Clinical characteristics.

LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and/or reduced systolic function preceded (sometimes by many years) by or accompanied by 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 minimal or no systolic dysfunction.

Diagnosis/testing.

The diagnosis of LMNA-related DCM is established in a proband with suggestive findings and a heterozygous pathogenic variant in LMNA identified by molecular genetic testing.

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 is treated with an electronic pacemaker. Symptomatic ventricular arrhythmias, ventricular tachycardia, ventricular fibrillation, and resuscitated sudden cardiac death are treated with an implantable cardioverter defibrillator (ICD) and drug therapy as needed. 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 other conventional approaches. Progressive deterioration in left ventricular function is treated with an ICD. 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 pathogenic variant who are found to have any EKG abnormality should undergo a cardiovascular evaluation for disease progression (EKG, 24-48 hour rhythm monitoring, LV function measurement) at least annually. Asymptomatic individuals with a pathogenic LMNA variant should undergo cardiovascular evaluation (medical history, physical examination, echocardiogram, and EKG) every one to two years and/or whenever new symptoms arise. In families with a known LMNA pathogenic variant, at-risk individuals for whom genetic testing is not possible should have yearly cardiovascular evaluation. 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 pathogenic variant is known; otherwise regular 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 genetic 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 individuals with LMNA-related DCM caused by a de novo pathogenic variant is unknown. Each child of an individual with LMNA-related DCM has a 50% chance of inheriting the pathogenic variant. Once an LMNA pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Suggestive Findings

LMNA-related dilated cardiomyopathy (DCM) should be considered in individuals with the following clinical findings and family history.

Clinical findings

• A clinical diagnosis of idiopathic DCM (etiology not attributed to coronary artery disease, structural heart disease, or other established clinical conditions that may cause DCM; see Dilated Cardiomyopathy Overview), almost always in the setting of conduction system disease and/or supraventricular or ventricular arrhythmias. The diagnosis of DCM is based on the principal findings of left ventricular enlargement and/or reduced systolic function (other causes excluded):
  • Left ventricular enlargement is most commonly identified with two-dimensional echocardiography, optimally assessed by a height- and sex-based approach [Vasan et al 1997], or by cardiac magnetic resonance (CMR) imaging.
  • Reduced systolic function is described clinically as a reduction in left ventricular ejection fraction, which can be measured by two-dimensional echocardiography, angiography, radioisotope scanning, or MRI of left ventricular function. An ejection fraction of less than 50% is considered systolic dysfunction [Bozkurt et al 2021].
• The key distinguishing characteristic of LMNA-related DCM is that conduction system disease and/or arrhythmias almost always occur prior to or in association with the evolution of DCM and commonly before the development of heart failure (see Clinical Description).

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). A detailed three- to four-generation family history looking for 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 in relatives is indicated to assess the possibility of LMNA-related DCM. Conduction system disease, particularly with pacemakers, is particularly suggestive of LMNA-related DCM.

Establishing the Diagnosis

The diagnosis of LMNA-related DCM is established in a proband with suggestive findings and a heterozygous pathogenic variant in LMNA identified on molecular genetic testing (see Table 1).

Note: Identification of a heterozygous LMNA variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Because the phenotype of LMNA-related DCM is indistinguishable from many other inherited disorders with DCM and DCM with a highly arrhythmic presentation, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of LMNA, followed by gene-targeted deletion/duplication analysis) for suspected LMNA-related DCM is rarely useful and typically NOT recommended.

• A comprehensive cardiomyopathy multigene panel that includes LMNA and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. When prominent arrhythmia with minimal DCM phenotype is present, a combined cardiomyopathy and arrhythmia multigene panel should be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and/or reduced systolic function frequently preceded or accompanied by significant conduction system disease.

Age of onset. 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 present in asymptomatic individuals: conduction system disease, arrhythmia, or DCM may be discovered during a medical evaluation conducted for another reason (e.g., a routine preoperative EKG) or clinical screening of at-risk relatives [Kumar et al 2016].

Presenting signs, timing, and progression. Family studies suggest that conduction system disease commonly precedes the development of DCM by a few years to a decade or more. In a study involving 64 individuals with an LMNA pathogenic variant, the median time differential from EKG abnormalities to observed left ventricular dysfunction was seven years [Brodt et al 2013]. In another retrospective study of 122 individuals with LMNA pathogenic variants, of those who had preserved left ventricular function and no heart failure at the time of presentation, new-onset left ventricular dysfunction or heart failure was observed in ~24% and 7% of individuals, respectively, after seven years [Kumar et al 2016].

