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Germline SMAD4 pathogenic variants (PVs) cause juvenile polyposis syndrome (JPS), which is known for an increased risk of gastrointestinal juvenile polyps and gastrointestinal cancer. Many patients with SMAD4 PV also show signs of hereditary hemorrhagic telangiectasia (HHT) and some patients have aneurysms and dissections of the thoracic aorta. Here we describe two patients with a germline SMAD4 PV and a remarkable clinical presentation including multiple medium-sized arterial aneurysms. More data are needed to confirm whether the more extensive vascular phenotype and the other described features in our patients are indeed part of a broader JPS spectrum., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic. They may result from genetic defects. Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism. Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out. This document is an expert opinion reflecting strategies put forward by medical experts and patient representatives involved in the HTAD Rare Disease Working Group of VASCERN. It aims to provide a patient pathway that improves patient care by diminishing time to diagnosis, facilitating the establishment of a correct diagnosis using molecular genetics when possible, excluding the diagnosis in unaffected persons through appropriate family screening and avoiding overuse of resources. It is being recommended that patients are referred to an expert centre for further evaluation if they meet at least one of the following criteria: (1) thoracic aortic dissection (<70 years if hypertensive; all ages if non-hypertensive), (2) thoracic aortic aneurysm (all adults with Z score >3.5 or 2.5-3.5 if non-hypertensive or hypertensive and <60 years; all children with Z score >3), (3) family history of HTAD with/without a pathogenic variant in a gene linked to HTAD, (4) ectopia lentis without other obvious explanation and (5) a systemic score of >5 in adults and >3 in children. Aortic imaging primarily relies on transthoracic echocardiography with magnetic resonance imaging or computed tomography as needed. Genetic testing should be considered in those with a high suspicion of underlying genetic aortopathy. Though panels vary among centers, for patients with thoracic aortic aneurysm or dissection or systemic features these should include genes with a definitive or strong association to HTAD. Genetic cascade screening and serial aortic imaging should be considered for family screening and follow-up. In conclusion, the implementation of these strategies should help standardise the diagnostic work-up and follow-up of patients with suspected HTAD and the screening of their relatives., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Marfan syndrome (MFS) is a connective tissue disorder causing aortic aneurysm formation. Currently, only prophylactic aortic surgery and blood pressure-lowering drugs are available to reduce the risk of aortic rupture. Upon whole genome sequencing of a Marfan family, we identified a complement gene C1R variant (p.Ser152Leu), which is associated with severe aortic patients. Therefore, we assessed the role of complement activation in MFS aortic tissue. Expression of various complement genes and proteins was detected in human and murine MFS aneurysm tissue, which prompted us to study complement inhibition in MFS mice. Treatment of the Fbn1C1041G/+ MFS mice with human plasma-derived C1-esterase inhibitor Cetor® resulted in reduced complement deposition, decreased macrophage influx in the aorta, and lower circulating TNFα levels. However, in line with previous anti-inflammatory treatments, complement inhibition did not change the aortic dilatation rate in this MFS mouse model. Thus, while complement factors/component 3 activation were detected in human/murine MFS aorta, Cetor® had no effect on aortic dilatation in MFS mice, indicating that complement inhibition is not a suitable treatment strategy in MFS.

Atrial septal defect (ASD) is the most common congenital heart defect clinically characterized by an opening in the atrial septum. Mutations in GATA4, TBX5, and NKX2-5 underlie this phenotype. Here, we report on the identification of a novel -6 G>C mutation in the highly conserved Kozak sequence in the 5'UTR of GATA4 in a small family presenting with two different forms of ASD. This is the first time a mutation in the Kozak sequence has been linked to heart disease. Functional assays demonstrate reduced GATA4 translation, though the GATA4 transcript levels remain normal. This leads to a reduction of GATA4 protein level, consequently diminishing the ability of GATA4 to transactivate target genes, as demonstrated by using the GATA4-driven Nppa (ANF) promoter. In conclusion, we identified a mutation in the GATA4 Kozak sequence that likely contributes to the pathogenesis of ASD. In general, it points to the importance of accurate protein level regulation during heart development and emphasizes the need to analyze the entire transcribed region when screening for mutations., (© 2014 Wiley Periodicals, Inc.)

