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Genetics of dilated cardiomyopathy

Genetics of dilated cardiomyopathy
Literature review current through: Jan 2024.
This topic last updated: May 17, 2023.

INTRODUCTION — Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and is the most common diagnosis in patients referred for cardiac transplantation. DCM is characterized by dilatation and systolic dysfunction of one or both ventricles. (See "Definition and classification of the cardiomyopathies".)

DCM is classified as idiopathic (idiopathic dilated cardiomyopathy, or IDC) when all usual clinically detectable, except genetic, causes have been excluded. Such detectable causes of DCM include ischemic DCM and a variety of toxic, metabolic, or infectious agents (see "Causes of dilated cardiomyopathy"). Although specialists commonly apply the diagnosis of IDC to DCMs of unknown cause, an etiology is present but undetected.

Family-based studies of first-degree relatives during the 1990s established that familial dilated cardiomyopathy (familial DCM) can be identified in 20 to 35 percent of patients diagnosed with IDC by clinical screening (electrocardiography, echocardiography) of family members. Most familial DCM is transmitted in an autosomal dominant inheritance pattern, although all inheritance patterns have been identified (autosomal recessive, X-linked, and mitochondrial). During the past 20 years, familial DCM genetic studies have identified mutations in more than 30 genes.

Most patients with a genetic basis causing their DCM will have an initial diagnosis of IDC. Given the frequency of familial DCM, evaluation of new IDC cases should include a careful three to four generation family history and clinical screening of first-degree family members as described below.

Developments have dramatically and favorably affected efforts to identify and understand the genetic basis of DCM, including the enormous impact of next generation sequencing (NGS) and the availability of very large databases of exome or genome sequences that can be used as reference sequences in gene discovery programs (eg, the Exome Study Project, Exome Variant Server, the Thousand Genomes Project, the Exome Aggregation Consortium [ExAC], and the Genome Aggregation Database [gnomAD]). Extensive discovery studies over the past 20 years have identified rare variants in numerous genes.

Despite this progress, several challenges remain:

Most genes implicated in familial DCM were identified in studies prior to NGS, where a putatively causal variant identified in a family may have had only a few hundred DNAs sequenced as controls. Now, much larger datasets, such as the ExAC browser of more than 60,000 exome sequences or the gnomAD browser of more than 135,000 exome and genome sequences, have provided new insights regarding variant adjudication that are making enormous contributions to the field.

Some genes were implicated from candidate gene studies that only examined the gene of interest and did not exclude variants in other known, and in many cases, more common DCM genes, raising the question of whether some other genetic cause may have been relevant in the discovery study. In many discovery studies, genome-wide sequencing approaches were not undertaken.

More studies that have utilized NGS have focused only on previously identified genes implicated in DCM ("known" genes), but the sensitivity of any NGS testing of known DCM genes only approximates 40 percent.

Clinical testing has rapidly evolved to large gene panels (30 to 80 or more genes) using NGS methods, although only a fraction of these genes, perhaps 10 to 15, have compelling or robust evidence of Mendelian causality of DCM.

A concern that more than one rare variant in different DCM genes may be relevant for disease causation or earlier presentation in some cases has been raised [1,2], although robust data to support this contention remain limited. One report suggested that more than one-third of genetic DCM cases may have multiple rare variants [3].

This topic will discuss the various phenotypes and genes associated with DCM. The prevalence, diagnosis, and treatment of familial DCM are discussed separately. (See "Familial dilated cardiomyopathy: Prevalence, diagnosis and treatment".)

GENES, PHENOTYPES, AND INHERITANCE — More than 30 genes have been implicated in harboring putative disease-causing rare variants (commonly called mutations) that cause DCM (table 1) [4]. The table is organized according to the estimated proportions of mutations detected in series of patients with familial or nonfamilial DCM.

