unexplained supraventricular or ventricular arrhythmias frequent or repetitive before the age of 50

years; 2) LV dilatation ⬎112% of the predicted value; 3) LV dysfunction with EF ⬍50% or FS ⬍28%; 4) unexplained conduction disease with atrioventricular block (AVB), left bundle branch block (LBBB), or sinus nodal dysfunction; 5) unexplained sudden death or stroke before 50 years of age; and 6) segmental wall motion abnormalities in the absence of bundle branch block or ischemic heart disease. The sum of 3 minor criteria was also a means of identifying an affected individual.

Results General population One hundred individuals from a single family were observed; 56 men and 44 women from 6 generations (Figure 1). The average age in 85 subjects whose ages were known was 32 ⫾ 19.5 years (range 2-80 years). No consanguinity was present in any family member. Fifty individuals were observed prospectively during a follow-up period of 25 ⫾ 14 months (range 6-58 months). Patients who had no symptoms or had normal findings stopped at phase I (14 patients); the other patients proceeded to phase II and were evaluated with ECHO (28 patients) and/or nuclear scintigraphy (4 patients) and Holter monitoring (16 patients). Patients who proceeded to phase III included 6 subjects who underwent stress tests, 5 who underwent EPS, and 4 who underwent EMB. Other studies included thyroid hormone determinations in 8 subjects

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(6 in phase III), serum CK in 4 subjects, and Gallium scintigraphy in 3 subjects. Because we observed no muscular or neuromuscular involvement clinically, we did not routinely practice CK serum determinations, though they were always normal when practiced. We did not systematically study patients for secondary causes of DCM, such as myocarditis and ischemic heart disease, but in patients in whom Gallium and Thallium studies were completed, the results were normal or negative, except in patient V.26, in whom the diffuse ischemia was nonatheroesclerotic in origin. Other laboratory determinations were normal. Fifteen family members were identified retrospectively, but only 13 were included for analysis because family confidence or medical information related to the disease was obtained. Thirty-seven individuals were not included because of death from unknown causes or death not related to the purpose of the research (5 patients), refusal to participate (6 patients), or inaccessible residence and other causes (26 patients). Because FDCM abnormalities were usually present after the fourth decade of life, we only studied younger subjects when their parents requested it or when the patient was referred for suspicious symptomatology; none of these subjects were affected.

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Table I. Affected patients Pedigree III.3 III.4 III.7 III.8 III.9 III.10 IV.1 IV.2 IV.4 IV.5 IV.6 IV.7 IV.8 IV.9 IV.10 IV.11 V.7 V.8 V.10 V.19 V.21 V.24 V.26 V.36

Sex

Age*

AV block

Pacemaker

DCM

Male Male Male Male Male Male Female Female Female Male Male Female Female Female Female Male Female Male Male Male Male Female Male Female

76 74 64 62 48 50 62 60 62 43 50 51 51 47 39 45 41 38 36 40 33 40 33 30

Undetermined Undetermined Undetermined Undetermined Unknown Complete Complete Complete Complete LBBB Undetermined I-III degree I-III degree I-III degree Complete I-II degree I degree I degree Complete I degree Undetermined I degree I-III degree I degree

Yes Yes Yes Yes No No Yes Yes Yes No Yes Yes Yes Yes Yes Yes No No Yes No No No Yes No

No No No No Yes Yes No No No Yes Yes No No No No No No No Yes No Yes No Yes No

DCM, Dilated cardiomyopathy; LBBB, left bundle branch block. *Patient age corresponds at moment of capture.

Affected individuals Table I shows the affected patients. The family study began in 1996, with a 51-year-old woman (IV.7) with syncope and first-degree AVB who underwent pacemaker (PM) implantation after 2 sisters (IV.4 and IV.10) with the same history. Two years later, 2 other sisters (IV.9 and IV.8) required PM implantation because of syncope and AVB. None of these women had structural heart disease. The protocol study was modified when a nephew (V.26) with first-degree AVB and heart failure (HF) caused by DCM also required PM implantation and died after 3 years of follow-up. It was revealed retrospectively by the screening study that patient IV.5, in whom DCM and LBBB were diagnosed, died of advanced HF and his brother (IV.6) died of a stroke and had had a PM implantation 3 years earlier, but AVB severity remains unknown. Their father (III.10) developed advanced AVB, mild radiographic-cardiomegaly, and HF some years before his death. His brother (III.9), who also died of a stroke, had a history of congestive HF; prospectively, we identified that his 2 daughters (IV.1 and IV.2) had chronic PM therapy and no structural heart disease. Another affected individual was identified, a 33-year-old man (V.21) who died suddenly after repeated events of syncope and an unknown history of HF. Finally, we detected, by means of information from a family member, 4 additional male individuals in the third generation with chronic PM implantation, in whom we assumed AVB (the severity of which are unknown).