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., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Bicuspid aortic valve (BAV) is common in Turner syndrome (TS). In adult TS, 82-95% of BAVs have fusion of the right and left coronary leaflets. Data in fetal stages are scarce. The purpose of this study was to gain insight into aortic valve morphology and associated cardiovascular abnormalities in a fetal TS cohort with adverse outcome early in development., Material and Methods: We studied post-mortem heart specimens of 36 TS fetuses and 1 TS newborn., Results: BAV was present in 28 (76%) hearts. BAVs showed fusion of the right and left coronary leaflet (type 1 BAV) in 61%, and fusion of the right coronary and non-coronary leaflet (type 2 BAV) in 39%. There were no significant differences in occurrence of additional cardiovascular abnormalities between type 1 and type 2 BAV. However, all type 2 BAV hearts showed ascending aorta hypoplasia and tubular hypoplasia of the B segment, as opposed to only 55 and 64% of type 1 BAV hearts, respectively., Discussion: The proportion of type 2 BAV seems higher in TS fetuses than in adults. Fetal type 2 BAV hearts all had severe aortic pathology, possibly contributing to a worse prognosis of type 2 than type 1 BAV in TS.

Left ventricular noncompaction (LVNC) is a relatively common genetic cardiomyopathy, characterized by prominent trabeculations with deep intertrabecular recesses in mainly the left ventricle. Although LVNC often occurs in an isolated entity, it may also be present in various types of congenital heart disease (CHD). The most prevalent CHD in LVNC is Ebstein anomaly, which is a rare form of CHD characterized by apical displacement and partial fusion of the septal and posterior leaflet of the tricuspid valve with the ventricular septum. Several reports of sporadic as well as familial cases of Ebstein anomaly associated with LVNC have been reported. Recent studies identified mutations in the MYH7 gene, encoding the sarcomeric β-myosin heavy chain protein, in patients harboring this specific phenotype. Here, we will review the association between Ebstein anomaly, LVNC and mutations in MYH7, which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance., (Copyright © 2013 Wiley Periodicals, Inc.)

For adult patients with congenital heart disease (CHD), knowledge about the origin and inheritance of their CHD is important. Clinical geneticists may play a significant role in their care. We explored the diagnostic yield of clinical genetic consultation of adult CHD patients, patients' motivations for the consultation, implications for reproductive decisions, patients' evaluation of the impact of provided information, and satisfaction with counseling. Chart review was performed on all adult patients referred for CHD to our clinical genetics department between 2000 and 2011 (n = 90). Additionally, a questionnaire was sent to those patients referred between 2005 and 2011 (n = 64), of which 46 useful questionnaires were returned (72% response). Of patients without an etiological diagnosis at referral (n = 83), 17 (20%) were eventually diagnosed with syndromic CHD, 6 (7%) with nonsyndromic monogenetic CHD and 45 (54%) with nonsyndromic multifactorial CHD. The diagnosis remained undetermined in 15 (18%) patients. Half of patients who returned the questionnaire had purposefully postponed having children until after genetic consultation and 13% had changed their mind about having children or not after the consultation. Counseling was valued positively. In this study, we showed the added value of clinical genetic consultation in the care for adult CHD patients: it improves diagnostics by establishing an etiological diagnosis and associated recurrence risk in a substantial proportion of patients and leads to more informed reproductive decisions. With new genetic testing technologies an etiological diagnosis may be established in an increasing number of patients in the near future., (Copyright © 2013 Wiley Periodicals, Inc.)

Ebstein's anomaly is a rare congenital heart malformation characterised by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. Associated abnormalities of left ventricular morphology and function including left ventricular noncompaction (LVNC) have been observed. An association between Ebstein's anomaly with LVNC and mutations in the sarcomeric protein gene MYH7, encoding β-myosin heavy chain, has been shown by recent studies. This might represent a specific subtype of Ebstein's anomaly with a Mendelian inheritance pattern. In this review we discuss the association of MYH7 mutations with Ebstein's anomaly and LVNC and its implications for the clinical care for patients and their family members.

Background: Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far., Methodology/principal Findings: Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients., Conclusion/significance: In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.

