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Objective: Conventional genetic tests (quantitative fluorescent-PCR [QF-PCR] and single nucleotide polymorphism-array) only diagnose similar to 40% of fetuses showing ultrasound abnormalities. Rapid exome sequencing (rES) may improve this diagnostic yield, but includes challenges such as uncertainties in fetal phenotyping, variant interpretation, incidental unsolicited findings, and rapid turnaround times. In this study, we implemented rES in prenatal care to increase diagnostic yield. Methods: We prospectively studied 55 fetuses. Inclusion criteria were: (a) two or more independent major fetal anomalies, (b) hydrops fetalis or bilateral renal cysts alone, or (c) one major fetal anomaly and a first-degree relative with the same anomaly. In addition to conventional genetic tests, we performed trio rES analysis using a custom virtual gene panel of similar to 3850 Online Mendelian Inheritance in Man (OMIM) genes. Results: We established a genetic rES-based diagnosis in 8 out of 23 fetuses (35%) without QF-PCR or array abnormalities. Diagnoses included MIRAGE (SAMD9), Zellweger (PEX1), Walker-Warburg (POMGNT1), Noonan (PTNP11), Kabuki (KMT2D), and CHARGE (CHD7) syndrome and two cases of Osteogenesis Imperfecta type 2 (COL1A1). In six cases, rES diagnosis aided perinatal management. The median turnaround time was 14 (range 8-20) days. Conclusion: Implementing rES as a routine test in the prenatal setting is challenging but technically feasible, with a promising diagnostic yield and significant clinical relevance.

Pharmacogenomics (PGx) can provide optimized treatment to individual patients while potentially reducing healthcare costs. However, widespread implementation remains absent. We performed a pilot study of PGx screening in Dutch outpatient hospital care to identify the barriers and facilitators to implementation experienced by patients (n=165), pharmacists (n=58) and physicians (n=21). Our results indeed suggest that the current practical experience of healthcare practitioners (HCPs) with PGx is limited, that proper education is necessary, that patients want to know the exact implications of the results, and that there is an unclear allocation of responsibilities between HCPs about who should discuss PGx with patients and apply PGx results in healthcare. We observed a positive attitude toward PGx among all the stakeholders in our study, and among patients this was independent of the occurrence of drug- gene interactions during their treatment. Facilitators included the availability of and adherence to Dutch Pharmacogenetic Working Group guidelines. While Clinical Decision Support (CDS) is available and valued in our medical center, the lack of availability of CDS might be an important barrier within Dutch healthcare in general.

Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We provide (i) a literature review on DRM, including clinical manifestations, inheritance, molecular genetics, myopathology and management and (ii) a meta-analysis of reported DES mutation carriers, focusing on their clinical characteristics and potential genotype-phenotype correlations. Meta-analysis: DES mutation carriers (n = 159) with 40 different mutations were included. Neurological signs were present in 74% and cardiological signs in 74% of carriers (both neurological and cardiological signs in 49%, isolated neurological signs in 22%, and isolated cardiological signs in 22%). More than 70% of carriers exhibited myopathy or muscular weakness, with normal creatine kinase levels present in one third of them. Up to 50% of carriers had cardiomyopathy and around 60% had cardiac conduction disease or arrhythmias, with atrioventricular block as an important hallmark. Symptoms generally started during the 30s; a quarter of carriers died at a mean age of 49 years. Sudden cardiac death occurred in two patients with a pacemaker, suggesting a ventricular tachyarrhythmia as cause of death. The majority of DES mutations were missense mutations, mostly located in the 2B domain. Mutations in the 2B domain were predominant in patients with an isolated neurological phenotype, whereas head and tail domain mutations were predominant in patients with an isolated cardiological phenotype.

Targeted genetic testing for certain genetic disorders (for example, chromosomal and monogenic/mendelian conditions) has been routinely offered in clinical settings for several decades. Tests were selected on the basis of signs, symptoms, or a family history of a condition or feature, because this was the most cost-effective way of achieving diagnoses. As the technology to analyze the genetic code has become several 1000-fold cheaper and faster than when such services were introduced, targeted analyses have been replaced by broader ones, notably array comparative genomic hybridization, and whole exome and whole genome analysis. The outputs from these broader technologies require novel bioinformatic approaches to interpret which of the millions of variations routinely detected are disease causing, or, more likely, influence disease predisposition. This chapter discusses some of the implications this shift from focused to broad approaches has for practices of consent and for communication of genetic testing results.

