Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations

doi:10.1016/j.amjcard.2004.03.029

The American Journal of Cardiology

Volume 94, Issue 1, 1 July 2004, Pages 50-54

https://doi.org/10.1016/j.amjcard.2004.03.029 Get rights and content

Abstract

LMNA mutations have been associated with familial or sporadic dilated cardiomyopathy (DC), with or without conduction system disease. We studied the LMNA gene in 67 consecutive patients with DC (18 had familial DC, 17 had possible familial DC, and 32 sporadic DC). From genomic DNA, coding regions of the LMNA gene were amplified by polymerase chain reaction, studied by single-strand conformation polymorphism, and cycle sequenced. Mutations were confirmed by restriction fragment length polymorphism. Two disease-causing mutations were found in families A and B. In family A, a novel R349L mutation was present in the mother and her identical twin daughters. They required cardiac transplantation at 36, 18, and 20 years of age. In family B, the R190W mutation was present in 2 cousins with DC and without conduction system disease (1 had cardiac transplantation at 45 years of age and 1 died suddenly at 46 years of age) and in 2 of their sons. The mothers of the 2 affected patients died due to cardiac causes in their 40s (1 died suddenly). One of the carriers fulfilled diagnostic criteria for isolated left ventricular noncompaction. Our data associated the R349L and R190W mutations in LMNA with severe forms of familial DC. LMNA mutations should be considered in the genetic screening of patients with familial DC without conduction system disease. Isolated left ventricular noncompaction may be part of the phenotypic spectrum of the laminopathies.

Section snippets

Methods

The first 67 patients with DC from different families consecutively referred to our familial cardiomyopathies clinic were included. Fifty were patients with previous cardiac transplantation for idiopathic DC and 17 were patients with idiopathic DC controlled in our heart failure clinics. These patients and their relatives were evaluated by detailed analysis of their medical histories, physical examination, 12-lead electrocardiography, blood analysis, and M-mode, 2-dimensional, and Doppler

Results

Of the 67 index patients, 18 had familial DC, 17 had possible familial DC, and 32 were considered to have sporadic DC. All patients were white. Clinical data of the families have been presented elsewhere.4

Two likely disease-causing mutations were found in 2 different families. Figure 1 shows their respective pedigrees. Clinical and electrocardiographic data are presented in TABLE 1, TABLE 2.

In family A, an abnormal single-strand conformation polymorphic motility was found in exon 6 of 3

Discussion

The most relevant findings of this study were (1) the description of 1 novel and 1 recurrent mutation in the lamin A/C gene associated with severe forms of familial DC and (2) the identification of isolated left ventricular noncompaction in a young carrier of the R190W lamin A/C mutation.

The novel R349L mutation affects a highly conserved residue localized in exon 6, which is in the central rod domain of the lamin A/C gene. Mutations in other residues in this region have been associated with

References (29)

E. Grunig et al.
Frequency and phenotypes of familial dilated cardiomyopathy
J Am Coll Cardiol
(1998)
L. Monserrat et al.
Familial dilated cardiomyopathy in cardiac transplanted patients
Rev Esp Cardiol
(2002)
E. Arbustini et al.
Autosomal dominant dilated cardiomyopathy with atrioventricular blocka lamin A/C defect related disease
J Am Coll Cardiol
(2002)
P.M. Jakobs et al.
Novel lamin A/C mutation in two families with dilated cardiomyopathy and conduction system disease
J Card Fail
(2001)
M.R. Taylor et al.
Natural history of dilated cardiomyopathy due to lamin A/C gene mutations
J Am Coll Cardiol
(2003)
A. De Sandre Giovannoli et al.
Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse
Am J Med Genet
(2002)
G. Novelli et al.
Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C
Am J Med Genet
(2002)
M.K. Baig et al.
Familial DCMcardiac abnormalities are common in asymptomatic relatives and may represent early disease
J Am Coll Cardiol
(1998)
R. Anan et al.
A novel lamin A/C missense mutation in a family with autosomal dominant dilated cardiomyopathy with conduction abnormalities
J Am Coll Cardiol
(2002)
Y. Agmon et al.
Noncompaction of the ventricular myocardium
J Am Soc Echocardiogr
(1999)

F. Ichida et al.

Clinical features of isolated noncompaction of the ventricular myocardiumlong-term clinical course, hemodynamic properties, and genetic background

J Am Coll Cardiol

(1999)

S.B. Bleyl et al.

