Publications by authors named "Yvonne M Hoedemaekers"

18 Publications

  • Page 1 of 1

Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients.

Int J Cardiol 2021 Mar 1. Epub 2021 Mar 1.

University of Groningen, University Medical Center Groningen, Department of Genetics, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.

Background: Next-generation sequencing (NGS) is increasingly used for clinical evaluation of cardiomyopathy patients as it allows for simultaneous screening of multiple cardiomyopathy-associated genes. Adding copy number variant (CNV) analysis of NGS data is not routine yet and may contribute to the diagnostic yield.

Objectives: Determine the diagnostic yield of our targeted NGS gene panel in routine clinical diagnostics of Dutch cardiomyopathy patients and explore the impact of exon CNVs on diagnostic yield.

Methods: Patients (N = 2002) referred for clinical genetic analysis underwent diagnostic testing of 55-61 genes associated with cardiomyopathies. Samples were analyzed and evaluated for single nucleotide variants (SNVs), indels and CNVs. CNVs identified in the NGS data and suspected of being pathogenic based on type, size and location were confirmed by additional molecular tests.

Results: A (likely) pathogenic (L)P variant was detected in 22.7% of patients, including 3 with CNVs and 25 where a variant was identified in a gene currently not associated with the patient's cardiomyopathy subtype. Only 15 out of 2002 patients (0.8%) were found to carry two (L)P variants.

Conclusion: The yield of routine clinical diagnostics of cardiomyopathies was relatively low when compared to literature. This is likely due to the fact that our study reports the outcome of patients in daily routine diagnostics, therefore also including patients not fully fulfilling (subtype specific) cardiomyopathy criteria. This may also explain why (L)P variants were identified in genes not associated with the reported subtype. The added value of CNV analysis was shown to be limited but not negligible.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.069DOI Listing
March 2021

A mutation update for the FLNC gene in myopathies and cardiomyopathies.

Hum Mutat 2020 06 20;41(6):1091-1111. Epub 2020 Mar 20.

Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype-phenotype correlations based on available evidence.
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http://dx.doi.org/10.1002/humu.24004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318287PMC
June 2020

Deciduous Teeth as an Alternative DNA Source for Postmortem Genetic Testing.

Circ Genom Precis Med 2020 04 31;13(2):e002674. Epub 2020 Jan 31.

Department of Genetics, University Medical Center Groningen, University of Groningen, the Netherlands (W.P.t.R., H.H.L., S.Z.J., Y.M.H.).

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http://dx.doi.org/10.1161/CIRCGEN.119.002674DOI Listing
April 2020

Three female patients with Danon disease presenting with predominant cardiac phenotype: a case series.

Eur Heart J Case Rep 2019 Sep 29;3(3):ytz132. Epub 2019 Jul 29.

Department of Cardiology, Thoraxcenter, University of Groningen, University Medical Center Groningen, PO Box 30.001, RB Groningen, The Netherlands.

Background: Danon disease is a rare X-linked multisystemic disorder that has primarily been described in male patients.

Case Summary: We present three female patients with Danon disease with a predominantly cardiac phenotype in whom disease onset and expression was very different from that of male patients. Case 1 was first admitted for acute heart failure and then readmitted a few months later for cardiac shock, necessitating mechanical support, and heart transplantation. Case 2 had complex arrhythmias for which many antiarrhythmic drugs were tried with only limited success. Her disease accelerated after her first pregnancy, and she showed reduced left ventricular function and dilated cardiomyopathy. Case 3 was referred for near syncope and ablated for an accessory pathway; she had extensive left ventricular hypertrophy. In all three cases, a final diagnosis of Danon disease was only made after genetic testing that identified a causal variant in the lysosome-associated membrane protein 2 gene.

Discussion: Danon disease in female patients is a challenging diagnosis that may not be identified until genetic testing has been performed.
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http://dx.doi.org/10.1093/ehjcr/ytz132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764575PMC
September 2019

A tailored approach towards informing relatives at risk of inherited cardiac conditions: study protocol for a randomised controlled trial.

