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Research Article
Originally Published 1 June 2010
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The Importance of Genetic Counseling, DNA Diagnostics, and Cardiologic Family Screening in Left Ventricular Noncompaction Cardiomyopathy

Yvonne M. Hoedemaekers, MD, Kadir Caliskan, MD, Michelle Michels, MD, Ingrid Frohn-Mulder, MD, Jasper J. van der Smagt, MD, Judith E. Phefferkorn, RN, Marja W. Wessels, MD, PhD, Folkert J. ten Cate, MD, PhD, Eric J.G. Sijbrands, MD, PhD, Dennis Dooijes, PhD, and Danielle F. Majoor-Krakauer, MD, PhDAuthor Info & Affiliations
Circulation: Cardiovascular Genetics
Volume 3, Number 3
https://doi.org/10.1161/CIRCGENETICS.109.903898
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Abstract

Background—

Left ventricular (LV) noncompaction (LVNC) is a distinct cardiomyopathy featuring a thickened bilayered LV wall consisting of a thick endocardial layer with prominent intertrabecular recesses with a thin, compact epicardial layer. Similar to hypertrophic and dilated cardiomyopathy, LVNC is genetically heterogeneous and was recently associated with mutations in sarcomere genes. To contribute to the genetic classification for LVNC, a systematic cardiological family study was performed in a cohort of 58 consecutively diagnosed and molecularly screened patients with isolated LVNC (49 adults and 9 children).

Methods and Results—

Combined molecular testing and cardiological family screening revealed that 67%of LVNC is genetic. Cardiological screening with electrocardiography and echocardiography of 194 relatives from 50 unrelated LVNC probands revealed familial cardiomyopathy in 32 families (64%), including LVNC, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Sixty-three percent of the relatives newly diagnosed with cardiomyopathy were asymptomatic. Of 17 asymptomatic relatives with a mutation, 9 had noncompaction cardiomyopathy. In 8 carriers, nonpenetrance was observed. This may explain that 44% (14 of 32) of familial disease remained undetected by ascertainment of family history before cardiological family screening. The molecular screening of 17 genes identified mutations in 11 genes in 41% (23 of 56) tested probands, 35% (17 of 48) adults and 6 of 8 children. In 18 families, single mutations were transmitted in an autosomal dominant mode. Two adults and 2 children were compound or double heterozygous for 2 different mutations. One adult proband had 3 mutations. In 50% (16 of 32) of familial LVNC, the genetic defect remained inconclusive.

Conclusion—

LVNC is predominantly a genetic cardiomyopathy with variable presentation ranging from asymptomatic to severe. Accordingly, the diagnosis of LVNC requires genetic counseling, DNA diagnostics, and cardiological family screening.
Left ventricular noncompaction (LVNC) is a cardiomyopathy featuring segmental thickening of the LV wall with a thin, compact, epicardial layer and an excessively thickened endocardial layer with prominent, deep intertrabecular recesses. Application of the echocardiographic diagnostic criteria for LVNC as postulated by Jenni et al1 together with advances in cardiological imaging techniques have enhanced awareness and diagnosis of LVNC. Consequently, LVNC was incorporated in the most recent classification of cardiomyopathies as a genetic disease.2
Clinical Perspective on p 239
Prevalence of LVNC, estimated from retrospective studies, ranges from 4.5 to 26 per 10 000 adult patients referred for echocardiography.3–5 LVNC was diagnosed in 3.7% of patients with an LV ejection fraction ≤45%, suggesting that LVNC might not be a rare disorder in adults.5 In pediatric series, LVNC is the most frequent cardiomyopathy after dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), comprising ≈9% of childhood cardiomyopathies.6 Clinical features include heart failure, arrhythmias, and thromboembolic events.3,7 Familial disease was estimated to occur in ≈18% to 50% of adults with isolated LVNC, mostly consistent with an autosomal dominant mode of inheritance.3,8–13Intrafamilial phenotypic variability, including LVNC, HCM, and DCM, suggests that these cardiomyopathies may be part of a broader cardiomyopathy spectrum. The first association of isolated LVNC with mutations in the cardiac β-myosin heavy chain gene (MYH7) was reported in 2 unrelated Dutch families.14 LVNC also was associated with mutations in other sarcomere genes (cardiac troponin T [TNNT2] and cardiac α-actin [ACTC1]) in 17% of 63 adult patients with LVNC.15–17 Linking LVNC to defects in the MYH7, TNNT2, and ACTC1 genes encoding sarcomere components that are frequent causes of HCM and DCM, provides additional evidence for a shared genetic susceptibility to LVNC, HCM, and DCM. Reports of mutations in lamin A/C (LMNA), α-dystrobrevin (DTNA), cypher/ZASP or lim domain binding 3 (LDB3), and sodium channel type Vα (SCN5A) expanded the genetic spectrum of LVNC.18–20 Other genetic causes, characteristically in complex childhood LVNC with congenital heart defects or (metabolic) syndromes, include Barth syndrome with mutations in the Tafazzin gene (TAZ)21,22 and rare chromosomal defects and loci.23–30 The present study investigates the heredity of LVNC, the spectrum of clinical features, and the genetic causes of LVNC by combining systematic cardiological family studies with extensive molecular analysis.