• 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, 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, with minimal or no left ventricular dysfunction [Meune et al 2006].
• Variable DCM. 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 an LMNA pathogenic variant who have clinical conduction system disease and/or arrhythmia prior to the left ventricular enlargement or with minimal or no systolic dysfunction.
• Skeletal muscle disorder. Occasionally, individuals with LMNA-related cardiomyopathy also manifest signs or symptoms of skeletal myopathy, which may be associated with elevated serum creatine kinase concentration.

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

Genotype-Phenotype Correlations

No specific genotype-phenotype correlations have been established for LMNA-related DCM.

A few studies focusing on pathogenic variant type suggest a correlation between splice site variants and increased risk for sudden cardiac death [van Rijsingen et al 2012], and between non-missense variants (indel, 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%.

Prevalence

Second to TTN, LMNA is the most common genetic cause of nonsyndromic DCM. Estimates of the frequency of LMNA-related DCM in persons with DCM of unknown cause (also referred to as idiopathic dilated cardiomyopathy) ranges from 5% to 13% [Morales et al 2020, Rosenbaum et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with LMNA-related DCM, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Management guidelines for genetic cardiomyopathies have been published [Hershberger et al 2018, Towbin et al 2019]. 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.
• 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 included in the Heart Failure Society guidelines in large part because of the risk for lethal arrhythmias in persons with an LMNA pathogenic variant 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.

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

Surveillance

Agents/Circumstances to Avoid

Drugs (beta blockers, calcium channel blockers, others) that exacerbate heart block, if present, should be avoided in LMNA-related DCM unless an electronic pacemaker or implantable cardioverter defibrillator is in place.

Evaluation of Relatives at Risk

Once a molecular diagnosis of LMNA-related DCM has been established in a family, molecular genetic testing for the familial LMNA pathogenic variant can be offered to relatives at risk in order to facilitate prompt diagnosis, surveillance, and treatment in those in whom the LMNA pathogenic variant has been detected.

The risk of DCM to family members who do not have the LMNA pathogenic variant identified in the proband is generally considered to be similar to that of the general population. However, because multiple variants in DCM-associated genes have been observed in individuals with nonsyndromic DCM [Morales et al 2020] and because families may segregate pathogenic variants in more than one DCM-related gene [Liu et al 2015, Cowan et al 2018], thorough individualized risk assessment through clinical, genetic, and family history analysis is warranted to determine if discharge from high-risk cardiac surveillance is appropriate.

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 EKG 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 EKG 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 pathogenic variant 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.

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 because of the significantly increased mortality with pregnancy in DCM. Women with DCM who become pregnant should be followed by a high-risk obstetrician. At-risk women with unknown genetic status should undergo a cardiovascular evaluation and be offered genetic counseling prior to pregnancy.

Therapies Under Investigation

Drugs aimed at reducing mitogen-activated protein (MAP) kinase signaling, a mechanism which has been shown to be increased in LMNA-associated DCM, are actively under investigation (ClinicalTrials.gov identifier NCT02351856) [Wu et al 2011, MacRae et al 2016].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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.
  Note: Both sides of the family should be considered as possibly contributing. Families with DCM in both maternal and paternal lineages have been described [Liu et al 2015, Cowan et al 2018], and experience has shown that regardless of an apparent inheritance pattern in a family, assumptions regarding maternal or paternal inheritance of pathogenic variants in genes causing familial DCM in a given family may be unreliable and potentially misleading.
• Some individuals diagnosed with LMNA-related DCM have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with LMNA-related DCM caused by a de novo pathogenic variant is unknown.
• Recommendations for the evaluation of reportedly unaffected parents of a proband include:
  • Review of medical history, physical examination, echocardiogram, and EKG to determine if a parent has detectable DCM and/or conduction system disease. Evaluation of parents may determine that one is affected but has previously escaped diagnosis possibly because of a milder phenotypic presentation (e.g., evidence of DCM on echocardiogram without clinical heart failure symptoms).
  • Molecular genetic testing for the familial LMNA pathogenic variant. Because LMNA-related DCM demonstrates age-related penetrance, an asymptomatic parent may be found to be heterozygous for the familial LMNA pathogenic.
• If the LMNA pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

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 LMNA pathogenic variant, the risk to the sibs of inheriting the variant is 50%. However, because of variable expression and reduced penetrance, no predictions can be made regarding age of onset, severity, or course of disease in sibs who inherit the pathogenic variant.
• Due to reduced penetrance, variable expression, and potentially subtle or unknown early cardiovascular phenotypes in the progression of LMNA-associated cardiomyopathy, the apparent absence of symptoms in parents who have not undergone molecular genetic testing should not be used to modify risk to sibs. Sibs should be considered to be at up to a 50% risk of developing features of LMNA-associated cardiomyopathy unless molecular genetic testing has confirmed that neither parent is heterozygous for the LMNA pathogenic identified in the proband. Recommendations for evaluation of sibs are included in Evaluation of Relatives at Risk.
• If the LMNA pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent and parental identity testing has confirmed biological maternity and paternity, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• Sibs may be offered genetic testing for the familial LMNA pathogenic variant to help clarify risk. In general, sibs without the LMNA pathogenic variant identified in the proband are no longer considered to be at increased risk for DCM and thus may be discharged from cardiac surveillance. However, because multiple variants in DCM-associated genes have been observed in individuals with nonsyndromic DCM [Morales et al 2020] and because families may segregate pathogenic variants in more than one DCM-related gene [Liu et al 2015, Cowan et al 2018], thorough individualized risk assessment through clinical, genetic, and family history analysis is warranted to determine if discharge from high-risk cardiac surveillance is appropriate.