Neonatal, lethal noncompaction of the left ventricular myocardium is allelic with Barth syndrome

Am J Hum Genet

(1997)

R. Chen et al.

Mutation analysis of the G4.5 gene in patients with isolated left ventricular noncompaction

Mol Genet Metab

(2002)

E. Zambrano et al.

Isolated noncompaction of the ventricular myocardiumclinical and molecular aspects of a rare cardiomyopathy

Lab Invest

(2002)

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Active research of noncompaction cardiomyopathy (NCM) has been going on for more than 30 years. A significant amount of information has been accumulated that is familiar to a much larger number of specialists than in the most recent past. Despite this, numerous issues remain unresolved, ranging from classification (congenital or acquired, nosology or morphological phenotype) to the ongoing search for clear diagnostic criteria that separate NCM from physiological hypertrabecularity and secondary noncompaction myocardium with the background of existing chronic processes. Meanwhile, a high risk of adverse cardiovascular events in a certain group of people with NCM is quite high. These patients need timely and often quite aggressive therapy. This review of sources of scientific and practical information is devoted to the current aspects of the classification, extremely diverse clinical picture, extremely complex genetic and instrumental diagnosis of NCM, and the possibilities of its treatment. The purpose of this review is to analyze current ideas about the controversial problems of noncompaction cardiomyopathy. The material for its preparation is the numerous sources of databases Web Science, PubMed, Google Scholar, eLIBRARY. As a result of their analysis, the authors tried to identify and summarize the main problems of the NCM and identify the ways to resolve them.
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La miocardiopatía dilatada (MCD) es la causa más frecuente de trasplante cardiaco. Se considera que es familiar hasta en el 50% de los casos. Nuestro objetivo es describir los resultados genéticos obtenidos en una cohorte de pacientes con MCD, de los cuales una elevada proporción había acabado en trasplante cardiaco.
Se incluyeron pacientes con MCD a los que se realizó next-generation sequencing (NGS, «secuenciación de nueva generación») de al menos 80 genes relacionados con la enfermedad. Se analizaron retrospectivamente los datos clínicos de los pacientes, la historia familiar y los resultados del estudio genético. En los casos en los que fue posible, se realizó una evaluación de sus familiares de primer grado.
Fueron evaluados 87 pacientes con MCD y 308 familiares de 70 familias distintas. La prevalencia clínica de enfermedad familiar fue del 37% (32 pacientes) y el 44% (38 pacientes) habían precisado un trasplante cardiaco. En 43 pacientes (49%) se encontró al menos una variante relevante, en 25 pacientes (29%) se identificaron variantes de significado incierto y en 19 pacientes (22%) el estudio fue negativo. La mayoría de las mutaciones se encontraron en genes sarcoméricos y la rentabilidad del estudio fue mayor en los pacientes con MCD familiar.
El estudio genético NGS en nuestra población de pacientes con MCD tuvo una elevada rentabilidad, alcanzando el 69% en los casos familiares. El espectro mutacional fue heterogéneo y con frecuencia la identificación de la etiología específica de la enfermedad aportó información pronóstica.
Dilated cardiomyopathy (DCM) is the most frequent cause of heart transplantation. The prevalence of familial disease can reach 50%. Our objective was to describe the genetic basis of DCM in a cohort with a high proportion of transplanted patients.
We included patients with DCM and genetic testing performed using next-generation sequencing (NGS) that included at least 80 genes. Clinical data, family history and genetic results were retrospectively analysed. When possible, assessment of first-degree relatives was carried out.
Eighty-seven DCM patients and 308 relatives from 70 families were evaluated. Clinical prevalence of familial disease was 37% (32 patients). Forty-four percent of patients (38 patients) had required heart transplantation. A relevant variant was found in 43 patients (49%), 25 patients (29%) carried variants of unknown significance and in 19 patients (22%) the study was negative. Most genetic variants were found in sarcomeric genes and the yield of genetic testing was higher in patients with familial DCM.
The yield of genetic testing in our DCM cohort was high, reaching 69% in familial cases. Mutational spectrum was heterogeneous and the identification of the specific aetiology of the disease often provided prognostic information.
Left ventricular noncompaction − Risk stratification and genetic consideration −
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Citation Excerpt :
LVNC, like other forms of inherited cardiomyopathy, is genetically heterogeneous and can be inherited as an autosomal dominant or X-linked recessive disorder. It has been linked to mutations in many genes, including LIM domain binding protein 3 (ZASP), α-dystrobrevin (DTNA), tafazzin (TAZ/G4.5), and those encoding sarcomeric, Z-disc, cytoskeleton proteins and mitochondria (Fig. 2) [9–20]. Disturbance of the NOTCH signaling pathway has been reported to be part of the genetic pathway for LVNC as well (Fig. 3) [21].
Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by two layered structures composed of prominent trabecular meshwork and deep intertrabecular recesses. LVNC was thought to be rare; however, heightened awareness has resulted in an increased detection of the morphological features of LVNC in routine clinical practice especially in the adult population. Although LVNC was classified as an independent primary cardiomyopathy of genetic origin by the American Heart Association in 2006, its definition, diagnostic criteria and clinical implications are still being debated. Clinical manifestations are highly variable, even in the same family, ranging from no symptoms to disabling congestive heart failure, life-threatening arrhythmias, systemic thromboemboli, and sudden cardiac death. Among phenotypic subtypes of LVNC, children with isolated LVNC with normal cardiac function had the best outcomes: children with LVNC and dilated cardiomyopathy had the worst outcomes. Myocardial dysfunction or ventricular arrhythmias are predictors of mortality in adults with LVNC. LVNC, like other forms of inherited cardiomyopathy, is genetically heterogeneous and can be inherited as an autosomal dominant or X-linked recessive disorder. It has been linked to mutations in many genes, including ZASP, TAZ/G4.5, and those encoding sarcomeric, Z-disc, cytoskeleton proteins, and mitochondria. Disturbance of the NOTCH signaling pathway has been reported to be part of genetic pathway for LVNC as well. Although there are an increasing number of reports, genotype-phenotype correlations have been challenging and investigations are ongoing. Patients with mutations are more likely to have major adverse cardiovascular events, further, LV systolic dysfunction in mutation carriers makes them at high risk for cardiac events. Treatments focus on improvement in cardiac function and reduction of mechanical stress in patients with systolic dysfunction and on treatment of arrhythmia and implantation of an automatic implantable cardioverter-defibrillator for prevention of sudden death. Given that 20–40% of cases may be familial, family screening is recommended.
Cardiac Phenotypes, Genetics, and Risks in Familial Noncompaction Cardiomyopathy
2019, Journal of the American College of Cardiology
There is overlap in genetic causes and cardiac features in noncompaction cardiomyopathy (NCCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM).
The goal of this study was to predict phenotype and outcome in relatives according to the clinical features and genotype of NCCM index cases.
Retrospective DNA and cardiac screening of relatives of 113 families from 143 index patients were used to classify NCCM cases according to the cardiac phenotype. These cases were classified as isolated NCCM, NCCM with left ventricular (LV) dilation (DCM), and NCCM with LV hypertrophy (HCM).
In 58 (51%) families, screening identified 73 relatives with NCCM and 34 with DCM or HCM without NCCM. The yield of family screening was higher in families with a mutation (p < 0.001). Fifty-four families had a mutation. Nonpenetrance was observed in 37% of the relatives with a mutation. Index cases were more often symptomatic than affected relatives (p < 0.001). NCCM with DCM (53%) was associated with LV systolic dysfunction (p < 0.001), increased risk for major adverse cardiac events, mutations in the tail of MYH7 (p < 0.001), and DCM without NCCM in relatives (p < 0.001). Isolated NCCM (43%) was associated with a milder course, mutations in the head of MYH7, asymptomatic NCCM (42%) (p = 0.018), and isolated NCCM in relatives (p = 0.004). NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in relatives (p < 0.001).
The phenotype of relatives may be predicted according to the NCCM phenotype and the mutation of index patients. NCCM phenotypes were related to outcome. In this way, clinical and genetic features of index patients may help prediction of outcome in relatives.
Left ventricular non-compaction: What should be known!
2019, Annales de Cardiologie et d'Angeiologie
La non-compaction isolée du ventricule gauche (NCVG) est une cardiomyopathie congénitale rare résultant de l’arrêt de l’embryogenèse normale du myocarde. Sa principale caractéristique anatomique est l’existence de trabéculations ventriculaires myocardiques nombreuses et profondes, en général, localisées au niveau de l’apex du ventricule gauche. Le diagnostic repose sur l’échocardiographie et l’imagerie par résonance magnétique (IRM), et peut être difficile dans les formes limites. La présentation clinique et le pronostique sont très variables. Les formes familiales ne sont pas rares, rendant obligatoire un dépistage familial.
Isolated non-compaction of the left ventricle (NCVG) is a rare congenital cardiomyopathy resulting from the shutdown of normal embryogenesis of the myocardium. Its main feature is the existence of many deep heart-related ventricular trabeculations, generally located at the level of the apex of the left ventricle. Diagnosis is based on echocardiography and magnetic resonance imaging (MRI), and may be difficult in the atypical forms. The clinical presentation and the prognosis are very variable. Familial forms are not rare, ordering a family screening.
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^☆: This work was supported by grants from the European Community (FEDER 97/2077) and Xunta de Galicia, Spain (PGIDT 00PXI13401PR).

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Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations☆

Abstract

Section snippets

Methods

Results

Discussion

J Am Coll Cardiol

Rev Esp Cardiol

J Am Coll Cardiol

J Card Fail

J Am Coll Cardiol

Am J Med Genet

Am J Med Genet

J Am Coll Cardiol

J Am Coll Cardiol

J Am Soc Echocardiogr

J Am Coll Cardiol

Am J Hum Genet

Mol Genet Metab

Lab Invest