NKX2-5 is a homeodomain-containing transcription factor implied in both heart and thyroid development. Numerous mutations in NKX2-5 have been reported in individuals with congenital heart disease (CHD), but recently a select few have been associated with thyroid dysgenesis, among which the p.A119S variation. We sequenced NKX2-5 in 303 sporadic CHD patients and 38 families with at least two individuals with CHD. The p.A119S variation was identified in two unrelated patients: one was found in the proband of a family with four affected individuals with CHD and the other in a sporadic CHD patient. Clinical evaluation of heart and thyroid showed that the mutation did not segregate with CHD in the familial case, nor did any of the seven mutation carriers have thyroid abnormalities. We tested the functional consequences of the p.A119S variation in a cellular context by performing transactivation assays with promoters relevant for both heart and thyroid development in rat heart derived H10 cells and HELA cells. There was no difference between wildtype NKX2-5 and p.A119S NKX2-5 in activation of the investigated promoters in both cell lines. Additionally, we reviewed the current literature on the topic, showing that there is no clear evidence for a major pathogenic role of NKX2-5 mutations in thyroid dysgenesis. In conclusion, our study demonstrates that p.A119S does not cause CHD or TD and that it is a rare variation that behaves equal to wildtype NKX2-5. Furthermore, given the wealth of published evidence, we suggest that NKX2-5 mutations do not play a major pathogenic role in thyroid dysgenesis, and that genetic testing of NKX2-5 in TD is not warranted.

Marfan syndrome (MFS) is a connective tissue disorder with major features in cardiovascular, ocular and skeletal systems. Recently, diagnostic criteria were revised where more weight was given to the aortic root dilatation. We applied the revised Marfan nosology in an established adult Marfan population to define practical repercussions of novel criteria for clinical practice and individual patients. Out of 180 MFS patients, in 91% (n = 164) the diagnosis of MFS remained. Out of 16 patients with rejected diagnosis, four patients were diagnosed as MASS (myopia, mitral valve prolapse, borderline non-progressive aortic root dilatation, skeletal findings and striae) phenotype, three as ectopia lentis syndrome and in nine patients no alternative diagnosis was established. In 13 patients, the diagnosis was rejected because the Z-score of the aortic root was <2, although the aortic diameter was larger than 40 mm in six of them. In three other patients, the diagnosis of MFS was rejected because dural ectasia was given less weight in the revised nosology. Following the revised Marfan nosology, the diagnosis of MFS was rejected in 9% of patients, mostly because of the absence of aortic root dilatation defined as Z-score ≥2. Currently used Z-scores seem to underestimate aortic root dilatation, especially in patients with large body surface area (BSA). We recommend re-evaluation of criteria for aortic root involvement in adult patients with a suspected diagnosis of MFS., (© 2011 John Wiley & Sons A/S.)

With recent advances in medical and surgical management, most patients with congenital heart disease (CHD) survive to reproductive age. Current guidelines recommend counseling about inheritance and transmission of CHD to offspring. We evaluated whether adult CHD patients recalled having received information about the inheritance of their CHD, patients' knowledge about inheritance and their concerns in this regard. A questionnaire was sent to 486 non-syndromic CHD patients aged 20-45 years. We received 332 useful questionnaires (response rate 68%). One-third (33%) of patients recalled receiving information about inheritance of CHD from their cardiologist, and 13% had consulted a clinical geneticist. Eight percent of patients who were considering having children estimated the recurrence risk for their own offspring to be 1% or lower, whereas one-fourth (25%) estimated it to be higher than 10%. According to our classification, 44% estimated the recurrence risk in a correct range of magnitude. Additional information about inheritance of CHD was desired by 41% of patients. Forty-two percent of patients considering having children reported concerns about transmitting CHD to offspring. We conclude that a substantial proportion of adult CHD patients lacks knowledge and desires more information about inheritance, indicating a need for better patient education. Current guidelines and/or their implementation do not seem to meet the needs of these patients. A dedicated program of counseling for adults with CHD has to be developed to optimize knowledge and satisfaction with information provision and to reduce or manage concerns regarding inheritance of CHD., (Copyright © 2011 Wiley-Liss, Inc.)

Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21-33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-cM critical interval corresponds to 39 Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region (INVS, TMOD1, TGFBR1, KLF4, IPPK, BARX1, PTCH1, MEGF9 and S1PR3) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.

