• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

LMNA-Related Dilated Cardiomyopathy

, MD and , MS, CGC.

Author Information
, MD
Professor of Medicine, Divisions of Human Genetics and Cardiovascular Medicine
The Ohio State University
Columbus, Ohio
, MS, CGC
Assistant Professor, Division of Human Genetics
The Ohio State University
Columbus, Ohio

Initial Posting: ; Last Update: September 19, 2013.

Summary

Disease characteristics. LMNA-related dilated cardiomyopathy (DCM) is caused by mutations in LMNA and is characterized by left ventricular enlargement and reduced systolic function preceded or accompanied by significant conduction system disease and/or arrhythmias. LMNA-related DCM usually presents in early to mid-adulthood with symptomatic conduction system disease or arrhythmias, or with symptomatic DCM including heart failure or embolus from a left ventricular mural thrombus. Sudden cardiac death can occur, and in some instances is the presenting manifestation; sudden cardiac death may occur with little systolic dysfunction.

Diagnosis/testing. LMNA sequence analysis identifies mutations in most individuals with LMNA-related DCM. Conduction system disease is detected by a 12-lead electrocardiogram (ECG); arrhythmias are detected by an ECG, 24-hour rhythm recording, or event monitor. Left ventricular enlargement is diagnosed with cardiac imaging; reduced systolic function is defined as ejection fraction of less than 50% or a fractional shortening of less than 25%-30%.

Management. Treatment of manifestations: Chronic atrial fibrillation is treated initially with attempts to restore normal sinus rhythm, anticoagulation, and rate control. Symptomatic supraventricular arrhythmias are usually treated with pharmacologic therapy or ablation; symptomatic bradyarrhythmias or significant heart block may be treated with an electronic pacemaker. Symptomatic ventricular arrhythmias, ventricular tachycardia, ventricular fibrillation, and resuscitated sudden cardiac death are treated with an implantable cardiac defibrillator (ICD). Because risk for sudden cardiac death in LMNA-related DCM accompanies heart block and bradyarrhythmias, ICD use (rather than just pacemaker use) has been recommended for all indications. Treatment of symptomatic DCM including heart failure is pharmacologic with ACE inhibitors, beta blockers and/or anti-aldosterone agents. Progressive deterioration in left ventricular function is treated with an ICD, and some experts recommend anticoagulation; cardiac transplantation or other advanced therapies may be considered for refractory disease in persons receiving comprehensive care from cardiovascular disease experts.

Surveillance: Individuals with an LMNA mutation who are found to have any ECG abnormality should undergo a cardiovascular evaluation for disease progression at least annually. Asymptomatic individuals with a pathogenic LMNA mutation should undergo cardiovascular evaluation (medical history, physical examination, echocardiogram, and ECG) every one to two years and/or whenever new symptoms arise. At-risk individuals from families with a known LMNA mutation, in whom genetic testing is not possible, may be offered yearly cardiovascular screening. At onset of new symptoms an immediate evaluation for evidence of DCM and/or conduction system disease is indicated regardless of genetic status.

Evaluation of relatives at risk: To facilitate prompt diagnosis, targeted LMNA genetic testing when the family-specific disease-causing mutation is known; otherwise routine surveillance with cardiovascular screening tests.

Pregnancy management: Pregnancy is contraindicated in women with DCM. Pregnant women with DCM should be followed by a high-risk obstetrician. At-risk women with unknown mutation status should undergo a cardiovascular evaluation and be offered genetic counseling, ideally prior to pregnancy.

Genetic counseling. LMNA-related DCM is inherited in an autosomal dominant manner. Some individuals diagnosed with LMNA-related DCM have an affected parent; the proportion of cases caused by de novo mutations is unknown. Each child of an individual with LMNA-related DCM has a 50% chance of inheriting the parent’s mutation. Prenatal diagnosis for LMNA-related DCM is technically possible when the disease-causing mutation in the family is known; however, requests for prenatal testing for (typically) adult-onset diseases are not common.

Diagnosis

Clinical Diagnosis

The diagnosis of LMNA-related dilated cardiomyopathy (DCM) is established in individuals with the following:

  • A clinical diagnosis of idiopathic DCM (etiology not attributed to coronary artery disease, structural heart disease, thyroid disorders, and acute myocarditis, among others; see Dilated Cardiomyopathy Overview), usually in the setting of conduction system disease and/or supraventricular or ventricular arrhythmias
  • An identified pathogenic mutation in LMNA

The diagnosis of DCM is based on the principal findings of left ventricular enlargement and reduced systolic function in which other causes have been excluded:

  • Reduced systolic function is usually described as a reduction in left ventricular ejection fraction, which can be measured by two-dimensional echocardiography, angiography, or nuclear left ventricular functional studies. An ejection fraction of less than 50% or a fractional shortening of less than 25%-30% is considered systolic dysfunction.
  • Left ventricular enlargement is most commonly identified with two-dimensional echocardiography, optimally assessed by a height- and gender-based approach [Vasan et al 1997]. Other testing modalities include cardiac computed tomography (CT), MRI, and left ventricular angiography or nuclear studies.

Note: LMNA-related DCM is almost always associated with conduction system disease and/or arrhythmias that commonly occur prior to the development of heart failure symptoms. Clinicians should also be aware that in some cases the conduction system disease precedes any evidence of DCM (see Clinical Description).

Molecular Genetic Testing

Gene. LMNA is the only gene in which mutations are known to cause LMNA-associated DCM.

Evidence for locus heterogeneity. The DCM-CSD/arrhythmia phenotype can also be present in individuals with mutations in genes other than LMNA, including RBM20, SCN5A and DES (see Differential Diagnosis ). Because not all individuals with a DCM-CSD/arrhythmia phenotype have a mutation in a known causative gene, other yet-to-be identified genes may be involved.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in LMNA-Related Dilated Cardiomyopathy

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
LMNASequence analysis / mutation scanning 4Sequence variants 5>99% 6
Duplication/deletion analysis 7(Multi)exonic or whole-gene deletions/duplicationUnknown 8

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Almost all mutations identified to date have been missense, nonsense, or splice-site mutations.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. Duplication/deletion analysis may increase testing sensitivity: two reports have identified LMNA-related DCM resulting from deletions [van Tintelen et al 2007, Gupta et al 2010].