This exploratory study serves to illustrate the psychological impact on an extended family in the process of genetic counselling and testing for a potentially life-threatening arrhythmia, the long-QT syndrome (LQTS).All members of the third generation and their partners (n=11) were interviewed, the mutation carriers with partners twice. In addition they completed measures for anxiety and depression three times in 18 months.During the interviews these family members emphasised the damaged solidarity when the family is divided into carriers and noncarriers of a mutation in a LQTS predisposing gene. This demonstrates one way in which a family can react to the reality of being at risk of a potentially severe disease. Rewriting family history and mourning early death seem other ways to deal with this. The distress scores, especially of the women, were moderate to clinically high, not because of their own chance of having an arrhythmia but more due to their children's risk.Mothers need educational even more than emotional support, because the lifestyle of their carrier children is in need of radical change. The setting of a combined outpatient cardiogenetic clinic with a medical and psychosocial staff meets such needs efficiently.

We recently identified a novel mutation in large family characterised by premature nocturnal sudden death. In the present paper we provide an overview of the findings in this family.From 1958 onwards, when the first patient presented, we collected clinical data on as many family members as possible. After identification in 1998 of the underlying genetic disorder (SCN5A, 1795insD), genotyping was performed diagnostically.Since 1905 unexplained sudden death occurred in 26 family members, 17 of whom died during the night. Besides sudden death, symptomatology was rather limited; only six patients reported syncopal attacks. In one of them, a 13-year-old boy, asystolic episodes up to nine seconds were documented. Until now, the mutation has been found in 114 family members (57 males, 57 females). Carriers of the mutant gene exhibited bradycardia-dependent QT-prolongation, intrinsic sinus node dysfunction, generalised conduction abnormalities, a paucity of ventricular ectopy, and the Brugada sign. Cardiomyopathy or other structural abnormalities were not found in any of the carriers. Electrophysiological studies showed that mutant channels were characterised by markedly reduced IWe have described a large family with a SCN5A-linked disorder (1795insD) with features of LQT

Objectives: To assess the psychological effect of predictive testing in parents of children at risk for long QT syndrome (LQTS) in a prospective study.Methods: After their child was clinically screened by electrocardiography and blood was taken for DNA analysis, and shortly after delivery of the DNA test result, 36 parents completed measures of psychological distress. Results: 24 parents were informed that at least one of their children is a mutation carrier. Up to 50% of the parents of carrier children showed clinically relevant high levels of distress. Parents who were familiar with the disease for a longer time, who had more experiences with the disease in their family and who received positive test results for all their children were most distressed. Conclusions: Predictive ECG testing together with DNA testing has a profound impact on parents whose minors undergo predictive testing for LQTS.

Genetic testing is traditionally preceded by counselling to discuss its advantages and disadvantages with individuals so they can make informed decisions. The new technique of whole genome or exome sequencing, which is currently only used in research settings, can identify many gene mutations, including substantial numbers of mutations with unknown pathological effect; it may, therefore, threaten this balanced approach if it is used in a clinical setting. We discuss the ethical challenges of several approaches to pre- and postnatal DNA testing, individual privacy versus the interests of families and of scientists, and the clinician's duty to re-contact if new information or options become available.

To determine the pattern of referral of Dutch patients with a long-QT syndrome (LQTS) on the basis of the postal codes of the LQTS probands from whom blood samples were submitted for DNA diagnostics.. Retrospective cohort study.From the databases that are coupled to DNA diagnostics, all index patients were included for whom LQTS diagnostics had been requested during the period 1996-2005 at two clinical genetics centres (the University Medical Centre in Amsterdam and Maastricht University Hospital). The results were related to the postal code of the referred patient and corrected for the number of inhabitants of the region concerned.A total of 421 potential LQTS probands were included. Corrected for the numbers of inhabitants in the various postal codes, the number of referrals varied from 3 per million to 110 per million inhabitants. In view of the most recent estimated prevalence of LQTS (1:2000), this means that only 15% ofthe carriers of the LQTS mutation have so far been detected.There were large regional differences in the Netherlands in the requests for DNA diagnostics in patients with clinical LQTS. The overwhelming majority of the LQTS patients in the Netherlands have not yet been referred or identified. Expanding the available courses for general practitioners and cardiologists that are given by the staff of the cardiogenetic centres would seem to be indicated.