Most familial DCM is transmitted in an autosomal dominant inheritance pattern, although all inheritance patterns have been identified (autosomal recessive, X-linked, and mitochondrial). The spectrum of inheritance patterns in familial DCM was illustrated by an Italian study that evaluated 350 patients with DCM and 281 of their relatives from 60 families [5]. This study, from a referral population to a specialty clinic, characterized the following subtypes:

Autosomal dominant DCM with normal skeletal muscle examination and histology.

Autosomal recessive DCM (16 percent), with younger age of onset and more rapid progression to death or transplant.

X-linked DCM (10 percent) in males with severe progressive heart failure (HF) associated with mutations of the dystrophin gene.

A form of autosomal dominant DCM (7.7 percent) associated with subclinical skeletal muscle disease with variable levels of serum CK-MM and with dystrophic changes on skeletal muscle biopsy.

Familial DCM associated with conduction defects (2.6 percent).

Rare, unclassifiable forms (7.7 percent).

Genetic evaluation of DCM traditionally was limited for the following reasons:

Pedigrees are often small in familial DCM, presumably due to age-related and/or incomplete penetrance, the impact on reproductive health in women with DCM, and premature death resulting from DCM.

Penetrance is commonly incomplete.

The sensitivity of genetic testing for DCM has been low, ranging from 15 to 25 percent.

The allelic heterogeneity ("private" mutations) common to all DCM genes requires sequencing of all coding regions and near intron/exon boundaries.

Sanger sequencing was slow and expensive, limiting testing to only one or a few genes.

These last three limitations have been largely addressed by the development of next generation sequencing. Genetic testing sensitivity reaches 40 percent with familial DCM. Clinical molecular genetic testing is now commercially available for essentially all of the identified genes mentioned below; the Genetic testing registry and GeneTests websites list genes and laboratories where testing is available in the United States [6-8].

Common phenotypes

Autosomal dominant DCM with or without conduction system disease

DCM without conduction system disease — By far the most common phenotype is DCM without accompanying distinctive features (in common practice, >90 to 95 percent). Most of the genes identified as harboring mutations that cause DCM are in this category. These genes are summarized in the table (table 1).

Sarcomere genes — Abnormalities involving sarcomere protein genes account for approximately 30 percent of cases of familial DCM (table 1) [9]. Mutations have been identified in the genes for beta myosin heavy chain (MYH7), alpha myosin heavy chain (MYH6), cardiac troponin T (TNNT2), titin (TTN), alpha-tropomyosin (TPM1), and cardiac troponin C (TNNC1) [10-13]. Different mutations in these sarcomere genes cause hypertrophic cardiomyopathy. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".)

TTN – Mutations in the TTN gene encoding titin, the largest human protein and a key component of sarcomeric force generation, are the most common known cause of DCM (table 1) [14]. In a study restricted to identification of TTN truncating mutations (mostly nonsense or "stop" mutations, or other mutations that plausibly caused the interruption of production the full titin protein), such mutations were observed in approximately 20 percent of referred populations of idiopathic DCM (25 percent of familial cases and 18 percent of sporadic cases). No unique clinical characteristics have been identified for these truncating mutations but adverse events may occur earlier in men than in women. The role of missense mutations, common among all patient groups, was not addressed in the study. Furthermore, approximately 3 percent of control DNAs also carried TTN truncating variants, raising the question of pathogenicity of even truncating variants. A subsequent exome sequencing study of 17 DCM families identified seven with segregating TTN truncating variants [15]. However, two TTN truncating variants were identified that did not segregate, emphasizing this latter concern.

MYH7 – Mutations in the MYH7 gene encoding beta myosin heavy chain, a key protein of the contractile apparatus, are among the more common causes of DCM (table 1). Discovered initially through a gene mapping and linkage study of a large pedigree with DCM [9], several additional reports (table 1) have shown a wide range of onset, from early to late-adulthood. No particular genotype/phenotype correlations have been identified. Different mutations in the MYH7 gene cause hypertrophic cardiomyopathy [13].

TNNT2 – Mutations in the troponin T gene have been observed to cause DCM in adolescence and in early adulthood and are associated with aggressive disease (table 1) [9]. However, disease onset may occur throughout later adulthood and even at 70 years [16].