Testing Strategy

To confirm/establish the diagnosis of LMNA-related DCM in a proband. Current evidence indicates that idiopathic dilated cardiomyopathy (i.e., DCM of unknown cause) may be familial (and therefore possibly genetic) in 20%-50% of cases [Burkett & Hershberger 2005]. A molecular evaluation is recommended for individuals with idiopathic DCM and/or significant conduction system disease with or without arrhythmias, which can precede or accompany early evidence of DCM.

  • Single gene molecular genetic testing for LMNA-related cardiomyopathy can be pursued.
  • Multigene panel. An alternative to single gene or sequential molecular genetic testing is a panel in which multiple genes that cause DCM are simultaneously analyzed. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual with DCM also varies.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and reduced systolic function frequently accompanied by significant conduction system disease. While LMNA-related DCM usually presents in adulthood either with conduction system disease commonly accompanied by arrhythmias or with symptomatic DCM (including heart failure or embolus from a left ventricular mural thrombus), it may also be discovered in an asymptomatic person during a medical evaluation conducted for another reason (e.g., a routine preoperative ECG) or clinical screening of at-risk relatives.

Family studies suggest that conduction system disease commonly precedes the development of DCM by a few years to a decade or more. In a recent study involving 64 individuals with an LMNA mutation, the median time differential from ECG abnormalities to observed left ventricular dysfunction was seven years [Brodt et al 2013]. Conduction system involvement usually starts with disease of the sinus node and/or atrioventricular node that can manifest as sinus bradycardia, sinus node arrest with junctional rhythms, or heart block (commonly first-degree heart block that progresses to second- and third-degree block).

The following are also common:

  • Symptomatic bradyarrhythmias requiring cardiac pacemakers
  • Supraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome)
  • Ventricular arrhythmias including frequent premature ventricular contractions (PVCs), ventricular tachycardia, and ventricular fibrillation

Sudden cardiac death may occur with progressive disease. Although more malignant, life-threatening arrhythmias may occur with longstanding and usually previously symptomatic DCM, sudden cardiac death can also be the presenting manifestation of LMNA-related DCM.

Furthermore, only mild to moderate left ventricular dilatation despite progressive disease has been noted by some investigators. Therefore, LMNA-related DCM may be an appropriate diagnosis in those with a pathogenic LMNA mutation who have clinical conduction system disease and/or arrhythmia prior to the left ventricular enlargement or with minimal or no systolic dysfunction.

Occasionally, individuals with LMNA-related cardiomyopathy also manifest signs or symptoms of skeletal myopathy, which may be associated with elevated serum creatine kinase (CK) concentration.

Large prospective longitudinal studies to define the range of natural history of individuals with LMNA mutations have not yet been published.

Selected reports highlighting the clinical cardiovascular manifestations of LMNA-related DCM

  • The initial report of LMNA-related DCM by Fatkin et al [1999] included five families with conduction system disease characterized by sinus bradycardia, atrioventricular conduction block, and atrial fibrillation or flutter. Fifty-four percent of affected individuals required pacemaker implantation. Disease onset ranged from age 19 to 53 years (mean age 38 years). Symptoms of skeletal myopathy were not observed, although three members of one family with a p.Arg571Ser mutation in the lamin C isoform had elevated serum CK concentrations.
  • Brodsky et al [2000] reported one family with a deletion in exon 6 (c.959delT) and severe DCM, conduction system disease, and variable skeletal muscle involvement. In five affected family members, three had Emery-Dreifuss muscular dystrophy-like and limb-girdle muscular dystrophy-like skeletal muscle myopathy; two had atrioventricular block, one had atrial arrhythmia, and one developed DCM. Two individuals progressed to heart failure; no family members required pacemaker implantation.
  • Becane et al [2000] reported findings in 17 affected individuals and two asymptomatic relatives from a family with the nonsense mutation p.Gln6*. Eight other family members had died suddenly: in two, sudden death was the sole sign; in six (three of whom had prior pacemaker implantation), sudden death was preceded by arrhythmias and left ventricular dysfunction. Mean age of disease onset was 34.6 years (range 15-56 years). In total, 6/17 required pacemaker intervention, 7/17 had DCM, 7/17 had atrial arrhythmias, and 11/17 had atrioventricular block. Five of 17 also had skeletal muscle involvement manifest as contractures involving the Achilles’ tendon, neck, and elbow.
  • Jakobs et al [2001] reported two families with conduction system disease characterized by progressive atrioventricular block and atrial arrhythmias. Onset was earlier in individuals with the p.Arg225* nonsense mutation (range 20-50 years) than in those with the p.Glu203Lys missense mutation (range 30-69 years). In both families DCM and heart failure occurred in the fifth and sixth decades and pacemaker implantation was common.
  • Hershberger et al [2002] reported findings in eight members of a family with a highly penetrant missense mutation (p.Leu215Pro). Presentation was similar and included DCM preceded by atrioventricular block and atrial arrhythmia. Seven of eight required pacemaker intervention, although only two of the eight reported had progression to DCM.
  • Sebillon et al [2003] identified three families with LMNA mutations from a cohort of 66 probands (47 with familial DCM and 19 simplex cases of DCM). LMNA mutations were identified only in families with conduction system disease. In one family, early-onset atrial fibrillation was observed, followed by DCM.
  • Taylor et al [2003] identified LMNA mutations in four of 49 probands (40 familial cases, 9 simplex cases) with DCM. Of the four probands with LMNA mutations, three had a positive family history and one was a simplex case. Prognosis was worse for the 12 individuals with an LMNA mutation, with an event-free survival at age 45 years of 31% versus 75% for those with DCM who did not have LMNA mutations.
  • Parks et al [2008] analyzed 324 unrelated probands with DCM of whom 187 had familial disease. Nineteen individuals (5.9% of all cases) had LMNA sequence variants, including 7.5% of probands with familial DCM and 3.6% of simplex cases.