Methods

Study Population

The study comprised 58 unrelated patients with isolated LVNC; 53 were diagnosed consecutively from 2005 to 2008 in the cardiogenetics clinic of the Erasmus MC in Rotterdam and 5 in other tertiary referral centers in The Netherlands. All fulfilled the 4 echocardiographic diagnostic Jenni criteria: (1) excessively thickened LV myocardial wall with a 2-layered structure comprising a compact epicardial layer (C) and a noncompacted endocardial layer (NC) of prominent trabeculations and deep intertrabecular recesses; (2) maximal end-systolic ratio of noncompacted to compacted wall >2 measured at the parasternal short axis; (3) color Doppler evidence of deep perfused intertrabecular recesses; and (4) absence of coexisting cardiac anomalies.1 Subsequently, all patients were referred for genetic counseling and DNA analysis and to initiate family studies, as depicted in Figure 1.
Figure 1. Flow chart for LVNC family screening.

Cardiological Family Study and Molecular Analysis

Family studies were initiated by ascertainment of family histories and inviting initially first- and second-degree relatives for genetic counseling. When possible, “cascade screening” for cardiomyopathies was pursued. Participation of 50 families of probands allowed inclusion of 194 relatives (Table 1). Relatives were referred for cardiological screening unless a familial pathogenic mutation had been detected. In that case, only mutation-positive individuals and relatives refusing DNA testing were examined cardiologically. Informed consent was requested to review medical records from 31 relatives who had cardiological examinations in other hospitals. Similarly, information was retrieved from the medical records of 13 deceased relatives reported to be affected. Details of the family studies of the probands identified with a genetic defect are presented in the Data Supplement.
Table 1. Descriptives of the LVNC Family Study
 TotalMenAge of Onset/Screening Mean Years±SD (Range)WomenAge of Onset/Screening Mean Years±SD (Range)
Probands583039±17 (0 to 63)2837±19 (0 to 66)
    Adults492644±12 (19 to 63)2343±13 (19 to 66)
    Children947±8 (0 to 17)56±6 (0 to 16)
Participating relatives1948941±21 (0 to 77)10543±20 (0 to 78)
    Parents402055±15 (23 to 74)2056±15 (23 to 78)
    Siblings642738±18 (3 to 66)3743±17 (0 to 71)
    Children412223±15 (0 to 56)1933±15 (11 to 47)
    Second-degree relatives431851±19 (15 to 76)2648±21 (6 to 74)
    Third-degree and more distant relatives6238±1 (37 to 39)441±13 (5 to 55)