Other sarcomere genes – Mutations in a variety of other sarcomeric proteins or proteins associated with the contractile apparatus have been associated with DCM (table 1). In general, no unique, specific, or identifying clinical (phenotypic) characteristics have yet been shown to be associated with these mutations.

Genes beyond the sarcomere

LAMA4 – Mutations in the laminin-alpha 4 (LAMA4) and integrin-linked kinase (ILK) genes affect endothelial cell and cardiomyocyte survival and lead to cardiomyopathy. A screen of patients with severe idiopathic DCM for mutations in these genes identified 3 of 180 with LAMA4 gene mutations and one of 192 with an ILK gene mutation [17].

VCL – A gene that codes for vinculin (VCL) and its isoform, metavinculin, has been identified on chromosome 10q22.1-q23 [18]. Vinculin and metavinculin are protein components of intercalated discs, structures that anchor thin actin filaments and transmit contractile force in the heart [19]. Missense and deletion mutations of this gene result in dysfunction of metavinculin, causing a DCM [20].

ABCC9 – The ATP-dependent potassium channel (KATP) is a functional complex of the sulfonylurea receptor (SUR1 or SUR2) subunit and an inward rectifier potassium channel subunit (Kir6.1 or Kir6.2). Two patients with DCM (one with a positive family history) were found to have mutations (one a frameshift mutation, and one a missense mutation) in the gene ABCC9, which encodes SUR2A [21].

Other nonsarcomeric genes – Other nonsarcomeric genes associated with DCM include PLN encoding phospholamban, a key protein for regulating calcium flux in cardiac contraction; RBM20, an RNA-related protein; and BAG3, a heat shock protein co-chaperone (table 1).

DCM with prominent conduction system disease

LMNA — After isolated DCM, the next most common DCM phenotype encountered is DCM with prominent conduction system disease caused by mutations in LMNA, a gene that encodes lamin A and lamin C, structural proteins of the nuclear lamina. To date, mutations in LMNA are the most commonly identified cause of genetic DCM in cohorts of patients with familial DCM with prevalence ranging from 5 to 8 percent.

Mutations in lamin A/C also cause skeletal muscle abnormalities including Emery-Dreifuss muscular dystrophy, type 1B limb-girdle muscular dystrophy, and LMNA-related congenital muscular dystrophy [22,23]. In some families, LMNA mutations are manifested only as cardiomyopathy, some have only skeletal myopathy, and some have both [22,24,25]. (See "Emery-Dreifuss muscular dystrophy", section on 'Symptoms and signs'.)

In a series of 164 patients with LMNA mutations from 124 families, the median age of the first clinical manifestations was 28 years (interquartile range 8 to 40 years); the first recorded disease manifestation was skeletal myopathy in 52 percent, cardiac in 43 percent, and both in 5 percent of patients [22]. By the end of median 10-year follow-up, 10 percent had isolated skeletal muscle involvement, 28 percent had isolated cardiac involvement, and 62 percent had signs of both. Among patients with cardiac disease, 93 percent had isolated electrical disease, and only 7 percent had structural cardiac disease as the initial cardiac manifestation.    

The onset of LMNA cardiomyopathy usually manifests with heart block (first degree, progressive to second and third degree), supraventricular arrhythmias (atrial flutter, atrial fibrillation), brady-tachy syndrome (sinus node dysfunction [SND]), with progressive ventricular arrhythmias including ventricular tachycardia or ventricular fibrillation. DCM onset can occur at any point in the development of conduction system disease and arrhythmia development, but usually occurs after conduction system disease (and at times years later). Sudden cardiac death is also prominent with LMNA cardiomyopathy, and can occur as the presenting symptom [22,24-32].