During the follow-up period we diagnosed prospectively, and in this order, symptomatic advanced AVB that required PM implantation in patient V.10, and asymptomatic first-degree AVB that progressed to symptomatic Mobitz I-II AVB in a 3-year interval in patient IV.11, who finally required a PM insertion. Five additional individuals with first-degree AVB were identified: 2 men with no symptoms (V.8 and V.19) and 3 women, 2 of whom had sporadic syncope events, predominantly during pregnancy (V.24 and V.36). AVB in both cases alternated with sinus rhythm, but the latter patient has prolonged nocturnal events of Mobitz I AVB on Holter monitoring. The third patient (V.7) had intermittent first-degree AVB and dizziness, but not syncope or presyncope. At the end of this study (April 6, 2001) the original clinical manifestations changed in 2 patients (V.10 and IV.2). Although patient V.10 remains asymptomatic, a recent ECHO compared with another performed 2 years previously showed enlargement of LV end-diastolic diameter (LVEDD), which was confirmed by LV function with scintigraphy, so we presume DCM will develop. Nevertheless, he also has a history of excessive alcohol consumption, which ended 10 years before PM insertion. The results of other studies are all normal or negative. His mother (IV.2), in whom severe HF developed for the first time 17 years after PM insertion, does not reach the criteria of enlarged diameters

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Table II. Results of studied affected patients

Pedigree

Symptoms

III.9

Emboli

III.10 IV.1 IV.2 IV.3 IV.4 IV.5 IV.6 IV.7

HF, chest pain Syncope HF Asymptomatic Syncope HF Emboli Palpitations and syncope

IV.8

Syncope, chest pain Palpitations, chest pain Syncope Palpitations, presyncope

IV.9 IV.10 IV.11

Age at onset of sympSpecific Last EF (ECHO) toms examinations /scintigraphy

No., stress test

EPS

EMB

Cause of Age at PM death/ implantation age (y) Stroke, HF/48 HF/50

49

Thyroid

54

Thyroid, CK

10

Thyroid

30

0 45

V.7 V.8

Dizziness Syncope

41 38

V.10

Presyncope

34

V.19 V.21

Asymptomatic Emboli and HF

40

V.24 V.26

Syncope Fatigue and HF

28

V.36

Syncope

16

66 64 68 60/? _/15

55 44 49

74

2/negative

65

Hypertensive response PVC

Thyroid

64

Gallium Thyroid, CK, Gallium

50 62

Thyroid

57/48

Thyroid, CK, Gallium

62/30

Extreme sinus nodal bradicardia, pathology Normal

47 51

Nonconclusive

HF/43 Stroke/50

47 51

Normal SND, nodal Nonconclusive pathology, VT nonsustained

39 45

3/nonconclusive/ thallium negative 36

63 Sudden death/ 33 74 15

Thyroid, CK

65

Diffuse ischemia Nodal by thallium pathology

2/negative

Myocytes disarray, lymphoblast infiltration

33

HF/36

SND, atrial flutter induction, nodal pathology

PVC, Premature ventricular complex; EF, ejection fraction; EPS, electrophysiological study; EMB, endomyocardial biopsy; SND, sinus node dysfunction.

by means of ECHO for DCM diagnosis, but had an initial EF of 46% and FS of 23%. LV dysfunction was attributed as a consequence of permanent supraventricular tachycardia (SVT), which, after reinforcement of antiarrhythmic drugs (AAD) and reprogramming her PM from DDD to VVI, improved to an EF of 64% by control ECHO.

Clinical presentation of affected individuals Patients with AVB. The clinical presentations of affected individuals are shown in Table II. The prevailing symptoms were syncope or presyncope; other less

frequent symptoms were fatigue, dizziness, lightheadedness, and weakness. The critical age when symptoms required medical assistance and management, and even included death caused by underlying cardiac disease, ranged between the fourth and sixth decades of life; no differences in sex were observed. Patients with dilated cardiomyopathy. Patients with overt DCM dyspnea and severe peripheral edema attributed to HF were observed, and in 3 additional cases so were repetitive emboli. For patient death caused by DCM we also observed its early appearance through successive generations: in the fifth generation

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(aged ⬍35 years), death occurred progressively earlier than in the fourth (aged ⬍40 years) and third (aged ⬍50 years) generations.