Cardiological Family Study

Cardiological screening of relatives was performed by 2 cardiologists (K.C. and M.M.) and included a review of the medical history, physical examination, electrocardiography (Mortara Portrait, Milwaukee, Wis), and 2-dimensional echocardiography (iE33 system with a S5–1 transducer; Philips Medical Systems, Best, The Netherlands). If the imaging quality was poor, especially at LV apical or midventricular walls, MRI (1.5-T scanner; Signa CV/l, GE Medical systems, Milwaukee, Wis) was performed (n=26). Measuring the maximal NC and C with electronic calipers in end-systolic parasternal short-axis or apical 4-chamber view assessed extent and severity of noncompaction. Relatives were diagnosed with LVNC when complying with the Jenni criteria and were diagnosed with DCM or HCM when meeting the current definitions.31 When the ECG and echocardiogram were normal in relatives, LVNC or another cardiomyopathy was excluded. Other cardiological findings observed in relatives possibly associated with cardiomyopathy included ECG with pathological Q waves (>40 ms or >25% of R waves in at least 2 leads), LV hypertrophy, complete bundle-branch block, other intraventricular conduction, or repolarization abnormalities.

Molecular Study

DNA analysis in 56 probands was performed at the Department of Clinical Genetics and consisted of direct sequencing of all coding regions and intron-exon boundaries of the following genes: MYH7, myosin binding protein C (MYBPC3), cardiac troponin C (TNNC1), TNNT2, cardiac troponin I (TNNI3), cardiac-regulatory myosin light chain (MYL2), cardiac-essential myosin light chain (MYL3), ACTC1, α-tropomyosin (TPM1), cysteine- and glycine-rich protein (CSRP3), theletonin (TCAP), calsequestrin (CASQ2), calreticulin (CALR3), phospholamban (PLN), TAZ, LDB3, and LMNA. One proband declined DNA analysis, and no DNA was available from 1 patient who died at 11 days of age. The parents of this patient were cardiologically unaffected and did not have a mutation.
The mutations previously associated with cardiomyopathy (LVNC or HCM) were regarded as pathogenic. Novel mutations were considered to be pathogenic when they were truncating, splice-site, or de novo mutations or if they fulfilled the following 3 criteria: (1) segregation with disease in a family, (2) absence on 384 ethnically matched healthy control chromosomes, and (3) likely pathogenic according to prediction software (SIFT and PolyPhen).32 DNA variants not fulfilling these criteria were considered unclassified variants.

Statistics

Statistical analyses were performed with SPSS for Windows 15.0 (SPSS Inc, Chicago, Ill). Unpaired Student t test analysis was used for continuous variables. Descriptive data for continuous variables were presented as mean±1 SD. χ2 analysis was used for categorical variables, and P values <0.05 were considered to be significant. The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.