Patients with LMNA-associated DCM commonly require a pacemaker. When a familial clustering of pacemakers is detected, especially when associated with DCM, the possibility of LMNA DCM should be strongly considered in the differential diagnosis. In those diagnosed with LMNA DCM, identification of an indication for a pacemaker should always trigger consideration of an implantable cardioverter-defibrillator (ICD), even if the left ventricular ejection fraction does not meet usual criteria for ICD implantation. (See "Familial dilated cardiomyopathy: Prevalence, diagnosis and treatment", section on 'Treatment guidelines'.)

SCN5A — Mutations in SCN5A also have been associated with prominent conduction system disease, but SCN5A cardiomyopathy differs from LMNA cardiomyopathy as some degree of ventricular dysfunction usually accompanies the conduction system disease. Sinoatrial node dysfunction and atrial arrhythmias are common [33-35]. In one report, 27 percent had early features of DCM (mean age at diagnosis 20 years), 38 percent had DCM (mean age at diagnosis 48 years), and 43 percent had atrial fibrillation (mean age at diagnosis 28 years) [35]. In addition to clear familial disease, screening of 156 unrelated patients with apparent idiopathic DCM revealed an SCN5A mutation in four (2.6 percent).

Mutations in SCN5A have also been identified in several other cardiac disorders, including congenital long QT syndrome type 3, the Brugada syndrome, familial atrioventricular conduction block, and familial SND. (See "Congenital long QT syndrome: Pathophysiology and genetics" and "Etiology of atrioventricular block" and "Sinus node dysfunction: Epidemiology, etiology, and natural history" and "Brugada syndrome: Epidemiology and pathogenesis", section on 'SCN5A'.)

Peripartum cardiomyopathy — Data are rapidly emerging that show that peripartum cardiomyopathy is a subset of genetic cardiomyopathy. First, reports in 2010 [36,37] demonstrated this connection. Later work found that TTN, the most common cause of DCM, is also prominent in peripartum cardiomyopathy [38,39]. (See "Peripartum cardiomyopathy: Etiology, clinical manifestations, and diagnosis".)

Other DCM phenotypes — In addition to isolated DCM and DCM with prominent conduction system disease, four other more specific phenotypes have been suggested: DCM with muscular dystrophy, juvenile DCM with a rapid progressive course in male relatives without muscular dystrophy, DCM with segmental hypokinesis of the left ventricle, and DCM with sensorineural hearing loss [40,41]. In addition, other inherited syndromes with systemic manifestations (eg, hereditary hemochromatosis) are associated with cardiomyopathy. (See "Inherited syndromes associated with cardiac disease".)

A familial predisposition to immune-mediated DCM has been suggested, although a heritable gene defect in the HLA region has not been identified [42]. Elevated serum cytokine levels (eg, interleukin-2) and asymptomatic left ventricular enlargement have been demonstrated in some relatives of patients who have DCM [43]. Inherited immune responses and/or circulating neurohumoral factors may influence disease penetrance and/or expression.

X-linked transmission

Dystrophin gene mutations — Familial DCM that is transmitted as an X-linked trait most often results from mutations in the dystrophin gene (Xp21) [44,45]. Most dystrophin mutations produce either Duchenne or Becker muscular dystrophy, both of which are associated with cardiac involvement (see "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis"). In addition, deletions in the 5' muscle promoter of the dystrophin gene can cause a predominant cardiac phenotype [44,46-49].

Skeletal muscle biopsies of individuals with X-linked DCM due to dystrophin deletions demonstrate the classic pathologic changes of Duchenne or Becker dystrophies, but the muscle manifestations may be subclinical. Skeletal muscle, but not cardiac muscle, may have compensatory expression of dystrophin by upregulation of brain and Purkinje cell isoforms [50,51].

Absence of, versus reduction in, dystrophin has been hypothesized to account for the variable dysfunction observed in cardiac compared with skeletal muscle. As an example, one study of a family with X-linked cardiomyopathy, but without skeletal muscle abnormalities, found that all affected family members had a translation-termination mutation (C4148T) in exon 29 of the dystrophin gene [48]. This mutation was associated with a reduction of beta-sarcoglycan and delta-sarcoglycan in the sarcolemma of cardiac, but not skeletal, muscle.