ECG abnormalities in affected subjects Different degrees of AVB were the prevailing ECG abnormality (Table I), but other less frequent abnormalities and arrhythmias were found (Table II). Fixed first-degree AVB, asymptomatic. A modest prolongation of PR interval was present in cases V.8 and V.19 (mean PR interval of 0.24” and 0.22” and heart rate of 55 beats/min). Recently, patient V.8 had frequent AVB Mobitz I during sleep on Holter monitoring. Intermittent first-degree AVB, sporadically symptomatic. These patients have first-degree AVB as a dominant rhythm, but occasionally sinus rhythm is present. We presume that AVB may eventually progress and become more severe, because the patients (V.24 and V.36) had repetitive syncope; this occurred in the latter patient who had a Holter recording with very frequent events of Mobitz I AVB while sleeping. Patient V.7 constitutes an exception because she had an ECG with first-degree AVB and sporadic dizziness as the only symptom, but a permanent sinus rhythm was shown with a control ECG and Holter recording 1 year later. Fixed first-degree AVB, progressive and symptomatic. A huge PR prolongation (PR 0.40” for 70 beats/min), was present in patients IV.7, IV.8, and IV.9, and it sporadically progressed or even turned into complete AVB and provoked syncope. Follow-up in patient IV.8 showed that first-degree AVB (PR interval 0.28” for a heart rate of 85 beats/min) was maintained, but AVB progression was shown in patients IV.7 and IV.9, who depend 100% on PM stimulation. Patient V.26 was found to directly complete AVB, and patient IV.11 was found to have very frequent events of Mobitz I and II after 4 years of follow-up. Permanent complete AVB, symptomatic. In cases III.10, IV.10, and V.10, complete AVBs were detected without knowing installation time and intermediate stages. Miscellaneous. LBBB was only present in patient IV.5, who died of HF caused by DCM without any other disturbance of atrioventricular conduction. In 3 cases (IV.11, V.26, V.36), extreme sinus bradycardia or sinus pauses compatible with sinus node dysfunction (SND) were disclosed by EPS; nodal pathology derived from an abnormal Wenckebach point ⱕ130 beats per minute was present in 4 cases (IV.7, IV.11, V.26, V.36), and repetitive induction of atrial flutter was present in 1 case (V.36). Concerning arrhythmias and collateral factors, during follow-up, SVT developed in 4 affected patients: chronic recurrent atrial flutter developed in patient IV.2 and atrioventricular nodal reentry

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tachycardia developed in patient IV.7, both of whom had a history of moderate systemic arterial hypertension and chronic PM therapy (17 and 2 years, respectively), and patient V.26 underwent paroxysmal atrial flutter late in the course of DCM. Paroxysmal atrial fibrillation (AF) and atrial flutter were detected within the first year after PM implantation in patient IV.11; he also had 2 premature ventricular complex morphologies and nonsustained monomorphic VT recorded by Holter monitoring and reproduced on EPS. This patient had mild systemic arterial hypertension that was recently detected and a history of heavy alcohol consumption, but had an additional 12 months of abstinence without cardiac structural abnormalities. Two additional patients with a history of moderate hypertension were found (IV.1 and V.7), but they did not have arrhythmias.

Predicted value of left ventricular dilatation We intentionally investigated predictive LVEDD in 17 cases as a parameter of early detection of LV dilation. In all cases, results were normal, with a mean value 79% ⫾ 8%. However, recently, patient V.10 had ECHO diastolic and systolic diameters larger than 2 years earlier (LVEDD 56 vs 53 mm, respectively); the actual LVEDD was 98%, versus 94% from the earlier data, probably indicating progressive LV enlargement. Although it has not reached the abnormal limit of LVEDD ⬎112%, an LVEF of 30% and severe hypokinesis that was apical, anterior, and inferior was revealed by nuclear scintigraphy.

Collateral findings in general population Endocrinous. Three affected patients had thyroid abnormalities: patient IV.9 with hemi-thyroidectomy 5 years before PM use, who was undergoing substitutive therapy; patient IV.1, who was undergoing substitutive therapy 5 years after PM insertion; and patient IV.2 with subclinical hypothyroidism, who was not undergoing treatment. Furthermore, hyperthyroidism was diagnosed in 2 nonaffected women (V.13 and V.2), but there was no cardiac involvement; the latter patient was undergoing radioactive iodine therapy. Two patients with diabetes mellitus were detected: patient V.7 with intermittent first-degree AVB, and patient VI.1, a nonaffected patient. Cardiac. A young adult (V.39) was found, by ECHO, to have primary mild aortic insufficiency, and a child (VI.12) was found to have idiopathic pulmonary arterial dilation.