The assembly of mitochondrial respiratory chain complex IV (cytochrome c oxidase) involves the coordinated action of several assembly chaperones. In Saccharomyces cerevisiae, at least 30 different assembly chaperones have been identified. To date, pathogenic mutations leading to a mitochondrial disorder have been identified in only seven of the corresponding human genes. One of the genes for which the relevance to human pathology is unknown is C2orf64, an ortholog of the S. cerevisiae gene PET191. This gene has previously been shown to be a complex IV assembly factor in yeast, although its exact role is still unknown. Previous research in a large cohort of complex IV deficient patients did not support an etiological role of C2orf64 in complex IV deficiency. In this report, a homozygous mutation in C2orf64 is described in two siblings affected by fatal neonatal cardiomyopathy. Pathogenicity of the mutation is supported by the results of a complementation experiment, showing that complex IV activity can be fully restored by retroviral transduction of wild-type C2orf64 in patient-derived fibroblasts. Detailed analysis of complex IV assembly intermediates in patient fibroblasts by 2D-BN PAGE revealed the accumulation of a small assembly intermediate containing subunit COX1 but not the COX2, COX4, or COX5b subunits, indicating that C2orf64 is involved in an early step of the complex IV assembly process. The results of this study demonstrate that C2orf64 is essential for human complex IV assembly and that C2orf64 mutational analysis should be considered for complex IV deficient patients, in particular those with hypertrophic cardiomyopathy., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Ebstein anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. An association between Ebstein anomaly with left ventricular noncompaction (LVNC) and mutations in MYH7 encoding β-myosin heavy chain has been shown; in this report, we have screened for MYH7 mutations in a cohort of probands with Ebstein anomaly in a large population-based study., Methods and Results: Mutational analysis in a cohort of 141 unrelated probands with Ebstein anomaly was performed by next-generation sequencing and direct DNA sequencing of MYH7. Heterozygous mutations were identified in 8 of 141 samples (6%). Seven distinct mutations were found; 5 were novel and 2 were known to cause hypertrophic cardiomyopathy. All mutations except for 1 3-bp deletion were missense mutations; 1 was a de novo change. Mutation-positive probands and family members showed various congenital heart malformations as well as LVNC. Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC. The frequency of MYH7 mutations was significantly different between probands with and without LVNC accompanying Ebstein anomaly (P<0.0001). LVNC segregated with the MYH7 mutation in the pedigrees of 3 of the probands, 1 of which also included another individual with Ebstein anomaly., Conclusions: Ebstein anomaly is a congenital heart malformation that is associated with mutations in MYH7. MYH7 mutations are predominantly found in Ebstein anomaly associated with LVNC and may warrant genetic testing and family evaluation in this subset of patients.

Marfan syndrome (MFS) is a dominant disorder with a recognizable phenotype. In most patients with the classical phenotype mutations are found in the fibrillin-1 gene (FBN1) on chromosome 15q21. It is thought that most mutations act in a dominant negative way or through haploinsufficiency. In 9 index cases referred for MFS we detected heterozygous missense mutations in FBN1 predicted to substitute the first aspartic acid of different calcium-binding Epidermal Growth Factor-like (cbEGF) fibrillin-1 domains. A similar mutation was found in homozygous state in 3 cases in a large consanguineous family. Heterozygous carriers of this mutation had no major skeletal, cardiovascular or ophthalmological features of MFS. In the literature 14 other heterozygous missense mutations are described leading to the substitution of the first aspartic acid of a cbEGF domain and resulting in a Marfan phenotype. Our data show that the phenotypic effect of aspartic acid substitutions in the first position of a cbEGF domain can range from asymptomatic to a severe neonatal phenotype. The recessive nature with reduced expression of FBN1 in one of the families suggests a threshold model combined with a mild functional defect of this specific mutation.

Background: Three quarters of patients with 22q11.2 Deletion Syndrome (22q11.2DS) have congenital heart disease (CHD), typically conotruncal heart defects. Although it is currently common practice to test all children with typical CHD for 22q11.2DS, many adult patients have not been tested in the past and therefore 22q11.2DS might be under-recognised in adults., Objectives: To determine the prevalence of 22q11.2DS in adults with tetralogy of Fallot (TOF) and pulmonary atresia (PA)/ventricular septal defect (VSD) and to assess the level of recognition of the syndrome in adult patients., Methods: Patients were identified from CONCOR, a nationwide registry for adult patients with CHD. Inclusion criteria were diagnosis of TOF or PA/VSD and the availability of DNA. Patients with syndromes other than 22q11.2DS were excluded. Multiplex ligation-dependent probe amplification was used to detect 22q11.2 microdeletions., Results: 479 patients with TOF and 79 patients with PA/VSD (56% male, median age 34.7 years) were included and analysed. Twenty patients were already known to have 22q11.2DS. A 22q11.2 microdeletion was detected in a further 24 patients. Thirty-one patients with TOF (6.5%) had 22q11.2DS, whereas 13 patients with PA/VSD had 22q11.2DS (16.5%). Of all 22q11.2 microdeletions, 54% (24/44) were unknown before this study., Conclusion: This study shows that although the prevalence of 22q11.2DS in adults with TOF and PA/VSD is substantial, it is unrecognised in more than half of patients. As the syndrome has important clinical and reproductive implications, a diagnostic test should be considered in all adult patients with TOF and PA/VSD.