BMJ Open 2019 07 9;9(7):e025660. Epub 2019 Jul 9.

Department of Clinical Genetics, Amsterdam University Medical Centres, Amsterdam, The Netherlands.

Introduction: In current practice, probands are asked to inform relatives about the possibility of predictive DNA testing when a pathogenic variant causing an inherited cardiac condition (ICC) is identified. Previous research on the uptake of genetic counselling and predictive DNA testing in relatives suggests that not all relatives are sufficiently informed. We developed a randomised controlled trial to evaluate the effectiveness of a tailored approach in which probands decide together with the genetic counsellor which relatives they inform themselves and which relatives they prefer to have informed by the genetic counsellor. Here, we present the study protocol of this randomised controlled trial.

Methods: A multicentre randomised controlled trial with parallel-group design will be conducted in which an intervention group receiving the tailored approach will be compared with a control group receiving usual care. Adult probands diagnosed with an ICC in whom a likely pathogenic or pathogenic variant is identified will be randomly assigned to the intervention or control group (total sample: n=85 probands). Primary outcomes are uptake of genetic counselling and predictive DNA testing by relatives (total sample: n=340 relatives). Secondary outcomes are appreciation of the approach used and impact on familial and psychological functioning, which will be assessed using questionnaires. Relatives who attend genetic counselling will be asked to fill out a questionnaire as well.

Ethics And Dissemination: Ethical approval was obtained from the Medical Ethical Committee of the Amsterdam University Medical Centres (MEC 2017-145), the Netherlands. All participants will provide informed consent prior to participation in the study. Results of the study on primary and secondary outcome measures will be published in peer-reviewed journals.

Trial Registration Number: NTR6657; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-025660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615798PMC
July 2019

Dyssynchronopathy Can be a Manifestation of Heritable Cardiomyopathy.

Circ Genom Precis Med 2019 05;12(5):e002528

Department of Cardiology (K.D., R.A.d.B., A.H.M., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, the Netherlands.

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http://dx.doi.org/10.1161/CIRCGEN.119.002528DOI Listing
May 2019

Informing relatives at risk of inherited cardiac conditions: experiences and attitudes of healthcare professionals and counselees.

Eur J Hum Genet 2019 09 3;27(9):1341-1350. Epub 2019 May 3.

Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Inherited cardiac conditions (ICCs) can lead to sudden cardiac death at young age, even without previous symptoms, yet often remain undetected. To prevent sudden cardiac death, cardiac monitoring and/or predictive DNA testing is advised for at-risk relatives. Probands in whom a causal variant is detected are asked to inform their relatives about the possibility of testing, often supported by a family letter. This qualitative study investigates experiences with and attitudes toward this family-mediated approach in ICCs and explores whether and how improvements can be made. Two online focus groups were conducted with 28 healthcare professionals (HCPs) from various disciplines, as were 25 face-to-face semi-structured interviews with counselees (10 probands; 15 relatives). Data were analysed by two researchers independently using a thematic approach. Participants, both HCPs and counselees, preferred that probands inform relatives about genetic risks in ICCs, but both groups struggled with the dependency on and burden on probands to inform their relatives. To overcome this, HCPs do see a more active role for themselves in informing relatives, but prefer uniformity in procedures in order to maintain their workload. Counselees, on the other hand, prefer a tailored information provision strategy adjusted to family dynamics and the personality characteristics of relatives. In conclusion, although it is generally preferred that probands inform relatives themselves, a more active role of HCPs could be considered to overcome the dependency and burden on probands. Further research is needed to study how HCPs can engage more actively in informing at-risk relatives in current clinical genetic practise.
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http://dx.doi.org/10.1038/s41431-019-0410-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777450PMC
September 2019

Cardiac Phenotypes, Genetics, and Risks in Familial Noncompaction Cardiomyopathy.

J Am Coll Cardiol 2019 04;73(13):1601-1611

Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands. Electronic address:

Background: There is overlap in genetic causes and cardiac features in noncompaction cardiomyopathy (NCCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM).