Discussion Data obtained from the study of a single family after 57 months of follow-up led us to the diagnosis of FDCM, according to the European Group definition,6

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on the basis of 7 men in 3 generations who had DCM. A diagnosis of DCM was documented in 3 cases: 2 patients who died (IV.5 and V.26) and patient V.10, in whom cardiac dilatation will develop, who has no HF data but advanced AVB. In the other 4 cases we assume the diagnosis of FDCM on the basis of the major criteria of family history of 2 affected patients and the sum of minor clinical criteria of ventricular dysfunction manifested by HF, stroke, and death in young adults: patient III.9 had a history of an embolic event, unknown cardiac disease; his brother (III.10) also had HF, advanced AVB, and mild radiographic-cardiomegaly; his son (IV.6) also had emboli events, a history of unknown cardiac disease, and PM implantation; and patient V.21 had syncope and a history of HF. In contrast, we have observed isolated AVB in 17 patients, 10 female and 7 male, most of whom are undergoing PM therapy because of symptoms, particularly syncope. Two women and 1 man in this population also had sinus node dysfunction. Thus, isolated related patients with AVB and a family history of DCM led us to conclude that these are affected individuals.6 However, we think that collateral findings, particularly those present in affected individuals, are independent from FDCM and that there is no relationship as a causal agent of cardiac abnormalities (ie, systemic arterial hypertension) that is not recognized as a cause of AVB, although it could have a role in SVT development. Thyroid abnormalities were present in both affected and nonaffected individuals, and substitutive therapy did not modify AVB. However, the suppression of alcohol exposure history (abstinence for years in patient V.10 and at least during 12 months in patient IV.11 documented before PM therapy) did not affect the clinical course of AVB. Atrial flutter and VT in this latter patient required class III AAD after PM implantation; nevertheless, we cannot eliminate alcohol as a potential cardiac insult. The frequency and predominance of AVB present in this family is uncommon; we have observed AVB propensity to a progressive course on the basis of records of different AVB degrees, probably as an expression of different stages of conduction system affection. Currently, there is one case in which AVB appears to be a premonitory sign of LV dilatation (V.10), a consistent finding in other population descriptions, in which indistinct rhythm and conduction disturbances herald DCM changes.4,7-9 Although patient V.26 was also found to be both first-degree AVB- and DCM-affected, we could not establish the sequence of events, such as AVB heralding DCM, because both conditions were entirely manifested at the time we first met the patient. To date, we do not know long-term evolution of AVB individually, but the development of isolated AVB appears to be the only overt clinical manifestation of this FDCM variety.

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Many descriptions of FDCM have been composed on the basis of genetic transmission patterns. Autosomal dominant inheritance is the most frequent variant, in which it is possible to find a marked interfamilial and intrafamilial variability on clinical expression. FDCM includes several types, such as juvenile-male DCM, DCM with segmental hypokinesia, right ventricular cardiomyopathy, DCM preceded by conduction disorders, and DCM associated with myopathy.6,10 An interesting FDCM type has recently been described, in which mutations were located on a single gene that partakes 3 different phenotypes: pure DCM, DCM associated with electrical disturbances, and scarce number of patients with isolated rhythm or conduction disorders; these mutations were located on a gene that is also responsible for Emery-Dreifuss muscular dystrophy.4,11 Because of vertical distribution of affected individuals and male-to-male transmission of DCM in this family, an autosomal dominant inheritance is attributed. Furthermore, the particular clinical expression observed along 3 generations, in which AV conduction abnormalities may occur as an isolated form or as associated to DCM or DCM pure, supports a variable expressivity. Pure heart dilatation, in which LBBB is considered as a component of DCM itself, was solely present in patient IV.5. Another particular observation is in patient IV.3, who remains without symptoms and whose results on successive studies are negative or normal. Although this patient is a carrier of the mutated gene, because her father and 2 siblings were affected, she is a nonpenetrant carrier of this FDCM mutation. Even more interesting is its exceptional clinical pattern, in which the male sex seems to be predominantly affected by cardiac dilatation. Some theoretical considerations about possible mechanisms are contemplated: hormonal influence could have a role as an explanation of susceptibility differences in developing heart dilatation. Furthermore, disproportion in sex rate of individuals affected by DCM could be a result of hormonal influence on gene expression, in which its ability has been demonstrated in changing chromatin conformation, local pattern of gene methylation, or both.12 In genomic imprinting (GI), another potential mechanism, there is a differential expression of genes that results in dissimilar allelic expression of a gene, on the basis of a specific pattern of DNA methylation, depending on the parent transmitting the gene. In paternal imprinting, such as in this family, the paternal allele is nonmethylated so that it is expressed as DCM development, whereas the maternal allele is methylated and remains silent, showing isolated conduction abnormalities.13-16 Another clinical characteristic of GI is the anticipation phenomenon, related to a progressively earlier appearance of the disease. However,