    An unusual finding in this study was that in six of the 19 kindreds (32%) with a protein-altering LMNA variant, at least one family member documented to have DCM did not have the LMNA variant. The authors suggest that this finding (termed “incomplete segregation”) indicates the existence of other causative factors (e.g., another causative mutation in a gene other than LMNA), challenging the assumption that a single-gene mutation explains all cardiac disease in a family with familial dilated cardiomyopathy.
  • Pasotti et al [2008] described the findings in 60 of 94 individuals with an LMNA mutation from 27 families who had disease manifestations: 40 had DCM with atrioventricular block; 12 had DCM with ventricular tachycardia/ventricular fibrillation; six had DCM with atrioventricular block and EDMD-2; and two had atrioventricular block and EDMD-2. Fifteen underwent heart transplantation; 15 had sudden cardiac death events; and 12 appropriate ICD interventions were reported. Penetrance was 68% by age 39 years, 86% by age 59 years, and 100% in those older than age 60 years.
  • van Rijsingen et al [2012] in a European cohort of 269 individuals with LMNA mutations suggested that four independent risk factors for malignant ventricular arrhythmias were as follows:
    • Non-sustained ventricular tachycardia;
    • A left ventricular ejection fraction less than 45%;
    • Male sex;
    • Insertion-deletion or other truncating mutations.
  • Anselme et al [2013] reported a case series of 47 individuals with LMNA mutations with significant conduction system disease regardless of normal or near-normal ejection fraction and observed that significant conduction system disease indicated risk for ventricular arrhythmias.

Genotype-Phenotype Correlations

Mutations in LMNA are associated with conduction system disease and arrhythmia; however no specific genotype-phenotype correlations have been established for LMNA-related DCM.

A few studies focusing on mutation type suggest a correlation between splice site mutations and increased risk for sudden cardiac death [Pasotti et al 2008] and between non-missense mutations (in-del, truncating, splice site) and risk for malignant ventricular arrhythmias.

Penetrance

LMNA-related DCM demonstrates age-related penetrance with onset in the third and fourth decades, so that by the seventh decade penetrance is considered greater than 90%-95%.

Anticipation

Anticipation has not been observed.

Prevalence

A population-based estimate of the prevalence of DCM of unknown cause is not available in the modern era (where echocardiography is routinely available). A recent review has suggested that the frequency of DCM is equal to the established frequency of hypertrophic cardiomyopathy (1:500) or greater [Hershberger et al 2013].

The frequency of LMNA-related DCM in persons with DCM of unknown cause (also referred to as idiopathic dilated cardiomyopathy [IDC]) ranges from 5% to 10% of familial DCM and 2% to 5% of non-familial DCM.

In the largest series to date, Parks et al [2008] analyzed 324 unrelated probands, of whom 187 had familial disease. Nineteen individuals (5.9% of all cases) had LMNA sequence variants, including 7.5% of probands with familial DCM and 3.6% of simplex cases.

Arbustini et al [2002] evaluated 73 probands with DCM and four families with atrioventricular block without DCM. Of the 15 of the 73 who had atrioventricular block, seven were familial cases and eight were simplex cases (i.e., a single occurrence in a family). Five of the seven familial cases had LMNA mutations. No LMNA mutations were identified in the eight simplex cases with DCM and atrioventricular block or in the four families with atrioventricular block without DCM.

Karkkainen et al [2006] identified six mutations in 66 probands with DCM who had survived heart transplantation in Finland (1986-1998).

Perrot et al [2009] identified LMNA mutations in five of 73 probands with DCM with conduction system disease.

Differential Diagnosis

The differential diagnosis of LMNA-related dilated cardiomyopathy (DCM) depends on physical examination to evaluate for extra cardiac features and molecular evaluation for LMNA (see Testing Strategy) to differentiate from other disorders causing DCM and conduction system disease (CSD):

  • RBM20-DCM. Mutations in RBM20 have been associated with an aggressive disease course including onset at 36-37 years, conduction and rhythm abnormalities requiring implantable cardioverter defibrillator (ICD) or pacemaker placement, and sudden, early onset death [Brauch et al 2009, Li et al 2010]. Molecular testing is required to distinguish RBM20-DCM from LMNA-DCM.
  • SCN5A-related DCM. DCM with conduction defects, arrhythmia, pacemaker/defibrillator requirement, and sudden death has also been reported with mutations in SCN5A [McNair et al 2004, Hershberger et al 2009, Cheng et al 2010]. Molecular testing is required to distinguish SCN5A-DCM from LMNA-DCM.
  • DES-related myopathy. While isolated DCM has been reported with mutations in DES [Li et al 1999], DES-related myopathy is characterized by DCM with conduction and neuromuscular disease involving desmin protein aggregates in cardiomyocytes and skeletal muscle cells. A clinical evaluation with focus on neuromuscular disease accompanied by molecular genetic testing is required to diagnose DES-related myopathy. Van Spaendonck-Zwarts et al [2011] reported that DES mutations in the 2B domain correlate with isolated neurologic involvement whereas head and tail domain mutations correlate with an isolated cardiac phenotype. Some individuals with DES mutations can present with mild conduction system disease [Taylor et al 2007].
  • Limb-girdle muscular dystrophy (LGMD type 1D). Collectively describing a group of disorders involving varying degrees and forms of skeletal muscle disease with or without cardiac involvement, LGMD can be caused by mutations in several genes. A splice site mutation in DES was reported in a family with DCM, CSD and proximal muscle involvement, constituting the LGMD1D subtype. A clinical evaluation with focus on neuromuscular disease accompanied by molecular genetic testing are required to diagnose LGMD1D.
  • Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death. While a recent report implicated LMNA mutations in some cases (see Genetically Related Disorders), most cases of ARVC are caused by mutations in TGFB3, RYR2 and TMEM43. A molecular evaluation along with a clinical evaluation focusing on cardiovascular findings [Marcus et al 2010] is usually required to diagnose ARVC.
  • Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of joint contractures that begin in early childhood; slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles; and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade. The three genes in which mutations are known to cause EDMD are EMD (encoding emerin) and FHL1 (encoding FHL1), which cause X-linked EDMD (XL-EDMD); and LMNA (encoding lamin A and C), which causes autosomal dominant EDMD (AD-EDMD) and autosomal recessive EDMD (AR-EDMD). A clinical evaluation with focus on neuromuscular disease and molecular analysis are required to diagnose Emery-Dreifuss muscular dystrophy.