The contribution of these and other loci to idiopathic DCM disease remains unknown. In one series, 5' dystrophin sequences were screened for mutations in a cohort of patients with idiopathic DCM: No mutations were identified [52]. In contrast, a second study of 201 men with a DCM found that 6.5 percent had dystrophin gene defects identified by immunohistochemical and molecular studies [53]. These data indicate that any of a multiplicity of gene defects can account for a proportion of heritable DCM. Immunohistochemical study of various dystrophin domains is important to establish this diagnosis [53].

Barth's syndrome — Barth's syndrome is an X-linked disorder characterized by congenital DCM, short stature, and neutropenia. Affected individuals usually die early in childhood. (See "Inherited syndromes associated with cardiac disease", section on 'Barth syndrome'.)

Autosomal recessive transmission — Alstrom syndrome causes a DCM and hearing impairment in association with cone-rod ocular dystrophy, obesity, and type 2 diabetes [54]. The disorder is due to mutations in the ALMS1 gene on chromosome 2p13 [55,56].

A family with autosomal recessive DCM has been reported to have a mutation in the gene for cardiac troponin I [57]. Other mutations in the troponin I gene have been found to cause hypertrophic cardiomyopathy or restrictive cardiomyopathy. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing" and "Restrictive cardiomyopathies".)

A minority of desminopathy families have autosomal recessive transmission. (See 'Desminopathy' below.)

Cardiomyopathy and sensorineural hearing loss — Many human syndromes exhibit heart and ear abnormalities in association with other organ disease.

Mutations in mitochondrial tRNAs, which have matrilineal inheritance, alter cardiac function and hearing; they are usually associated with encephalopathy, skeletal myopathies, and metabolic abnormalities [58].

A syndrome of juvenile-onset autosomal dominant sensorineural hearing loss and adult-onset DCM is caused by a mutation in the transcriptional activator gene EYA4 (also known as CMD1J) located at 6q23-24 [59]. Early in childhood, hearing is normal, and hearing loss occurs by the second decade; a cardiomyopathy is insidious in onset, with a rapidly progressive clinical course after the age of 40 [60]. Other mutations in this gene can cause hearing loss without cardiomyopathy [59].

Rosenberg syndrome — Rosenberg syndrome causes an X-linked cardiomyopathy and sensorineural hearing loss with hyperuricemia and ataxia.

Desminopathy — A mixture of genetic transmission patterns may occur for certain types of genetic cardiomyopathies, such as desminopathy. Desminopathy is a skeletal and cardiac myopathy caused by mutations in desmin, a type III intermediate filament protein, or alpha B crystallin, a chaperone for desmin. Desmin mutations were found in 1.4 percent of a cohort of 457 patients drawn from a familial DCM registry and a subgroup from a clinical trial [61].

Eighty percent of desminopathy families show an autosomal dominant pattern of inheritance [62]. Six percent of patients appear to have autosomal recessive transmission. Some patients have a combination of desmin and other neuromuscular gene mutations [63].

Desminopathies are also clinically variable, with a quarter of patients presenting with cardiomyopathy [63]. Clinical characteristics include slowly progressive muscle weakness, typically starting with the lower extremities with variable progression to the upper extremities, trunk, neck, and face; dyspnea with restrictive ventilatory defect; and cardiomyopathy, cardiac arrhythmias, or conduction blocks. Test findings include electromyography evidence of myopathy, elevated serum creatinine kinase levels, and amorphous or granular deposits (immunopositive for desmin and dystrophin) in muscle biopsy specimens. Isolated cardiac involvement has also been reported. (See "Overview of electromyography".)

Autoimmune mechanisms — The role of autoimmunity has been implicated, and one study demonstrated antibodies to a variety of cardiac proteins in approximately 30 percent of patients with DCM. These issues are discussed separately. (See "Causes of dilated cardiomyopathy", section on 'Autoimmunity'.)