Results

The cardiological screening of relatives and the molecular analysis of probands and relatives combined showed that 67% (39 of 58) of LVNC is genetic (Table 2). The cardiological family study identified 64% (32 of 50) of isolated LVNC as familial. Genetic defects were identified in 50% (16 of 32) of cardiologically confirmed familial LVNC. In 50% (16 of 32) of familial disease, the genetic defect remained unknown. With extensive DNA screening, we found a mutation in 41% (23 of 56) of all tested probands. These results clearly indicate the importance of combining cardiological family screening for cardiomyopathy with genetic testing of patients with LVNC.
Table 2. Cardiological Family Studies and Genotyping of 58 LVNC Probands
ProbandCardiological Family ScreeningTotal
PositiveDe NovoInconclusiveNot Performed
With mutation16*1*3*3*23
Without mutation15* 13533
Without DNA analysis1* 1 2
Total32 18†858
*
Genetic LVNC (total 39).
†
Including the family of the de novo proband.
Family histories reported by probands before DNA testing and cardiological family studies were performed failed to identify 44% (14 of 32) of familial disease. Only 9 (53%) of the 17 adult patients with a mutation reported familial disease before DNA testing and cardiological family evaluation. Familial disease was correctly reported by 8 of 14 (57%) adults without a mutation and by none of the parents of children with LVNC. Mutations were observed in 6 of 8 children with LVNC and in 17 of 48 (35%) of adult probands. LVNC was associated with defects in 6 sarcomere, 2 Ca2+-handling, and the LMNA, LDB3, and TAZ genes in this study. Mutations in sarcomere genes, in particular in MYH7, were the most frequent genetic defects: 9 of 57 adults and 2 of 9 children (Data Supplement; 1 through 9 and 18 and 19). None of the MYH7 mutation carriers had neuromuscular symptoms. Eighteen (32%) probands (14 adults and 4 children) had a single mutation consistent with an autosomal dominant mode of inheritance. Two de novo mutations were observed: 1 in the asymptomatic father of an affected newborn and 1 in a young patient (Data Supplement; 20 and 21). Multiple pathogenic mutations occurred in 9% (5 of 56) of the probands. Two (22%) children (diagnosed at age 4 months and 7 years) had, respectively, mutations in TNNI3 and TPM1 and 2 different MYBPC3 mutations (Data Supplement; 22 and 23;Figure 2). Complex genotypes in adults constituted, respectively, of mutations TNNT2-LDB3 and LMNA-LDB3. One adult proband had 2 TNNT2 mutations and a CASQ2 mutation. In 5 families, unclassified variants were observed. Family studies are ongoing to determine the segregation in families and the phenotypic effect of multiple mutations or unclassified variants, especially in families where affected relatives were observed with single mutations (Data Supplement; 14, 16, and 22).
Figure 2. MYBPC3 p.Gly148Arg and c. 2373dupG mutations in 1 family. Compound heterozygosity for 2 different MYBPC3 mutations in a patient with LVNC diagnosed at age 7 years from a family where 1 grandparent was previously diagnosed with HCM (Data Supplement; 23). Family studies identified a spectrum of cardiomyopathies: The asymptomatic parents were carriers, LVNC in the father and HCM in the paternal grandfather associated with the p.Gly148Arg mutation, and HCM in the maternal grandfather associated with c. 2373dupG. Arrow indicates the proband; dagger, deceased. CVA indicates cerebrovascular accident; ND, not determined (ie, no cardiologic and molecular testing); SIDS, sudden infant death syndrome; CoAo, coarctation of the aorta; and HTX, heart transplant.
DNA analysis was performed in 61 relatives from 20 families, confirming previous clinical diagnosis of 16 relatives: 12 with LVNC, 2 with HCM, and 2 with DCM. Four symptomatic relatives (presenting with palpitations, fatigue, and shortness of breath) had a mutation and were diagnosed with LVNC by subsequent cardiological exams. Predictive DNA testing identified a mutation in 49% (17 of 41) asymptomatic relatives. Cardiological evaluation revealed that 53% (9 of 17) of the asymptomatic carriers had LVNC and 8 carriers showed nonpenetrance. Results of DNA analysis in relatives endorsed the pathogenicity of the mutation in 17 families. In 3 families with mutations, only unaffected carriers were identified; in 3 families, no cardiological or DNA family studies have been performed (Table 2).