The differential diagnosis of LMNA-related dilated cardiomyopathy (DCM) relates to the general phenotype of DCM of unknown cause. Current evidence indicates that IDC (i.e., DCM of unknown cause) may be familial (and therefore possibly genetic) in 20%-50% of cases [Burkett & Hershberger 2005].

With a clear pattern of familial disease, a genetic cause of DCM is likely (see Dilated Cardiomyopathy Overview).

Among genetic disorders, LMNA-related cardiomyopathy may be the most common cause of familial DCM with prominent conduction system disease (see Prevalence).

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Guidelines for the clinical management of individuals with LMNA-related DCM have been published [Hershberger et al 2009 (full text)].

Evaluations Following Initial Diagnosis

The diagnosis of LMNA-related dilated cardiomyopathy (DCM) should be accompanied by a targeted three- to four-generation family history. The following evaluations should be performed.

Comprehensive cardiovascular evaluation

  • Evaluation for conduction system disease and arrhythmia:
    • Personal and family history of presyncope, syncope, resuscitated sudden cardiac death, palpitations, and other symptoms of arrhythmia
    • Electrocardiography:
      • Follow up of abnormalities with additional testing as indicated (e.g., 24-hour monitoring or event monitors)
      • Referral to a cardiologist or electrophysiologist for any indication of symptomatic disease
      • Indicated in some patients: invasive electrophysiologic evaluation for conduction system disease
  • Evaluation for left ventricular dysfunction and DCM:
    • Family history for cardiomyopathy of any type, personal history of shortness of breath, dyspnea on exertion, paroxysmal nocturnal dyspnea, chest pain
    • Assessment of left ventricular function (most commonly by two-dimensional echocardiography) to determine left ventricular dimension and function. Alternatively, MRI provides similar data, and radionuclide ventriculography provides a measure of the ejection fraction.

Measurement of serum CK concentration to evaluate for skeletal myopathy. In some affected individuals elevated serum CK concentrations with or without a skeletal muscle myopathy similar to Emery-Dreifuss muscular dystrophy or limb-girdle muscular dystrophy is observed. If CK levels are elevated, an evaluation for skeletal muscle weakness, including neuromuscular evaluation, may be necessary.

History and physical examination for signs and symptoms of skeletal myopathy. If there is evidence of myopathy, refer to a neuromuscular disease specialist for evaluation.

Treatment of Manifestations

For the general approach to managing DCM, see Dilated Cardiomyopathy Overview, Management.

The Pasotti et al [2008] report (see Natural History) provides the most longitudinal data on LMNA-related DCM: 94 individuals with an LMNA mutation were followed for a median of 57 months (range: 36-107 months). Additional reports of large prospective longitudinal natural history studies of LMNA-related DCM are not yet available.

The Heart Failure Society of America and Heart Rhythm Society (in conjunction with the European Heart Rhythm Association) have commissioned guideline documents for the management of genetic cardiomyopathies that included specific mention of LMNA-related DCM [Hershberger et al 2009 (full text), Ackerman et al 2011]. Elements of the guidelines include the following:

  • Because of the complexity of treatment interventions in LMNA-related DCM in symptomatic and asymptomatic individuals, referral to centers with special expertise in cardiovascular genetic medicine should be considered.
  • Genetic testing for LMNA is recommended for all individuals with idiopathic DCM, especially those with CSD and arrhythmia.
  • Consider therapy based on cardiac phenotype (i.e., DCM or arrhythmia).
  • With an established arrhythmia or known risk of arrhythmia, consider ICD implantation before the ejection fraction falls below 35%. Note that this recommendation was developed in the Heart Failure Society guidelines in large part because of the risk for lethal arrhythmias in persons with an LMNA mutation who have systolic function well above a left ventricular ejection fraction of 35%, the usual measure of systolic dysfunction below which ICDs are indicated in most US guidelines.
  • Evaluate first-degree relatives, including extended family history, medical history, physical examination, echocardiogram, and ECG; offer targeted testing for the family mutation, if known.

The management of LMNA-related DCM is focused on treatment of conduction system disease, arrhythmia, and DCM.

Cardiac conduction system disease and arrhythmias

  • Chronic atrial fibrillation unresponsive to cardioversion is treated with anticoagulants and agents for ventricular rate control.
  • Other symptomatic supraventricular arrhythmias are treated with pharmacologic agents, and at times are augmented with electrophysiologic intervention (e.g., atrial or atrioventricular node ablations).
  • Symptomatic bradyarrhythmias or asymptomatic but significant heart block is treated with an implantable electronic pacemaker. However, when a device is to be implanted, use of an implantable cardiac defibrillator (ICD) rather than an electronic pacemaker has been advocated and should be strongly considered, as the risk of mortality from sudden cardiac death usually accompanies supraventricular arrhythmias and conduction system disease. Sudden cardiac death presumably results from lethal tachyarrhythmias despite the presence of a pacemaker to treat bradyarrhythmias [van Berlo et al 2005, Meune et al 2006], and for this reason use of an ICD has been advocated for LMNA-related cardiomyopathy with significant conduction system disease and/or arrhythmia regardless of the left ventricular ejection fraction [Hershberger et al 2009].
  • Symptomatic ventricular arrhythmias, ventricular tachycardia, ventricular fibrillation, and resuscitated sudden cardiac death are treated with an ICD.
  • When DCM is present and the left ventricular ejection fraction is less than 35%, an ICD should be implanted following the usual guidelines [Yancy et al 2013 (full text)].