Genetic testing for familial dilated cardiomyopathy — Clinical genetic testing for DCM is indicated in patients with familial DCM [64,65]. Testing is now available in large panels of genes, which increase testing sensitivity and also decrease cost. Clinicians ordering genetic testing should ensure that all tested patients receive pre- as well as post-test genetic counseling (including discussion of test sensitivity, risks, and benefits) and results interpretation, which may be facilitated by genetic counselors or physicians with appropriate training and experience.

NONFAMILIAL DILATED CARDIOMYOPATHY — DCMs in patients who do not have a known family history and whose relatives are shown by screening clinical studies to have no evidence of any myocardial disease may still have a genetic basis. Whether most nonfamilial disease arises from genetic causes or results from other processes has not been formally tested, although a large multicenter National Institutes of Health-funded study is now underway to test this hypothesis [66]. Guideline documents address these issues, and cardiovascular genetic specialists who deal with the cardiomyopathies are routinely conducting molecular genetic testing for patients who meet formal criteria of idiopathic DCM where all usual clinically detectable causes (except genetic causes) have been ruled out regardless of a positive or negative family history or family screening [64,65].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiomyopathy".)

SUMMARY

Dilated cardiomyopathy (DCM) is characterized by dilatation and systolic dysfunction of one or both ventricles. DCM is categorized as idiopathic (idiopathic dilated cardiomyopathy, or IDC) when all recognized causes have been excluded. (See 'Introduction' above.)

Animal modes of DCM have provided insight into the pathogenesis of this disorder.

Genetic studies of familial dilated cardiomyopathy (FDC) pedigrees have identified mutations in more than 30 autosomal and two X-linked genes. Most FDC follows autosomal dominant inheritance patterns, but autosomal recessive, X-linked and mitochondrial inheritance has been reported. (See 'Genes, phenotypes, and inheritance' above.)

While numerous genes causing FDC have been identified, it is estimated that they account for approximately one-half of the genetic cause of FDC.

The genetic contribution to IDC in those with no evidence of DCM in family members has not yet been formally tested. Most cardiovascular genetics experts who deal with the cardiomyopathies now routinely conduct molecular genetic testing in these patients. (See 'Genes, phenotypes, and inheritance' above and 'Nonfamilial dilated cardiomyopathy' above.)