Cardiological Studies

There was no difference in age at diagnosis in adult probands with respect to gender (P=0.4), between adults with 1 or multiple mutations and those without a mutation (P=0.4), or between the probands and affected relatives (P=0.2). In families with a mutation, unaffected adult carriers of a mutation were approximately the same age as the affected carriers (P=0.2). Fifty-six percent of unaffected carriers were older than 40 years, indicating nondependent or age-dependent penetrance of LVNC.
Similar proportions of adult probands with a single mutation and without a mutation were asymptomatic when diagnosed (29% and 16%; P=0.3;Table 3). All adult patients with multiple mutations presented with New York Heart Association class II and III. These differences cannot be attributed to a selection bias because clinical diagnosis of LVNC preceded DNA testing.
Table 3. Cardiological Features in LVNC Families
 Mutation*No Mutation*
 Probands (23)Relatives (39)Probands (35)Relatives (49)
 Adult (17)Children (6)Affected (34)Other† (5)Adult (32)Children (3)Affected (35)Other† (14)
Age±SD, y41±116±641±2143±1546±136±1043±1548±16
Men82212193158
Presentation        
    Asymptomatic4 2533 2414
    Heart failure665 1826 
    Arrhythmias5   6111
    Thromboembolism1   3 1 
    Other‡1 2 3 1 
NYHA I5 2125 2415
    II7 10119 9 
    III5 2 8   
    IV        
NC/C ratio ≧217 25 32 22 
NC/C ratio 1.0 to 1.9   3   9
ECG abnormal   1   8
    LVH1 4 4  9
    Abnormal repolarization4   8   
    Abnormal Q1 1 1  1
    Bundle-branch block4   9 2 
    AV block  4     
    T-wave inversion1 1 4 1 
Diagnosis        
    LVNC17625 32322 
    HCM  2   3 
    DCM  6   9 
    Congestive CM  1   1 
Family history of CM§90  80  
Familial screening‖155  273  
Familial CM134  142  
Congenital heart defect in relative22  31  
NYHA indicates New York Heart Association classification; NC/C ratio, ratio of noncompacted to compacted wall; LVH, left ventricular hypertrophy; and CM, cardiomyopathy.
*
Families with and without mutation.
†
Other includes NC/C ratio between 1.0 and 1.9 and/or ECG anomalies.
‡
Chest pain (n=4), enlarged heart on x-ray, preoperative screening, prenatal sonography, and cardiac screening before Ritalin use.
§
Before cardiological family studies.
‖
Cardiological screening/DNA analysis.
Ebstein malformation, Fallot tetralogy, atrial septal defect type II and ventricular septal defect, or aortic coarctation in 4 families with a mutation. Valvular pulmonic stenosis; atrial septal defect type II, ventricular septal defect, or pulmonic atresia; or patent ductus arteriosus and aortic coarctation in 4 families without mutation.
In 9 children, LVNC was diagnosed: in 4 before age 1 year, in 3 between 1 to 10 years, and in 2 between 10 and 18 years. The 2 children with multiple mutations were severely affected with cerebral infarctions, and 1 had a heart transplant at age 7 years (Figure 2). All the children were the first in their families to be diagnosed with cardiomyopathy; cardiological screening and DNA testing indicated familial LVNC in 89% (8 of 9) of their families; LVNC was diagnosed in 3 of 17 (18%) parents (as illustrated in Figure 3); and 3 of 15 (20%) were unaffected carriers.
Figure 3. Cardiac MRI (A) and echocardiogram (B) illustrating a 2-layered myocardium with prominent intertrabecular recesses in the asymptomatic father with an MYBPC3 mutation (Figure 2).
In total, cardiological screening was performed in 145 first-degree, 43 second-degree, and 6 more distantly related relatives (Table 1). Of the 69 (35%) relatives diagnosed with cardiomyopathy 47 had LVNC, 5 had HCM, 15 DCM, and 2 congestive CM (Table 3). The majority (63%) of the relatives diagnosed with cardiomyopathy was asymptomatic. There was no significant difference in severe complications in affected relatives (heart failure, arrhythmia and thromboembolic events) in families without and families with a mutation (23% versus 13%; OR, 2.01; P=0.36). Two large families without mutation had recurrence of a severe phenotype; affected relatives in these families had been diagnosed prior to this study.
In 34% (11 of 32) of familial disease, familial aggregation of LVNC, HCM, and DCM was observed. HCM and/or DCM was diagnosed in 4 families with a mutation (Data Supplement; 8, 10, 16, and 23;Figure 2) and in 7 families without a mutation (Table 3).
In 7 families, congenital heart malformations were diagnosed. In 1 family with an MYH7 mutation, LVNC was associated with Ebstein anomaly, and in 2 families with MYBPC3 mutations, 1 relative with the mutation had Fallot tetralogy without LVNC and 1 had an aortic coarctation but did not have a DNA test (Data Supplement; 1, 10, and 22; Figure 2). In 3 families without a mutation, LVNC occurred together with valvular pulmonic stenosis, ventricular septal defect, atrial septal defect type II, pulmonic atresia, patent ductus arteriosus, or aortic coarctation in 6 relatives.