LMNA-related DCM

  • Treatment of symptomatic DCM, including heart failure, is pharmacologic with ACE inhibitors and beta blockers, as summarized in guideline documents [Yancy et al 2013 (full text)].
  • With progressive deterioration in left ventricular function (left ventricular ejection fraction <30%), some experts recommend full anticoagulation to prevent the development of left ventricular mural thrombus and embolic events including stroke.
  • Cardiac transplantation or other advanced therapies should be considered with progressive DCM, advancing heart failure, and otherwise refractory disease in persons receiving comprehensive cardiovascular care from experts in the field [Yancy et al 2013].

Prevention of Secondary Complications

Whether conventional medical therapy (ACE inhibitors, beta blockers) is able to ameliorate or prevent DCM or heart failure has not been formally tested and is therefore unknown.

Implantable cardiac defibrillators or pacemakers are highly effective in preventing sudden cardiac death.

Surveillance

Screening and identification of DCM before the onset of symptoms enables the initiation of medical therapy that may delay disease progression.

  • Individuals with an LMNA mutation who are found to have any ECG abnormality should undergo a cardiovascular evaluation for disease progression at least annually [Brodt et al 2013].
  • Unaffected relatives who have the family-specific LMNA mutation are advised to undergo cardiovascular screening tests (medical history, physical examination, echocardiogram, and ECG) every one to two years and/or whenever new symptoms present [Burkett & Hershberger 2005, Hershberger et al 2009]. Yearly screening may also be offered to at-risk individuals for whom genetic testing is not possible despite a known LMNA mutation in the family.
  • At onset of new symptoms an immediate evaluation for evidence of DCM and/or conduction system disease is indicated, regardless of genetic status.

Evaluation of Relatives at Risk

When the disease-causing LMNA mutation has been identified in a family, molecular genetic testing can be offered to relatives at risk in order to facilitate prompt diagnosis, surveillance, and treatment in those in whom the disease-causing LMNA mutation has been detected.

If molecular genetic testing is not possible, the first-degree relatives of a proband with LMNA-related DCM should be evaluated annually by medical history, physical examination, echocardiogram, and ECG to determine if any have detectable DCM and/or conduction system disease.

Note: Because the age of onset is variable and penetrance is reduced, a normal baseline echocardiogram and ECG in a first-degree relative who has not undergone molecular genetic testing does not rule out LMNA-related DCM in that individual, and the recommendations set forth in Surveillance should be followed.

Any abnormal cardiovascular test results in a relative of a proband with a known LMNA mutation should be followed up with a full cardiovascular assessment to evaluate for any acquired causes of disease (e.g., coronary artery disease). Results on screening tests that do not meet criteria for DCM but do show some abnormality (e.g., left ventricular enlargement but normal function; decreased ejection fraction but normal-sized left ventricle) may reflect variable expression of LMNA-related DCM in that relative. Targeted genetic testing to clarify the diagnosis as well as close surveillance (e.g., cardiovascular testing every 1-2 years) for progression of cardiovascular disease is recommended for such individuals.

Note: Because most LMNA-related DCM is adult onset, clinical screening is usually not recommended for children or adolescents unless onset of disease in the proband was in these age groups, or unless cardiovascular symptoms are present.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy is contraindicated in women with DCM. Pregnant women with DCM should be followed by a high-risk obstetrician. At-risk women with unknown mutation status should undergo a cardiovascular evaluation and be offered genetic counseling prior to pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

LMNA-related dilated cardiomyopathy (DCM) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with LMNA-related DCM have an affected parent.
  • A proband with LMNA-related DCM may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
  • Recommendations for the evaluation of parents of a proband with LMNA-DCM from an apparent de novo mutation include review of medical history, physical examination, echocardiogram, ECG to determine if a parent has detectable DCM and/or conduction system disease, and molecular genetic testing if the mutation has been identified in the proband. Evaluation of parents may determine that one is affected but has previously escaped diagnosis and/or has a milder phenotypic presentation, including evidence of DCM on echocardiogram without clinical heart failure symptoms (i.e., asymptomatic affected).

Note: (1) Although some individuals diagnosed with LMNA-related DCM have an affected parent, the family history may appear to be negative because of early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or non-penetrance of the LMNA mutation. (2) If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected, although this has not yet been reported.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If one parent of the proband has the mutation, the risk to the sibs is 50%. However, because of variable expression and reduced penetrance, no predictions can be made regarding age of onset, severity, or course of disease.
  • When neither parent has signs of LMNA-related DCM, the risk to the sibs of a proband is increased over the general population risk, but cannot be precisely calculated. Genetic testing may help to clarify risk. Recommendations for evaluation of sibs are included in Evaluation of Relatives at Risk.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism, although this has not yet been reported.
  • When the family-specific mutation is known, the sibs may be offered genetic testing to help clarify risk. However, the absence of a likely disease-causing mutation in an unaffected sib should be interpreted with caution, as it is possible that in some families with DCM more than one etiology may be causative. See discussion of Parks et al [2008] in Natural History.

Offspring of a proband. Each child of an individual with LMNA-related DCM has a 50% chance of inheriting the parent’s mutation. However, because of variable expression and reduced penetrance, no predictions can be made regarding age of onset, severity, or course of disease.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has an LMNA mutation despite being clinically asymptomatic, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family history. A detailed three- to four-generation family history (including heart failure, DCM, cardiac transplantation, pacemakers or implantable cardiac defibrillators, unexplained sudden death, unexplained cardiac conduction system disease and/or arrhythmia, or unexplained stroke or other thromboembolic disease) should be obtained from relatives to assess the possibility of familial disease. Conduction system disease, particularly with pacemakers, is particularly suggestive of LMNA-related DCM.