  1. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol 2013; 10:531.
  2. Cowan JR, Kinnamon DD, Morales A, et al. Multigenic Disease and Bilineal Inheritance in Dilated Cardiomyopathy Is Illustrated in Nonsegregating LMNA Pedigrees. Circ Genom Precis Med 2018; 11:e002038.
  3. Haas J, Frese KS, Peil B, et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J 2015; 36:1123.
  4. Jordan E, Peterson L, Ai T, et al. Evidence-Based Assessment of Genes in Dilated Cardiomyopathy. Circulation 2021; 144:7.
  5. Mestroni L, Rocco C, Gregori D, et al. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J Am Coll Cardiol 1999; 34:181.
  6. http://www.ncbi.nlm.nih.gov/gtr/.
  7. www.ncbi.nlm.nih.gov/sites/GeneTests/review/disease/dilated%20cardiomyopathy?db=genetests&search_param=contains/ (Accessed on August 31, 2009).
  8. www.genetests.org.
  9. Kamisago M, Sharma SD, DePalma SR, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 2000; 343:1688.
  10. Olson TM, Kishimoto NY, Whitby FG, Michels VV. Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. J Mol Cell Cardiol 2001; 33:723.
  11. Li D, Czernuszewicz GZ, Gonzalez O, et al. Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation 2001; 104:2188.
  12. Mogensen J, Murphy RT, Shaw T, et al. Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2004; 44:2033.
  13. Carniel E, Taylor MR, Sinagra G, et al. Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy. Circulation 2005; 112:54.
  14. Herman DS, Lam L, Taylor MR, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 2012; 366:619.
  15. Norton N, Li D, Rampersaud E, et al. Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy. Circ Cardiovasc Genet 2013; 6:144.
  16. Morales A, Pinto JR, Siegfried JD, et al. Late onset sporadic dilated cardiomyopathy caused by a cardiac troponin T mutation. Clin Transl Sci 2010; 3:219.
  17. Knöll R, Postel R, Wang J, et al. Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells. Circulation 2007; 116:515.
  18. Moiseyeva EP, Weller PA, Zhidkova NI, et al. Organization of the human gene encoding the cytoskeletal protein vinculin and the sequence of the vinculin promoter. J Biol Chem 1993; 268:4318.
  19. Maeda M, Holder E, Lowes B, et al. Dilated cardiomyopathy associated with deficiency of the cytoskeletal protein metavinculin. Circulation 1997; 95:17.
  20. Olson TM, Illenberger S, Kishimoto NY, et al. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation 2002; 105:431.
  21. Bienengraeber M, Olson TM, Selivanov VA, et al. ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nat Genet 2004; 36:382.
  22. Peretto G, Di Resta C, Perversi J, et al. Cardiac and Neuromuscular Features of Patients With LMNA-Related Cardiomyopathy. Ann Intern Med 2019; 171:458.
  23. Maggi L, Carboni N, Bernasconi P. Skeletal Muscle Laminopathies: A Review of Clinical and Molecular Features. Cells 2016; 5.
  24. Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999; 341:1715.
  25. Brodsky GL, Muntoni F, Miocic S, et al. Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation 2000; 101:473.
  26. Parks SB, Kushner JD, Nauman D, et al. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am Heart J 2008; 156:161.
  27. Arbustini E, Pilotto A, Repetto A, et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol 2002; 39:981.
  28. Taylor MR, Fain PR, Sinagra G, et al. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 2003; 41:771.
  29. van Tintelen JP, Tio RA, Kerstjens-Frederikse WS, et al. Severe myocardial fibrosis caused by a deletion of the 5' end of the lamin A/C gene. J Am Coll Cardiol 2007; 49:2430.
  30. Kass S, MacRae C, Graber HL, et al. A gene defect that causes conduction system disease and dilated cardiomyopathy maps to chromosome 1p1-1q1. Nat Genet 1994; 7:546.
  31. MacLeod HM, Culley MR, Huber JM, McNally EM. Lamin A/C truncation in dilated cardiomyopathy with conduction disease. BMC Med Genet 2003; 4:4.
  32. Pasotti M, Klersy C, Pilotto A, et al. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol 2008; 52:1250.
  33. Olson TM, Keating MT. Mapping a cardiomyopathy locus to chromosome 3p22-p25. J Clin Invest 1996; 97:528.
  34. McNair WP, Ku L, Taylor MR, et al. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation 2004; 110:2163.
  35. Olson TM, Michels VV, Ballew JD, et al. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA 2005; 293:447.
  36. van Spaendonck-Zwarts KY, van Tintelen JP, van Veldhuisen DJ, et al. Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy. Circulation 2010; 121:2169.