Background: Marfan syndrome (MFS) is one of the most common systemic disorders of connective tissue with the incidence of approximately 2-3 per 10 000 individuals. Aortic disease, leading to progressive aneurysmal dilatation and dissection is the main cause of morbidity and mortality of Marfan patients. Current treatment (e.g. beta blockers and elective surgery) does postpone but cannot prevent aortic complications in these patients. Recent studies have found transforming growth factor beta (TGF beta) to be involved in the aortic aneurysm formation. Losartan, an angiotensin II type 1 receptor blocker inhibits TGFbeta in a mouse model of Marfan syndrome leading to inhibition of aortic growth. The main objective of this trial is to assess whether losartan treatment leads to a clinically relevant decrease of aortic dilatation in adult patients with Marfan syndrome., Methods/design: COMPARE study (COzaar in Marfan Patients Reduces aortic Enlargement) is an open-label, randomized, controlled trial with blinded end-points. Treatment with losartan will be compared with no additional treatment after 3 years of follow-up. We will enroll 330 patients with MFS who will be randomly assigned to receive losartan or not. Patients taking beta-blockers will continue taking their standard treatment. The primary end-point is the largest change in aortic diameter at any aortic level measured by means of MRI. Secondary end-points are change in mortality, incidence of dissection, elective aortic surgery, aortic volume, aortic stiffness and ventricular function. We will also investigate gene and protein expression change in the skin under losartan therapy and create prediction models for losartan-treatment response and aortic dilatation., Discussion: The COMPARE study will provide important evidence of effects of losartan treatment in adult Marfan patient population. We expect losartan to significantly reduce the occurrence and progression of aortic dilatation. This trial investigates a wide spectrum of clinical, genetic and biochemical effects of losartan aiming to provide further insight in the pathogenesis and treatment of Marfan syndrome., Trial Registration: Netherlands Trial Register NTR1423.

Data on the prevalence of congenital heart defects (CHD) in neuroblastoma patients are inconsistent. If CHD are more common in neuroblastoma patients than in the general population, cardiac screening might be warranted. In this study we used echocardiography to determine the prevalence of CHD in a single centre cohort of surviving neuroblastoma patients. In addition, we performed a systematic review of the literature. Echocardiography was performed in 119 of 133 patients (89.5%). Only two patients (1.7%) had CHD. The prevalence of CHD was not significantly different from a previously published control group of 192 leukaemia patients examined by echocardiography (P = 0.49). Literature search revealed 17 studies, showing prevalence rates of CHD in neuroblastoma patients ranging from 0 to 20%. Prevalence was less than 3.6% in the majority of studies. Most studies lacked information on validity. We conclude that current evidence does not support standard cardiac screening in all patients with neuroblastoma.

Background: Within Europe many guidelines exist regarding the genetic testing of minors. Predictive and presymptomatic genetic testing of minors is recommended for disorders for which medical intervention/preventive measures exist, and for which early detection improves future medical health., Aim: This study, which is part of the larger 5th EU-framework "genetic education" (GenEd) study, aimed to evaluate the self-reported responses of nongenetic health-care providers in five different EU countries (Germany, France, Sweden, the United Kingdom, and the Netherlands) when confronted with a parent requesting presymptomatic testing on a minor child for a treatable disease., Methods: A cross-sectional study design using postal, structured scenario-based questionnaires that were sent to 8129 general practitioners (GPs) and pediatricians, between July 2004 and October 2004, addressing self-reported management of a genetic case for which early medical intervention during childhood is beneficial, involving a minor., Results: Most practitioners agreed on testing the oldest child, aged 12 years (81.5% for GPs and 87.2% for pediatricians), and not testing the youngest child, aged 6 months (72.6% for GPs and 61.3% for pediatricians). After multivariate adjustment there were statistical differences between countries in recommending a genetic test for the child at the age of 8 years. Pediatricians in France (50%) and Germany (58%) would recommend a test, whereas in the United Kingdom (22%), Sweden (30%), and the Netherlands (32%) they would not., Conclusion: Even though presymptomatic genetic testing in minors is recommended for disorders for which medical intervention exists, EU physicians are uncertain at what age starting to do so in young children.