Discussion

The approach of this study was to combine cardiological family studies with extensive genetic testing to establish a genetic classification of LVNC. The results showed that isolated LVNC is predominantly (67%) a genetic condition, including HCM and DCM in 11 families (34%). The molecular screening of a large number of genes in this study allowed expanding the genetic spectrum of LVNC with novel genetic defects.
Genetic defects were identified in 41% of all patients and in 50% (16 of 32) of the cardiologically confirmed familial forms and consisted of 1 or more mutations in 11 different genes, indicating that further studies are needed to find causes for the remaining familial forms of LVNC. Molecular diagnosis of LVNC is important because it offers reliable identification of asymptomatic relatives at risk. In the absence of an identified genetic cause for LVNC, or when relatives decline DNA testing, cardiological screening remains the appropriate method to identify familial disease.
The proportion of familial disease in this study is higher than reported previously (18% to 50%) by studies investigating the prevalence of genetic defects in adult patients or ascertaining family histories of cardiomyopathy.3,8–13 The systematic cardiological family screening showed that the majority (63%) of the affected relatives were asymptomatic, explaining that family histories without cardiological family studies failed to identify 44% of familial disease. Intrafamilial variability and incomplete penetrance, including asymptomatic disease, as well as small family size, may contribute to underestimation of familial disease. Therefore, cardiological evaluation of at-risk relatives of all patients with LVNC is recommended to enhance detection of familial disease, in accordance with the current expert consensus for family screening in HCM.31 Familial screening for cardiomyopathies is important because early diagnosis in relatives may prevent severe complications. Nevertheless, predictive DNA testing and cardiological evaluation should only take place after relatives have been well informed about possible medical benefits of early diagnosis, including suitable treatment and lifestyle recommendations as well as psychological and socioeconomic consequences of predictive testing (particularly in countries where genetic discrimination by insurance companies or employers is not prohibited).
Similar to other familial cardiomyopathies, familial LVNC showed intrafamilial phenotypic variability, including HCM and DCM and reduced penetrance (ie, clinical symptoms not expressed or expressed to a lesser degree in some persons with the familial mutation).3,12,33,34 In this study, nonpenetrance was observed in 8 relatives with a mutation ranging in age from 12 to 72 years. The risk of developing a cardiomyopathy in unaffected carriers is currently unknown and late onset cannot be excluded. Therefore, the implications of nonpenetrance include pursuing cardiological follow-up of unaffected relatives (as depicted in Figure 1). Nonpenetrance of LVNC calls for the continuation of cardiological surveillance of unaffected carriers. For families in which the genetic defect is unknown, continuation of cardiological follow-up of unaffected relatives and of family screening remains recommended until more families can be genotyped and the correct risk status of relatives can be established. Improved imaging by echocardiography and cardiac MRI has enhanced diagnosis and awareness of LVNC. However, establishing the extent to which physiological trabeculations are pathological remains difficult.35
Mutations in the sarcomere genes were found in 6 of 8 affected infants tested and in 17 of 48 adult probands. Although the number of children included in this study is too small to draw conclusions on the cause of childhood disease, molecular testing of sarcomere genes and systemic cardiological evaluation of first-degree relatives are recommended in early onset LVNC, especially in absence of dysmorphic features or metabolic defects. Congenital heart malformations in patients with LVNC should not refer from analyzing sarcomere genes. Our results endorse that co-occurrence of LVNC and congenital heart defects with and without sarcomere gene defect are not rare, warranting careful evaluation of the validity of the fourth of the Jenni diagnostic criteria.15,17,36–38
Two severely affected children and 3 adults were compound/double heterozygous, indicating that multiple mutations seem not to be significantly more prevalent in LVNC (22%) than in HCM (7%) (P=0.15).39 In HCM, double heterozygosity for truncating sarcomere mutations have been associated with severe congenital forms of HCM, inherited in an autosomal recessive mode.40–42 In this study, double mutations also were observed in adults with LVNC. The complex genetic defects in adults involved the combination of a sarcomere gene with another gene, suggesting that 2 sarcomere mutations may cause a more severe phenotype than the combination of a sarcomere mutation and a nonsarcomere mutation. The epigenic effect of multiple mutations may depend on the specific defects involved. Further studies are needed to investigate the role of additional mutations and determine whether they play a role in the phenotypic variability.
For now, the evidence that sarcomere defects are an important cause for LVNC, together with the occurrence of LVNC, HCM, and DCM within families, suggests that these cardiomyopathies represent phenotypic variability within a spectrum and thus require comparable approach with respect to family screening.
The results of cardiological follow-up of families will help to understand the natural history of LVNC, to determine whether LVNC represents a congenital endomyocardial defect or may develop later in life, and eventually to attain recommendations for follow-up of relatives on the basis of accurate risk classification.43 The perspective of new studies investigating modifying genetic effects or genome-environment interactions to explain variability and age-dependent penetrance of this phenotype is challenging.