Both sides of the family should be considered as possibly contributing. Families with dilated cardiomyopathy in both maternal and paternal lineages have been described [Crispell et al 1999, Parks et al 2008], and experience has shown that regardless of an apparent inheritance pattern in a family, assumptions regarding maternal or paternal inheritance of mutations in genes causing familial dilated cardiomyopathy in a given family may be unreliable and potentially misleading. See discussion of Parks et al [2008] in Natural History.

Molecular genetic testing of at-risk asymptomatic adult relatives of individuals with LMNA-related DCM is possible if molecular genetic testing has identified the specific mutation in an affected relative. Such testing should only be performed in the context of formal genetic counseling, and is not useful in predicting age of disease onset, severity, or rate of progression. Testing of asymptomatic at-risk individuals is considered predictive testing for predisposition to LMNA-related DCM, not diagnostic testing.

Molecular genetic testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

However, early clinical or molecular genetic diagnosis of DCM may offer a benefit that outweighs the arguments against testing asymptomatic minors. Early treatment may forestall development of more advanced disease including slowing of progression to advanced heart failure or prevention of sudden cardiac death, and thus may justify screening and genetic testing of asymptomatic minors in families demonstrating early-onset and/or aggressive disease. In these cases, knowledge that a child has inherited an LMNA mutation may help guide more stringent clinical screening for asymptomatic but clinically detectable cardiovascular disease.

Genetic testing is always indicated in affected or symptomatic individuals in a family with established LMNA-related DCM, regardless of age.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for LMNA-related DCM is technically possible by analyzing fetal DNA extracted from cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or from cells obtained through amniocentesis at approximately 15 to 18 weeks' gestation. The disease-causing mutation of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for (typically) adult-onset diseases are not common. Differences in perspective exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Cardiomyopathy Association (CMA)
    Chiltern Court
    Asheridge Road
    Unit 10
    Chesham Buckinghamshire HP5 2PX
    United Kingdom
    Phone: +44 01494 791224; 0800 018 1024 (UK only)
    Fax: +44 01494 797199
    Email: info@cardiomyopathy.org
  • Medline Plus
  • Children's Cardiomyopathy Foundation (CCF)
    PO Box 547
    Tenafly NJ 07670
    Phone: 866-808-2873 (toll-free)
    Fax: 201-227-7016
    Email: info@childrenscardiomyopathy.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. LMNA-Related Dilated Cardiomyopathy: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for LMNA-Related Dilated Cardiomyopathy (View All in OMIM)

115200CARDIOMYOPATHY, DILATED, 1A; CMD1A
150330LAMIN A/C; LMNA

Normal allelic variants. LMNA comprises twelve exons. Alternative splicing of exon 10 produces two proteins, lamin A and lamin C (see Normal gene product).

Pathologic allelic variants. See Table 2. More than 200 sequence variants in LMNA have been reported (see Leiden Muscular Dystrophy site). LMNA-related dilated cardiomyopathy (DCM) results from missense mutations, with occasional nonsense or splice-site mutations and short insertions or deletions of LMNA.

Table 2. Selected LMNA Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1711C>Ap.Arg571SerNM_005572​.3 1
NP_005563​.1
c.16C>Tp.Gln6*NM_170707​.2 2
NP_733821​.1
c.607G>Ap.Glu203Lys
c.644T>Cp.Leu215Pro
c.673C>Tp.Arg225*
c.959delTp.Arg321Glufs*159

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.This transcript variant uses an alternate splice site in the 3' coding region, compared to variant NM_170707.2, resulting in a shorter isoform (also known as lamin C) with a C terminus distinct from that in the lamin A isoform.

2. This transcript variant encodes isoform 1, also known as lamin A.

Normal gene product. Alternative splicing of exon 10 produces two proteins: lamin C, with 572 amino acids (NM_005572.3; NP_005563.1) and lamin A (NM_170707.2; NP_733821.1), which is identical to lamin C for the first 566 amino acids, but has an additional 98 terminal amino acids (total of 664).

Both lamins A and C are structural proteins of the inner nuclear membrane and are found in many different tissues [Capell & Collins 2006].

Abnormal gene product. The mechanism of cellular injury that causes LMNA-related DCM remains incompletely understood. Because lamin A/C is a structural protein of the nuclear membrane, it has been suggested that fragility of the nuclear membrane in the setting of repetitive contraction of skeletal or cardiac muscle may predispose to nuclear injury and cellular apoptosis. An alternative hypothesis suggests that an abnormal lamin A/C protein may disrupt the chromatin/lamin-associated protein complex, thereby disturbing gene expression.

References

Published Guidelines/Consensus Statements

  1. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MR, Towbin JA; Heart Failure Society of America. Genetic evaluation of cardiomyopathy--a Heart Failure Society of America practice guideline. Available online. 2009. Accessed 9-10-13. [PubMed: 19254666]
  2. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJV, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WHW, Tsai EJ, Wilkoff BL. ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Available online. 2013. Accessed 9-12-13. [PubMed: 23747642]