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there are several patients in whom clinical expression does not correspond to that expected according to paternal GI.17-19 Finally, interfamilial and intrafamilial phenotype variability could also be influenced by one or more modifier genes.20

Study limitations The diagnosis of cardiac damage in this study is principally clinical, and diagnostic tools are not a sufficiently sensitive means of detecting the subtle cardiac abnormalities. This is particularly important in cases in which AVB is the only abnormality present, but we are unable to judge when it is a signal of later myocardial disease development or establish the time it could take. However, the predictive value of LV dilatation was not obtained in all cases and should be included in the follow-up study, particularly in cases in which isolated AVB is present, as an attempt to determine whether electrical abnormalities precede cardiac dilation development and its relationship. To date, we have been unable to afford molecular genetic studies, which would provide recognition of the issue of genetic mutation, in addition to the mechanism responsible in clinical expression variability including sex differences of heart disease, which led us to face new conditions not described to date in genetic counseling.

Conclusions The presence of AVB and DCM in a large number of individuals in the same family led us to reach the diagnosis of autosomal dominant FDCM with variable expressivity. Two clinical particularities make this form of FDCM a new variant that has not been described: the strong predominance of male population in whom dilatation of the heart develops, and isolated AVB that may constitute in itself the only manifestation of this entity.

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3. Olson TM, Michles VV, Thibodeau SN, et al. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science 1998;280:750-2. 4. Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999;341:1715-24. 5. Kamisago M, Sharma SD, De Palma SR, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 200;343:1688-96. 6. Mestroni L, Maisch B, McKenna WJ, et al. Guidelines for the study of familial dilated cardiomyopathies. Eur Heart J 1999;20:93-102. 7. Graber HL, Unverferth DV, Baker PB, et al. Evolution of a hereditary cardiac conduction and muscle disorder: a study involving a family with six generations affected. Circulation 1986;74:21-35. 8. Kass S, MacRae C, Graber HL, et al. A gene defect that causes conduction system disease and dilated cardiomyopathy maps to chromosome 1p1-1q1. Nature Genet 1994;7:546-51. 9. Olson TM, Keating MT. Mapping a cardiomyopathy locus to chromosome 3p22-p25. J Clin Invest 1996;97:528-32. 10. Gru¨ning E, Tasman JA, Ku¨cherer H, et al. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol 1998; 31:186-94. 11. Bonne G, Mercuri E, Muchir A, et al. Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Ann Neurol 2000;48:170-80. 12. Petronis A. Human morbid genetics revisited: relevance of epigenetics. Trends Genet 2001;17:142-6. 13. Monk M. Memories of mother and father. Nature 1987;328:203304. 14. Hall JG. Genomic imprinting: review and relevance to human diseases. Am J Hum Genet 1990;46:857-73. 15. Sapienza C, Hall JG. Genetic imprinting in human disease. In: Scriber CR, Beaudet AL, Sly WS, et al, editors. The metabolic and molecular bases of inherited disease. 7th ed. New York: McGrawHill; 1995. p. 437-58. 16. Feinberg AP. Methylation meets genomics. Nat Genet 2001;27:910. 17. Ogawa O, Eccles MR, Szeto J, et al. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilm’s tumor. Nature 1993;362:749-51. 18. Rainier S, Johnson LA, Dobry CJ, et al. Relaxation of imprinted genes in human cancer. Nature 1993;362:747-9. 19. Jackson-Grusby L, Beard C, Possemato R, et al. Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nature Genet 2001;27:31-9. 20. Martin CC, Sapienza C. A role for modifier genes in genome imprinting. Results Probl Cell Differ 1999;25:251-70.