Objectives: The goal of this study was to predict phenotype and outcome in relatives according to the clinical features and genotype of NCCM index cases.

Methods: 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).

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1016/j.jacc.2018.12.085DOI Listing
April 2019

Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy.

J Am Coll Cardiol 2018 02;71(7):711-722

Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands. Electronic address:

Background: The clinical outcomes of noncompaction cardiomyopathy (NCCM) range from asymptomatic to heart failure, arrhythmias, and sudden cardiac death. Genetics play an important role in NCCM.

Objectives: This study investigated the correlations among genetics, clinical features, and outcomes in adults and children diagnosed with NCCM.

Methods: A retrospective multicenter study from 4 cardiogenetic centers in the Netherlands classified 327 unrelated NCCM patients into 3 categories: 1) genetic, with a mutation in 32% (81 adults; 23 children) of patients; 2) probably genetic, familial cardiomyopathy without a mutation in 16% (45 adults; 8 children) of patients; or 3) sporadic, no family history, without mutation in 52% (149 adults; 21 children) of patients. Clinical features and major adverse cardiac events (MACE) during follow-up were compared across the children and adults.

Results: MYH7, MYBPC3, and TTN mutations were the most common mutations (71%) found in genetic NCCM. The risk of having reduced left ventricular (LV) systolic dysfunction was higher for genetic patients compared with the probably genetic and sporadic cases (p = 0.024), with the highest risk in patients with multiple mutations and TTN mutations. Mutations were more frequent in children (p = 0.04) and were associated with MACE (p = 0.025). Adults were more likely to have sporadic NCCM. High risk for cardiac events in children and adults was related to LV systolic dysfunction in mutation carriers, but not in sporadic cases. Patients with MYH7 mutations had low risk for MACE (p = 0.03).

Conclusions: NCCM is a heterogeneous condition, and genetic stratification has a role in clinical care. Distinguishing genetic from nongenetic NCCM complements prediction of outcome and may lead to management and follow-up tailored to genetic status.
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http://dx.doi.org/10.1016/j.jacc.2017.12.019DOI Listing
February 2018

Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects.

Eur J Hum Genet 2015 Jul 22;23(7):922-8. Epub 2014 Oct 22.

Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous or homozygous pathogenic MYBPC3 mutations and describe their clinical characteristics. All four children presented with feeding difficulties, failure to thrive, and dyspnea. They died from cardiac failure before age 13 weeks. Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded. All of them had septal defects. Two patients were compound heterozygotes for the pathogenic c.2373dup p.(Trp792fs) and c.2827C>T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C>T mutations. All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n=21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life. In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy. In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients.
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http://dx.doi.org/10.1038/ejhg.2014.211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463499PMC
July 2015

HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.

J Am Coll Cardiol 2014 Aug;64(8):745-56

Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands. Electronic address:

Background: Familial forms of primary sinus bradycardia have sometimes been attributed to mutations in HCN4, SCN5A, and ANK2. In these studies, no structural cardiac alterations were reported in mutation carriers. However, a cluster of reports in the literature describe patients presenting with sinus bradycardia in association with left ventricular noncompaction cardiomyopathy (LVNC), pointing to a shared genetic cause.

Objectives: This study sought to identify the genetic defect underlying the combined clinical presentation of bradycardia and LVNC, hypothesizing that these 2 clinical abnormalities have a common genetic cause.

Methods: Exome sequencing was carried out in 2 cousins from the index family that were affected by the combined bradycardia-LVNC phenotype; shared variants thus identified were subsequently overlaid with the chromosomal regions shared among 5 affected family members that were identified using single nucleotide polymorphism array analysis.

Results: The combined linkage analysis and exome sequencing in the index family identified 11 novel variants shared among the 2 affected cousins. One of these, p.Gly482Arg in HCN4, segregated with the combined bradycardia and LVNC phenotype in the entire family. Subsequent screening of HCN4 in 3 additional families with the same clinical combination of bradycardia and LVNC identified HCN4 mutations in each. In electrophysiological studies, all found HCN4 mutations showed a more negative voltage dependence of activation, consistent with the observed bradycardia.