  37. Morales A, Painter T, Li R, et al. Rare variant mutations in pregnancy-associated or peripartum cardiomyopathy. Circulation 2010; 121:2176.
  38. van Spaendonck-Zwarts KY, Posafalvi A, van den Berg MP, et al. Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy. Eur Heart J 2014; 35:2165.
  39. Ware JS, Li J, Mazaika E, et al. Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies. N Engl J Med 2016; 374:233.
  40. Grünig E, Tasman JA, Kücherer H, et al. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol 1998; 31:186.
  41. Gavazzi A, Repetto A, Scelsi L, et al. Evidence-based diagnosis of familial non-X-linked dilated cardiomyopathy. Prevalence, inheritance and characteristics. Eur Heart J 2001; 22:73.
  42. Olson TM, Thibodeau SN, Lundquist PA, et al. Exclusion of a primary gene defect at the HLA locus in familial idiopathic dilated cardiomyopathy. J Med Genet 1995; 32:876.
  43. Marriott JB, Goldman JH, Keeling PJ, et al. Abnormal cytokine profiles in patients with idiopathic dilated cardiomyopathy and their asymptomatic relatives. Heart 1996; 75:287.
  44. Muntoni F, Cau M, Ganau A, et al. Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N Engl J Med 1993; 329:921.
  45. Towbin JA, Hejtmancik JF, Brink P, et al. X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 1993; 87:1854.
  46. Franz WM, Cremer M, Herrmann R, et al. X-linked dilated cardiomyopathy. Novel mutation of the dystrophin gene. Ann N Y Acad Sci 1995; 752:470.
  47. Ortiz-Lopez R, Li H, Su J, et al. Evidence for a dystrophin missense mutation as a cause of X-linked dilated cardiomyopathy. Circulation 1997; 95:2434.
  48. Franz WM, Müller M, Müller OJ, et al. Association of nonsense mutation of dystrophin gene with disruption of sarcoglycan complex in X-linked dilated cardiomyopathy. Lancet 2000; 355:1781.
  49. Bies RD, Maeda M, Roberds SL, et al. A 5' dystrophin duplication mutation causes membrane deficiency of alpha-dystroglycan in a family with X-linked cardiomyopathy. J Mol Cell Cardiol 1997; 29:3175.
  50. Muntoni F, Wilson L, Marrosu G, et al. A mutation in the dystrophin gene selectively affecting dystrophin expression in the heart. J Clin Invest 1995; 96:693.
  51. Nigro G, Politano L, Nigro V, et al. Mutation of dystrophin gene and cardiomyopathy. Neuromuscul Disord 1994; 4:371.
  52. Michels VV, Pastores GM, Moll PP, et al. Dystrophin analysis in idiopathic dilated cardiomyopathy. J Med Genet 1993; 30:955.
  53. Arbustini E, Diegoli M, Morbini P, et al. Prevalence and characteristics of dystrophin defects in adult male patients with dilated cardiomyopathy. J Am Coll Cardiol 2000; 35:1760.
  54. Marshall JD, Bronson RT, Collin GB, et al. New Alström syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med 2005; 165:675.
  55. Collin GB, Marshall JD, Ikeda A, et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nat Genet 2002; 31:74.
  56. Hearn T, Renforth GL, Spalluto C, et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alström syndrome. Nat Genet 2002; 31:79.
  57. Murphy RT, Mogensen J, Shaw A, et al. Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. Lancet 2004; 363:371.
  58. Santorelli FM, Mak SC, El-Schahawi M, et al. Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA(Lys) gene (G8363A). Am J Hum Genet 1996; 58:933.
  59. Schönberger J, Wang L, Shin JT, et al. Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nat Genet 2005; 37:418.
  60. Schönberger J, Levy H, Grünig E, et al. Dilated cardiomyopathy and sensorineural hearing loss: a heritable syndrome that maps to 6q23-24. Circulation 2000; 101:1812.
  61. Taylor MR, Slavov D, Ku L, et al. Prevalence of desmin mutations in dilated cardiomyopathy. Circulation 2007; 115:1244.
  62. Goldfarb LG, Vicart P, Goebel HH, Dalakas MC. Desmin myopathy. Brain 2004; 127:723.
  63. Goldfarb LG, Dalakas MC. Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease. J Clin Invest 2009; 119:1806.
  64. Hershberger RE, Givertz MM, Ho CY, et al. Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2018; 20:899.
  65. Hershberger RE, Givertz MM, Ho CY, et al. Genetic Evaluation of Cardiomyopathy-A Heart Failure Society of America Practice Guideline. J Card Fail 2018; 24:281.
  66. Kinnamon DD, Morales A, Bowen DJ, et al. Toward Genetics-Driven Early Intervention in Dilated Cardiomyopathy: Design and Implementation of the DCM Precision Medicine Study. Circ Cardiovasc Genet 2017; 10.
Topic 4911 Version 24.0

References

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