Literature Cited

  1. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. Heart Rhythm Society (HRS); European Heart Rhythm Association (EHRA). HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace. 2011;13:1077–109. [PubMed: 21810866]
  2. Anselme F, Moubarak G, Savouré A, Godin B, Borz B, Drouin-Garraud V, Gay A. Implantable cardioverter-defibrillators in lamin A/C mutation carriers with cardiac conduction disorders. Heart Rhythm. 2013 [PubMed: 23811080]
  3. Arbustini E, Pilotto A, Repetto A, Grasso M, Negri A, Diegoli M, Campana C, Scelsi L, Baldini E, Gavazzi A, Tavazzi L. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol. 2002;39:981–90. [PubMed: 11897440]
  4. Becane HM, Bonne G, Varnous S, Muchir A, Ortega V, Hammouda EH, Urtizberea JA, Lavergne T, Fardeau M, Eymard B, Weber S, Schwartz K, Duboc D. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol. 2000;23:1661–6. [PubMed: 11138304]
  5. Brauch KM, Karst ML, Herron KJ, de Andrade M, Pellikka PA, Rodeheffer RJ, Michels VV, Olson TM. Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. J Am Coll Cardiol. 2009;54:930–41. [PMC free article: PMC2782634] [PubMed: 19712804]
  6. Brodsky GL, Muntoni F, Miocic S, Sinagra G, Sewry C, Mestroni L. Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation. 2000;101:473–6. [PubMed: 10662742]
  7. Brodt C, Siegfried JD, Hofmeyer M, Martel J, Rampersaud E, Li D, Morales A, Hershberger RE. Temporal relationship of conduction system disease and ventricular dysfunction in LMNA cardiomyopathy. J Card Fail. 2013;19:233–9. [PMC free article: PMC3699310] [PubMed: 23582089]
  8. Burkett EL, Hershberger RE. State of the Art: Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol. 2005;45:969–81. [PubMed: 15808750]
  9. Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan- type familial partial lipodystrophy. Hum Mol Genet. 2000;9:109–12. [PubMed: 10587585]
  10. Capell BC, Collins FS. Human laminopathies: nuclei gone genetically awry. Nat Rev Genet. 2006;7:940–52. [PubMed: 17139325]
  11. Cheng J, Morales A, Siegfried JD, Li D, Norton N, Song J, Gonzalez-Quintana J, Makielski JC, Hershberger RE. SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del. Clin Transl Sci. 2010;3:287–94. [PMC free article: PMC3026282] [PubMed: 21167004]
  12. Crispell KA, Wray A, Ni H, Nauman DJ, Hershberger RE. Clinical profiles of four large pedigrees with familial dilated cardiomyopathy: preliminary recommendations for clinical practice. J Am Coll Cardiol. 1999;34:837–47. [PubMed: 10483968]
  13. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M, Levy N. Lamin a truncation in Hutchinson-Gilford progeria. Science. 2003;300:2055. [PubMed: 12702809]
  14. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423:293–8. [PubMed: 12714972]
  15. Fatkin D, MacRae C, Sasaki T, Wolff M, Porcu M, Frenneaux M, Atherton J, Vidaillet H, Spudich S, Girolami U, Seidman J, Seidman C. 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. [PubMed: 10580070]
  16. Gupta P, Bilinska ZT, Sylvius N, Boudreau E, Veinot JP, Labib S, Bolongo PM, Hamza A, Jackson T, Ploski R, Walski M, Grzybowski J, Walczak E, Religa G, Fidzianska A, Tesson F. Genetic and ultrastructural studies in dilated cardiomyopathy patients: a large deletion in the lamin A/C gene is associated with cardiomyocyte nuclear envelope disruption. Basic Res Cardiol. 2010;105:365–77. [PMC free article: PMC3934843] [PubMed: 20127487]
  17. Hegele RA, Anderson CM, Wang J, Jones DC, Cao H. Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes. Genome Res. 2000;10:652–8. [PMC free article: PMC310873] [PubMed: 10810087]
  18. Hershberger RE, Hanson E, Jakobs PM, Keegan H, Coates K, Bousman S, Litt M. A novel lamin A/C mutation in a family with dilated cardiomyopathy, prominent conduction system disease, and need for permanent pacemaker implantation. Am Heart J. 2002;144:1081–6. [PubMed: 12486434]
  19. Hershberger RE, Hedges DJ, Morales A. Dilated Cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. 2013;10:531–47. [PubMed: 23900355]
  20. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MR, Towbin JA. Heart Failure Society of America; Genetic evaluation of cardiomyopathy--a Heart Failure Society of America practice guideline. J Card Fail. 2009;15:83–97. [PubMed: 19254666]
  21. Jakobs PM, Hanson E, Crispell KA, Toy W, Keegan H, Schilling K, Icenogle T, Litt M, Hershberger RE. Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease. J Card Fail. 2001;7:249–56. [PubMed: 11561226]
  22. Karkkainen S, Reissell E, Helio T, Kaartinen M, Tuomainen P, Toivonen L, Kuusisto J, Kupari M, Nieminen MS, Laakso M, Peuhkurinen K. Novel mutations in the lamin A/C gene in heart transplant recipients with end stage dilated cardiomyopathy. Heart. 2006;92:524–6. [PMC free article: PMC1860858] [PubMed: 16537768]
  23. Li D, Morales A, Gonzalez-Quintana J, Norton N, Siegfried JD, Hofmeyer M, Hershberger RE. Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy. Clin Transl Sci. 2010;3:90–7. [PMC free article: PMC2898174] [PubMed: 20590677]
  24. Li D, Tapscoft T, Gonzalez O, Burch PE, Quiñones MA, Zoghbi WA, Hill R, Bachinski LL, Mann DL, Roberts R. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation. 1999;100:461–4. [PubMed: 10430757]
  25. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J. 2010;31:806–14. [PMC free article: PMC2848326] [PubMed: 20172912]