Offspring of a proband. Each child of an individual with LMNA-related DCM has a 50% chance of inheriting the pathogenic variant identified in the proband. 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. The risk to other family members depends on the status of the proband's parents: if a parent has an LMNA pathogenic variant, his or her family members may be at risk regardless of the clinical status of the parent.

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.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the LMNA-related DCM pathogenic variant has been identified in an affected family member.
• Testing of asymptomatic at-risk individuals is considered predictive testing for predisposition to LMNA-related DCM, not diagnostic testing.
• Predictive testing should only be performed in the context of formal genetic counseling, and is not useful in predicting age of DCM onset, severity, or rate of progression.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

• Recent estimates of the likelihood of clinically detectable presentation of LMNA-related DCM in children is ~1.4% [Ware et al 2022]. Although relatively low, genetic testing should be offered as it can facilitate identification of at-risk children who may benefit from early treatment, potentially forestalling the development of advanced disease.
• In families with early-onset aggressive disease, identification of the familial pathogenic variant may guide more stringent clinical screening for asymptomatic but clinically detectable cardiovascular disease.
• See the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement for discussion of ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of LMNA-related DCM, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once an LMNA pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Differences in perspective exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

LMNA encodes two proteins: lamin A and lamin C. Both lamins A and C are structural proteins of the inner nuclear membrane and are found in many different tissues. While the role and function of lamin proteins are clearly essential to several mechanical processes, 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 [Chen et al 2019].

Mechanism of disease causation. LMNA-related DCM has been shown to occur via a loss-of-function mechanism associated with indel, splicing, or missense variants [Chen et al 2019], and to include both truncating and non-truncating variants in LMNA [Mazzarotto et al 2020].

NOTE: Curation of clinical and experimental evidence through the ClinGen DCM Gene Curation efforts resulted in a definitive classification for the relationship of LMNA variants with the DCM phenotype (see Gene-Disease Validity Classification Summary: LMNA - dilated cardiomyopathy) [Jordan et al 2021].

Author Notes

Website: Dilated Cardiomyopathy Research Project

The Dilated Cardiomyopathy Research Project, originally launched in 1993 by Dr. Ray Hershberger while at the Oregon Health & Science University, aims to advance our understanding of dilated cardiomyopathy genetics. Multiple studies including data from more than 1500 families affected by DCM across the country have contributed genetic and clinical information to this research program. This multi-institutional effort, still led by Dr Hershberger and now housed at The Ohio State University, leverages the many sites collaborating in the DCM Consortium to identify families eligible for studies within the DCM Research Project, including the recently completed DCM Precision Medicine Study and the ongoing DCM Discovery Study. More information about the DCM Project, affiliated research studies, and other information and resources can be found on the website (www.dcmproject.com) or by emailing [email protected].

Acknowledgments

We are deeply grateful for the numerous families who have contributed to the research efforts in the DCM Research Project over the past nearly three decades. Without their gracious participation and engagement, the advances driven by the work of the DCM Research Project to the field would not be possible.

Author History

Jason Cowan, MS; University of Miami Miller School of Medicine (2008-2011)
Ray E Hershberger, MD (2008-present)
Ana Morales, MS, CGC; The Ohio State University (2008-2011; 2013-2021)
Elizabeth Jordan, MMSc, CGC (2022-present)

Revision History

• 17 March 2022 (ha) Comprehensive update posted live
• 7 July 2016 (ha) Comprehensive update posted live
• 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

Published Guidelines/Consensus Statements

• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 3-8-22. [PubMed: 23428972]
• Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM, et al. Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Available online. 2018. Accessed 3-8-22. [PubMed: 29904160]
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 3-8-22.
• Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, Daubert JP, de Chillou C, DePasquale EC, Desai MY, Estes NAM 3rd, Hua W, Indik JH, Ingles J, James CA, John RM, Judge DP, Keegan R, Krahn AD, Link MS, Marcus FI, McLeod CJ, Mestroni L, Priori SG, Saffitz JE, Sanatani S, Shimizu W, van Tintelen JP, Wilde AAM, Zareba W. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Available online. 2019. Accessed 3-8-22.

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