Objective: The aim of the present study was to investigate whether medical care providers in the Netherlands are adequately educated in genetics by collecting information about the current state of genetics education of non-genetics health care professionals., Method: The curricula of the 8 universities providing medical education and of all varieties of specialised medical training were examined for the year 2002., Results: In most universities, the number of hours spent on genetics education is small, and genetics is relatively invisible, being integrated within several courses, comprising only a small proportion of the total course (a mean of 8%). Only 3 of the programmes for medical specialist training and the training of medical doctors for mentally handicapped people indicated a formal genetics education programme. Continued education courses on genetics are offered irregularly. Training in midwifery involves at least 3 weeks of genetics education. Courses on genetics are offered frequently to practicing midwives., Conclusion: There appear to be no general, nationally defined final goals for education in genetics for non-genetics health care professionals in the Netherlands. Furthermore, the lack of visibility of genetics in medical education in the Netherlands was striking.

Purpose: The objective of this study was to assess knowledge of genetics and awareness of genetic tests among Dutch general practitioners (GPs), gynecologists (GYNs), and pediatricians (PEDs), as well as factors influencing their knowledge and awareness., Methods: An anonymous questionnaire inquiry was used, validated with a sample of 52 clinical geneticists (CGs). The study was carried out in primary care (general practice) and secondary care (general and university hospitals) in The Netherlands. A random sample of 200 GPs, 300 GYNs, and 265 PEDs received a questionnaire. In addition, all registered CGs (58) received a questionnaire for validation. In total, 122 GPs, 187 GYNs, 164 PEDs, and 52 CGs returned a completed questionnaire. The main outcome measures were differences in knowledge scores between physicians working in different disciplines and factors influencing these scores., Results: Knowledge scores of GPs (mean 64% correct answers, 61%-66% [95% confidence interval]), GYNs (mean 75% correct answers, 73%-76% [95% confidence interval]), and PEDs (mean 81% correct answers, 79%-82% [95% confidence interval]) were lower than those in the CG validation group (mean 95% correct answers, 94%-96% [95% confidence interval]). The 5th percentile of GPs, GYNs, and PEDs was at approximately 40%, 52% and 62% correct answers, respectively. There was a specific lack of knowledge about DNA testing. In addition to specialty, important factors positively associated with the knowledge scores of nongeneticists are more recent graduation, having taken an elective course in genetics, and providing genetic counseling in their own practice., Conclusion: The overall knowledge levels of genetics in many nongeneticist health care providers show clear deficiencies. This is in line with reports from other countries, showing that these deficiencies are a global problem.

Purpose: The objective of this study was to investigate whether the knowledge of genetics relevant for daily practice among medical students nearing graduation in the Netherlands was sufficient to react appropriately to the change of relevance of genetics in medicine., Methods: A computer examination validated in a group of clinical geneticists, medical students nearing graduation, and nonmedical students. The examination consisted of 215 genetic questions classified by the designers into three categories of relevance: "essential" knowledge (requirement: > 95% correct answers), "desirable" knowledge (requirement: > 60% correct answers), and "too specialized" knowledge (no requirement). To set an independent standard, the questions were also judged by clinical geneticists and nongenetic health care providers in an Angoff procedure. In total, 291 medical students nearing graduation from seven out of the eight medical schools in the Netherlands participated., Results: As expected, the mean score for "essential" knowledge (71.63%, 95% CI 70.74-72.52) was higher than for "desirable" knowledge (55.99%, 95% CI 55.08-56.90); the mean score for "too specialized" knowledge (44.40%, 95% CI 43.19-45.62) was the lowest. According to passing scores set for "essential" knowledge as defined by the designers, the clinical geneticists, and the nongenetic health care providers, only 0%, 26%, and 3%, respectively, of the participants would have passed., Conclusions: Medical students nearing graduation lack genetic knowledge that is essential for daily practice. Therefore, changes should be made in the medical curricula.