Conclusions: Although mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence to our knowledge that mutations in this ion channel gene also may be associated with structural abnormalities of the myocardium.
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http://dx.doi.org/10.1016/j.jacc.2014.05.045DOI Listing
August 2014

Mortality risk of untreated myosin-binding protein C-related hypertrophic cardiomyopathy: insight into the natural history.

J Am Coll Cardiol 2011 Nov;58(23):2406-14

Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands.

Objectives: The goal of this study was to assess the mortality of hypertrophic cardiomyopathy (HCM), partly in times when the disease was not elucidated and patients were untreated.

Background: HCM is feared for the risk of sudden cardiac death (SCD). Insight in the natural history of the disorder is needed to design proper screening strategies for families with HCM.

Methods: In 6 large, 200-year multigenerational pedigrees (identified by using genealogical searches) and in 140 small (contemporary) pedigrees (first-degree relatives of the proband) with HCM caused by a truncating mutation in the myosin-binding protein C gene (n = 1,118), we determined all-cause mortality using the family tree mortality ratio method. The study's main outcome measure was the standardized mortality ratio (SMR).

Results: In the large pedigrees, overall mortality was not increased (SMR 0.86 [95% confidence interval (CI): 0.72 to 1.03]), but significant excess mortality occurred between 10 and 19 years (SMR 2.7 [95% CI: 1.2 to 5.2]). In the small families, the SMR was increased (SMR 1.5 [95% CI: 1.3 to 1.6]) [corrected] and excess mortality was observed between 10 and 39 years (SMR 3.2 [95% CI: 2.3 to 4.3]) and 50 and 59 years (SMR 1.9 [95% CI: 1.4 to 2.5]).

Conclusions: We identified specific age categories with increased mortality risks in HCM families. The small, referred pedigrees had higher mortality risks than the large 200-year multigenerational pedigrees. Our findings support the strategy of starting cardiological and genetic screening in the first-degree relatives of a proband from 10 years onward and including persons in the screening at least until the age of 60 years. Screening of more distant relatives is probably most efficient between 10 and 19 years.
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http://dx.doi.org/10.1016/j.jacc.2011.07.044DOI Listing
November 2011

Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis.

Nat Genet 2011 Feb 9;43(2):121-6. Epub 2011 Jan 9.

Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.
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http://dx.doi.org/10.1038/ng.744DOI Listing
February 2011

The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy.

Circ Cardiovasc Genet 2010 Jun 8;3(3):232-9. Epub 2010 Jun 8.

Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.

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.
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http://dx.doi.org/10.1161/CIRCGENETICS.109.903898DOI Listing
June 2010

Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers.

Eur Heart J 2009 Nov 6;30(21):2593-8. Epub 2009 Aug 6.

Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, The Netherlands.

Aims: To investigate the outcome of cardiac evaluation and the risk stratification for sudden cardiac death (SCD) in asymptomatic hypertrophic cardiomyopathy (HCM) mutation carriers.

Methods And Results: Seventy-six HCM mutation carriers from 32 families identified by predictive DNA testing underwent cardiac evaluation including history, examination, electrocardiography, Doppler echocardiography, exercise testing, and 24 h Holter monitoring. The published diagnostic criteria for HCM in adult members of affected families were used to diagnose HCM. Thirty-three (43%) men and 43 (57%) women with a mean age of 42 years (range 16-79) were examined; in 31 (41%) HCM was diagnosed. Disease penetrance was age related and men were more often affected than women (P = 0.04). Myosin Binding Protein C (MYBPC3) mutation carriers were affected at higher age than Myosin Heavy Chain (MYH7) mutation carriers (P = 0.01). Risk factors for SCD were present in affected and unaffected carriers.

Conclusion: Hypertrophic cardiomyopathy was diagnosed in 41% of carriers. Disease penetrance was age dependent, warranting repeated cardiologic evaluation. The MYBPC3 mutation carriers were affected at higher age than MYH7 mutation carriers. Risk factors for SCD were present in carriers with and without HCM. Follow-up studies are necessary to evaluate the effectiveness of risk stratification for SCD in this population.
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http://dx.doi.org/10.1093/eurheartj/ehp306DOI Listing
November 2009

Diastolic abnormalities as the first feature of hypertrophic cardiomyopathy in Dutch myosin-binding protein C founder mutations.