Acknowledgments

We are grateful to the families for their participation and to R.T. van Domburg for support in the statistical analysis.

Clinical Perspective

In left ventricular (LV) noncompaction cardiomyopathy (LVNC), part of the LV wall is thickened and bilayered, consisting of a thick endocardial layer with prominent intertrabecular recesses and a thin, compact epicardial layer. To investigate the genetics of LVNC, we performed systematic family screening and extensive molecular testing of 58 consecutively diagnosed LVNC probands (49 adults and 9 children). This combined approach showed that 67% of LVNC is genetic in origin. In 64% of the probands, familial disease was demonstrated by screening 194 first- and second-degree relatives with electrocardiography and echocardiography. The majority (63%) of the relatives diagnosed with LVNC was asymptomatic, including 9 relatives with a mutation. Presymptomatic DNA testing also identified 8 unaffected (without the cardiac phenotype) carriers, explaining why many probands were initially unaware of familial disease. The molecular screening for mutations in 17 genes identified mutations in 11 genes in 41% of the probands (17 adults and 6 children). Most mutations were transmitted in an autosomal dominant mode. Two adults and 2 children were compound or double heterozygous for 2 different mutations. One adult proband had 3 mutations. In half of familial LVNC, the genetic defect remained inconclusive. These results show that LVNC is predominantly a genetic cardiomyopathy with variable clinical presentation ranging from asymptomatic to severe manifestations. Accordingly, the diagnosis of LVNC requires genetic counseling, DNA diagnostics, and echocardiographic family screening.

Supplemental Material

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Published In

Go to Circulation: Cardiovascular Genetics
Circulation: Cardiovascular Genetics
Volume 3 • Number 3 • June 2010
Pages: 232 - 239

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© 2010 American Heart Association, Inc.

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History

Received: 30 August 2009
Accepted: 12 April 2010
Published online: 1 June 2010
Published in print: June 2010

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Keywords

  1. noncompaction
  2. cardiomyopathy
  3. family study
  4. genetics
  5. hypertrophy
  6. ventricles