Nevoid basal cell carcinoma syndrome (NBCCS, basal cell naevus syndrome, Gorlin syndrome) is an autosomal dominant disorder, caused by mutations in the PTCH gene mapped to chromosome 9q22.3. It is characterised by multiple basal cell carcinomas, keratocysts of the jaws, palmar and plantar pits, cerebral ectopic calcification and several skeletal anomalies. Occasionally, patients with NBCCS develop other neoplasms, particularly medulloblastomas and ovarian fibromas, indicating that the PTCH gene is a tumor-suppressor gene. Early recognition and careful follow-up are needed. Guidelines for managing these patients are presented.

Knowledge of the opinions of physicians with regard to preconceptional cystic fibrosis (CF) carrier screening and the possible factors that are associated with their opinions is important for the implementation of such a screening program. Data were obtained from a study in which genetic knowledge, opinions with regard to genetic testing and related skills were investigated. A questionnaire, developed and used by American researchers, was adapted to the Dutch health care situation, and sent to randomly selected general practitioners (GPs) (n = 200), gynecologists (GYNs) (n = 300), and pediatricians (PEDs) (n = 265). In this part of the study, their opinions with regard to genetic preconceptional CF carrier screening in different situations were assessed. The response rate for the GPs, GYNs, and PEDs was 64%, 69%, and 72%, respectively. In total, 63% of the GPs, 69% of the GYNs and 72% of the PEDs supported preconceptional CF carrier testing if a couple requested a test. Sixteen percent, 19% and 25%, respectively, were in favor of actively offering a test with 95% test sensitivity to all couples who were planning a pregnancy. A positive opinion on preconceptional CF carrier screening was associated with the following variables: "considering the test sensitivity as less important" (GPs, GYNs), "high perceived risk of having a child with CF" (GYNs), "providing genetic counselling in their own practice" (PEDs) and "reassurance when both partners test negative" (PEDs). Physicians are sympathetic toward preconceptional CF carrier screening if the couples themselves request a test. Physicians had reservations about routinely offering a CF carrier test.

The aim of this study was to investigate whether the activities and attitudes of general practitioners (GPs) concerning genetic counseling have changed between 1989 and 1999. In 1989 a random sample of 124 GPs in The Netherlands was selected. Of these GPs, 98 were contacted again in 1999 and 71 completed the questionnaire. The study showed an increase in the percentage of GPs who provided genetic counseling when a risk factor for having a child with a congenital disorder was present and known. In both 1989 and 1999, the GPs seldom used a recommended combination of oral and written information, and only data that was available in the databases on the risk indicator 'use of medication' increased over the years. GPs are still supporters of a directive method of counseling, and seem to believe that the main goal of genetic counseling is to prevent hereditary and congenital disorders. Although, between 1989 and 1999 more GPs provided genetic counseling when a risk indicator was present and known or referred to a clinical geneticist, only limited improvement was found in the activities of GPs to attempt to collect these data.

A novel near-infrared (NIR) fluorescent dye (NN382, LICOR, Inc.) was evaluated as an ultrasensitive peptide-labeling reagent for use with capillary electrophoresis (CE). Six angiotensin I (Ang-I) variants were selected as model peptides for the derivatization and separation studies. The closely related decapeptides were labeled with the NIR dye, separated using CE, and detected by NIR laser-induced fluorescence. Derivatization of the peptides was achieved under aqueous conditions using 2.5-500 pmol of Ang-I in a 50-microL sample (5 x 10(-8)-1 x 10(-5)M), and between 1.3 and 254 amol of the labeled peptides were injected on column. The fluorescence response was linear over a 200-fold range (correlation r > or = 0.9986). The limit of detection (SNR = 3, signal/RMS noise) ranged from 100 to 300 zmol, for the six Ang-I variants. Four of six peptides were resolved from each other and excess dye using capillary zone electrophoresis with a simple 50 mM phosphate run buffer, pH 7.2. Two pairs of coeluting peptides were successfully resolved using micellar electrokinetic chromatography with a nonionic surfactant, Triton X-100. The NIR amine-labeling reagent NN382 is a viable alternative to using visible fluorophores for CE methods requiring high sensitivity.