JACC Cardiovasc Imaging 2009 Jan;2(1):58-64

Department of Cardiology, Thoraxcenter, Erasmus University Medical Center Rotterdam, the Netherlands.

Objectives: To test the hypothesis that carriers of Dutch founder mutations in cardiac myosin-binding protein C (MYBPC3), without left ventricular hypertrophy (LVH) or electrocardiographic abnormalities, have diastolic dysfunction on tissue Doppler imaging (TDI), which can be used for the screening of family members in the hypertrophic cardiomyopathy (HCM) population.

Background: TDI is a more sensitive technique for the assessment of left ventricular contraction and relaxation abnormalities than is conventional echocardiography.

Methods: Echocardiographic studies including TDI were performed in genotyped hypertrophic cardiomyopathy patients (genotype-positive, G+/LVH+; n = 27), mutation carriers without LVH (G+/LVH-; n = 27), and healthy controls (n = 55). The identified mutations in MYBPC3 in the G+/LVH+ subjects were c.2864_2865delCT (12 subjects), c.2373dupG (n = 8), and p. Arg943X (n = 7). In the G+/LVH- subjects, the following mutations were identified: c.2864_2865delCT (n = 11), c.2373dupG (n = 8), and p. Arg943X (n = 8).

Results: Mean TDI-derived systolic and early and late diastolic mitral annular velocities were significantly lower in the G+/LVH+ subjects compared with the other groups. However, there was no difference between controls and G+/LVH- subjects. Mean TDI-derived late mitral annular diastolic velocities were significantly higher in the G+/LVH- subjects compared with controls and G+/LVH+ subjects. Using a cut-off value of mean +/- 2 SD, an abnormal late mitral annular diastolic velocity was found in 14 (51%) of G+/LVH- patients. There was no difference among the 3 different mutations.

Conclusions: In contrast to earlier reports, mean mitral annular systolic velocity and early mitral annular diastolic velocity velocities were not reduced in G+/LVH- subjects, and TDI velocities were not sufficiently sensitive for determination of the affected status of an individual subject. Our findings, however, support the theory that diastolic dysfunction is a primary component of pre-clinical HCM.
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http://dx.doi.org/10.1016/j.jcmg.2008.08.003DOI Listing
January 2009

Cardiac beta-myosin heavy chain defects in two families with non-compaction cardiomyopathy: linking non-compaction to hypertrophic, restrictive, and dilated cardiomyopathies.

Eur Heart J 2007 Nov 17;28(22):2732-7. Epub 2007 Oct 17.

Department of Clinical Genetics, Erasmus Medical Centre, Dr Molewaterplein 50, 3015GE Rotterdam, The Netherlands.

Cardiomyopathies are classified according to distinct morphological characteristics. They occur relatively frequent and are an important cause of mortality and morbidity. Isolated ventricular non-compaction or non-compaction cardiomyopathy (NCCM) is characterized by an excessively thickened endocardial layer with deep intertrabecular recesses, reminiscent of the myocardium during early embryogenesis. Aims Autosomal-dominant as well as X-linked inheritance for NCCM has been described and several loci have been associated with the disease. Nevertheless, a major genetic cause for familial NCCM remains to be identified. Methods and Results We describe, in two separate autosomal-dominant NCCM families, the identification of mutations in the sarcomeric cardiac beta-myosin heavy chain gene (MYH7), known to be associated with hypertrophic cardiomyopathy (HCM), restricted cardiomyopathy (RCM), and dilated cardiomyopathy (DCM). Conclusion These results confirm the genetic heterogeneity of NCCM and suggest that the molecular classification of cardiomyopathies includes an MYH7-associated spectrum of NCCM with HCM, RCM, and DCM.
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http://dx.doi.org/10.1093/eurheartj/ehm429DOI Listing
November 2007