Subjects

  1. Cardiomyopathy
  2. Diagnostic Testing
  3. Genetics

Authors

Affiliations

Yvonne M. Hoedemaekers, MD
From the Departments of Clinical Genetics (Y.M.H., J.E.P., M.W.W., D.D., D.F.M.-K.), Cardiology (K.C., M.M., F.J.t.C.), Pediatric Cardiology (I.F.-M.), and Internal Medicine (E.J.G.S.), Erasmus MC, Rotterdam, The Netherlands; and the Department of Medical Genetics (J.J.v.d.S.), University Medical Centre, Utrecht, The Netherlands.
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Kadir Caliskan, MD
From the Departments of Clinical Genetics (Y.M.H., J.E.P., M.W.W., D.D., D.F.M.-K.), Cardiology (K.C., M.M., F.J.t.C.), Pediatric Cardiology (I.F.-M.), and Internal Medicine (E.J.G.S.), Erasmus MC, Rotterdam, The Netherlands; and the Department of Medical Genetics (J.J.v.d.S.), University Medical Centre, Utrecht, The Netherlands.
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Michelle Michels, MD
From the Departments of Clinical Genetics (Y.M.H., J.E.P., M.W.W., D.D., D.F.M.-K.), Cardiology (K.C., M.M., F.J.t.C.), Pediatric Cardiology (I.F.-M.), and Internal Medicine (E.J.G.S.), Erasmus MC, Rotterdam, The Netherlands; and the Department of Medical Genetics (J.J.v.d.S.), University Medical Centre, Utrecht, The Netherlands.
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Ingrid Frohn-Mulder, MD
From the Departments of Clinical Genetics (Y.M.H., J.E.P., M.W.W., D.D., D.F.M.-K.), Cardiology (K.C., M.M., F.J.t.C.), Pediatric Cardiology (I.F.-M.), and Internal Medicine (E.J.G.S.), Erasmus MC, Rotterdam, The Netherlands; and the Department of Medical Genetics (J.J.v.d.S.), University Medical Centre, Utrecht, The Netherlands.
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Jasper J. van der Smagt, MD
From the Departments of Clinical Genetics (Y.M.H., J.E.P., M.W.W., D.D., D.F.M.-K.), Cardiology (K.C., M.M., F.J.t.C.), Pediatric Cardiology (I.F.-M.), and Internal Medicine (E.J.G.S.), Erasmus MC, Rotterdam, The Netherlands; and the Department of Medical Genetics (J.J.v.d.S.), University Medical Centre, Utrecht, The Netherlands.
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Judith E. Phefferkorn, RN
From the Departments of Clinical Genetics (Y.M.H., J.E.P., M.W.W., D.D., D.F.M.-K.), Cardiology (K.C., M.M., F.J.t.C.), Pediatric Cardiology (I.F.-M.), and Internal Medicine (E.J.G.S.), Erasmus MC, Rotterdam, The Netherlands; and the Department of Medical Genetics (J.J.v.d.S.), University Medical Centre, Utrecht, The Netherlands.
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Marja W. Wessels, MD, PhD
From the Departments of Clinical Genetics (Y.M.H., J.E.P., M.W.W., D.D., D.F.M.-K.), Cardiology (K.C., M.M., F.J.t.C.), Pediatric Cardiology (I.F.-M.), and Internal Medicine (E.J.G.S.), Erasmus MC, Rotterdam, The Netherlands; and the Department of Medical Genetics (J.J.v.d.S.), University Medical Centre, Utrecht, The Netherlands.
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Folkert J. ten Cate, MD, PhD
From the Departments of Clinical Genetics (Y.M.H., J.E.P., M.W.W., D.D., D.F.M.-K.), Cardiology (K.C., M.M., F.J.t.C.), Pediatric Cardiology (I.F.-M.), and Internal Medicine (E.J.G.S.), Erasmus MC, Rotterdam, The Netherlands; and the Department of Medical Genetics (J.J.v.d.S.), University Medical Centre, Utrecht, The Netherlands.
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Eric J.G. Sijbrands, MD, PhD
From the Departments of Clinical Genetics (Y.M.H., J.E.P., M.W.W., D.D., D.F.M.-K.), Cardiology (K.C., M.M., F.J.t.C.), Pediatric Cardiology (I.F.-M.), and Internal Medicine (E.J.G.S.), Erasmus MC, Rotterdam, The Netherlands; and the Department of Medical Genetics (J.J.v.d.S.), University Medical Centre, Utrecht, The Netherlands.
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Dennis Dooijes, PhD
From the Departments of Clinical Genetics (Y.M.H., J.E.P., M.W.W., D.D., D.F.M.-K.), Cardiology (K.C., M.M., F.J.t.C.), Pediatric Cardiology (I.F.-M.), and Internal Medicine (E.J.G.S.), Erasmus MC, Rotterdam, The Netherlands; and the Department of Medical Genetics (J.J.v.d.S.), University Medical Centre, Utrecht, The Netherlands.
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Danielle F. Majoor-Krakauer, MD, PhD
From the Departments of Clinical Genetics (Y.M.H., J.E.P., M.W.W., D.D., D.F.M.-K.), Cardiology (K.C., M.M., F.J.t.C.), Pediatric Cardiology (I.F.-M.), and Internal Medicine (E.J.G.S.), Erasmus MC, Rotterdam, The Netherlands; and the Department of Medical Genetics (J.J.v.d.S.), University Medical Centre, Utrecht, The Netherlands.
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Notes

Correspondence to D.F. Majoor-Krakauer, MD, Department of Clinical Genetics, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail [email protected]

Funding Information

Sources of Funding
This study was supported by the Dutch Heart Foundation (Dr E. Dekker scholarship).
Disclosures
None.

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The Importance of Genetic Counseling, DNA Diagnostics, and Cardiologic Family Screening in Left Ventricular Noncompaction Cardiomyopathy
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