  26. McNair WP, Ku L, Taylor MR, Fain PR, Dao D, Wolfel E, Mestroni L. Familial Cardiomyopathy Registry Research Group.; SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation. 2004;110:2163–7. [PubMed: 15466643]
  27. Meune C, Van Berlo JH, Anselme F, Bonne G, Pinto YM, Duboc D. Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med. 2006;354:209–10. [PubMed: 16407522]
  28. Parks S, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Peterson A, Li D, Jakobs PM, Litt M, Porter CB, Rahko PS, Hershberger RE. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or idiopathic dilated cardiomyopathy. Am Heart J. 2008;156:161–9. [PMC free article: PMC2527054] [PubMed: 18585512]
  29. Pasotti M, Klersy C, Pilotto A, Marziliano N, Rapezzi C, Serio A, Mannarino S, Gambarin F, Favalli V, Grasso M, Agozzino M, Campana C, Gavazzi A, Febo O, Marini M, Landolina M, Mortara A, Piccolo G, Viganò M, Tavazzi L, Arbustini E. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol. 2008;52:1250–60. [PubMed: 18926329]
  30. Perrot A, Hussein S, Ruppert V, Schmidt HH, Wehnert MS, Duong NT, Posch MG, Panek A, Dietz R, Kindermann I, Böhm M, Michalewska-Wludarczyk A, Richter A, Maisch B, Pankuweit S, Ozcelik C. Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy. Basic Res Cardiol. 2009;104:90–9. [PubMed: 18795223]
  31. Quarta G, Syrris P, Ashworth M, Jenkins S, Zuborne Alapi K, Morgan J, Muir A, Pantazis A, McKenna WJ, Elliott PM. Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2012;33:1128–36. [PubMed: 22199124]
  32. Renou L, Stora S, Yaou RB, Volk M, Sinkovec M, Demay L, Richard P, Peterlin B, Bonne G. Heart-hand syndrome of Slovenian type: a new kind of laminopathy. J Med Genet. 2008;45:666–71. [PubMed: 18611980]
  33. Sebillon P, Bouchier C, Bidot LD, Bonne G, Ahamed K, Charron P, Drouin-Garraud V, Millaire A, Desrumeaux G, Benaiche A, Charniot JC, Schwartz K, Villard E, Komajda M. Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations. J Med Genet. 2003;40:560–7. [PMC free article: PMC1735561] [PubMed: 12920062]
  34. Speckman RA, Garg A, Du F, Bennett L, Veile R, Arioglu E, Taylor SI, Lovett M, Bowcock AM. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C. Am J Hum Genet. 2000;66:1192–8. [PMC free article: PMC1288186] [PubMed: 10739751]
  35. Taylor MR, Slavov D, Ku L, Di Lenarda A, Sinagra G, Carniel E, Haubold K, Boucek MM, Ferguson D, Graw SL, Zhu X, Cavanaugh J, Sucharov CC, Long CS, Bristow MR, Lavori P, Mestroni L. Familial Cardiomyopathy Registry; BEST (Beta-Blocker Evaluation of Survival Trial) DNA Bank. Prevalence of desmin mutations in dilated cardiomyopathy. Circulation. 2007;115:1244–51. [PubMed: 17325244]
  36. Taylor MR, Fain PR, Sinagra G, Robinson ML, Robertson AD, Carniel E, Di Lenarda A, Bohlmeyer TJ, Ferguson DA, Brodsky GL, Boucek MM, Lascor J, Moss AC, Li WL, Stetler GL, Muntoni F, Bristow MR, Mestroni L. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol. 2003;41:771–80. [PubMed: 12628721]
  37. Todorova A, Halliger-Keller B, Walter MC, Dabauvalle MC, Lochmuller H, Muller CR. A synonymous codon change in the LMNA gene alters mRNA splicing and causes limb girdle muscular dystrophy type 1B. J Med Genet. 2003;40:e115. [PMC free article: PMC1735280] [PubMed: 14569138]
  38. van Berlo JH, de Voogt WG, van der Kooi AJ, van Tintelen JP, Bonne G, Yaou RB, Duboc D, Rossenbacker T, Heidbüchel H, de Visser M, Crijns HJ, Pinto YM. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med. 2005;83:79–83. [PubMed: 15551023]
  39. van Rijsingen IA, Arbustini E, Elliott PM, Mogensen J, Hermans-van Ast JF, van der Kooi AJ, van Tintelen JP, van den Berg MP, Pilotto A, Pasotti M, Jenkins S, Rowland C, Aslam U, Wilde AA, Perrot A, Pankuweit S, Zwinderman AH, Charron P, Pinto YM. Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study. J Am Coll Cardiol. 2012;59:493–500. [PubMed: 22281253]
  40. van Spaendonck-Zwarts KY, van Hessem L, Jongbloed JD, de Walle HE, Capetanaki Y, van der Kooi AJ, van Langen IM, van den Berg MP, van Tintelen JP. Desmin-related myopathy. Clin Genet. 2011;80:354–66. [PubMed: 20718792]
  41. van Tintelen JP, Tio RA, Kerstjens-Frederikse WS, van Berlo JH, Boven LG, Suurmeijer AJ, White SJ, den Dunnen JT, te Meerman GJ, Vos YJ, van der Hout AH, Osinga J, van den Berg MP, van Veldhuisen DJ, Buys CH, Hofstra RM, Pinto YM. Severe myocardial fibrosis caused by a deletion of the 5' end of the lamin A/C gene. J Am Coll Cardiol. 2007;49:2430–9. [PubMed: 17599607]
  42. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJV, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WHW, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013. Epub ahead of print. [PubMed: 23747642]

Suggested Reading

  1. Hershberger RE. Cardiovascular genetic medicine: evolving concepts, rationale, and implementation. J Cardiovasc Transl Res. 2008;1:137–43. [PubMed: 20559908]
  2. Sylvius N, Tesson F. Lamin A/C and cardiac diseases. Curr Opin Cardiol. 2006;21:159–65. [PubMed: 16601451]

Chapter Notes

Author History

Jason Cowan, MS; University of Miami Miller School of Medicine (2008-2011)
Ray E Hershberger, MD (2008-present)
Ana Morales, MS, CGC (2008-2011; 2013-present)

Revision History

  • 19 September 2013 (me) Comprehensive update posted live
  • 5 April 2011 (me) Comprehensive update posted live
  • 12 June 2008 (me) Review posted live
  • 7 January 2008 (rh) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1674PMID: 20301717
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...