AIMS: Previously published diagnostic systems, based on ECG analysis and clinical parameters (Schwartz criteria and Keating criteria), have been used to estimate the probability of inherited long QT syndrome (LQTS). Nowadays, a certain diagnosis can often be made by DNA testing. We aimed to establish the predictive power of the Schwartz and Keating criteria, using DNA testing as a reference, and to determine the best diagnostic strategy. METHODS AND RESULTS: We studied 513 relatives (aged >10 years) of 77 consecutive LQTS probands with a known disease-causing mutation. The Schwartz criteria identified 'high probability of LQTS' (score >or=4) in 41 of 208 mutation carriers, yielding 19% sensitivity and 99% specificity. The Keating criteria had 36% sensitivity and 99% specificity. Alternatively, by analysing QTc duration alone, we found that 430 ms is the optimal cut-off value to distinguish carriers (>or=430 ms) from non-carriers ( or= 430 ms) as its sensitivity is far superior, although its specificity remains acceptable. In genotyped families, genetic testing is the preferred diagnostic test

Can a parent adjust to the idea that its child is at risk for a sudden death? This question is raised by a diagnostic procedure in which children were tested for an inherited Long QT Syndrome (LQTS). This potentially life-threatening but treatable cardiac arrhythmia syndrome may cause sudden death, especially in children and young adults. The long-term psychological effects are described for parents whose children were tested for inherited LQTS. The adverse short-term impact of such testing has been described previously. The goal of this investigation is to determine whether this distress endures. Thirty-six parents completed measures of psychological distress. With the twenty-four parents of carrier children, a semi-structured interview was held 18 months after DNA disclosure. Parents of carrier children reported more distress than parents of non-carrier children. Parents of carrier children remained vulnerable to high levels of distress; up to one-third of these parents showed clinically relevant high levels of distress. High levels of distress were reported by parents of carrier children who (1) were highly distressed at previous assessments, (2) were familiar with the disease for a longer time, (3) had experienced a sudden death in the family, (4) were lesser educated, and who (5) were unsatisfied with the given information. Parents were particularly concerned about possible hazardous behavior during puberty. We conclude that the continuous threat of developing LQTS symptoms despite prophylactic treatment affected the psychological well-being of the parents for a long time. In light of the tempetuous developments in the areas of cardiac genetics, periodical information on new insight and developments may act as a buffer for the parents' (growing) concerns about their child's inherited disorder. (c) 2005 Wiley-Liss, Inc.

In view of the increasing demands for genetic counselling and DNA diagnostics in cardiogenetics, the roles of cardiologists and clinical geneticists in the delivery of care need to be redefined. We investigated the preferences of both groups of professionals with regard to the future allocation of six cardiogenetic responsibilities in counselling and testing, using hypertrophic cardiomyopathy (HCM) as a prevalent model disease. In this cross-sectional survey, the participants were Dutch cardiologists (n = 643) and clinical geneticists (n = 60), all members of professional societies. Response rates were 33 and 82%, respectively. In both groups, the majority preferred to perform most of the tasks described above in collaboration. Informing HCM patients about the genetics of HCM and requesting DNA testing in symptomatic patients was viewed by 43 and 35% of cardiologists, respectively, as their sole responsibility, however, and 39 and 59% of clinical geneticists did not object to these views. Both groups felt that the task of discussing the consequences of HCM for offspring and that of discussing the results of DNA diagnostics should be shared or performed by clinical geneticists. Both groups considered co-ordination of family screening the sole responsibility of clinical geneticists. Opinions on who should request DNA diagnostics in asymptomatic relatives were divided: 86% of clinical geneticists considered it their exclusive responsibility, 10% of cardiologists believed that this task could be performed individually by either group and 30% preferred to collaborate. Most professionals said that they would appreciate education programmes and clinical guidelines. Both cardiologists and clinical geneticists prefer to share rather than divide most cardiogenetic responsibilities in caring for HCM patients. Consequently, capacity problems in both groups are to be expected. To safeguard current professional standards in genetic counselling and testing, deployment of non-medical personnel might be essential.

The autopsy of a 16-year-old boy who had died suddenly revealed hypertrophic cardiomyopathy (HCM). Molecular genetic investigation revealed mutations in the MYBPC3 gene. His surviving family members could then be examined and reassured that they did not carry the mutation. An 18-year-old boy who died suddenly turned out to have known HCM. No further investigations were done and no tissue was saved. Genetic investigation of his immediate family was impossible due to the lack of a known mutation in the family. Periodic examination in clinically unaffected family members was therefore advised. Sudden cardiac death at young age is not infrequently the first symptom of an inherited cardiac disease. Because these diseases usually inherit as an autosomal dominant trait, first-degree family members have a 50% chance of carrying the same genetic defect. Besides clinical cardiologic examination of the remaining family members, post-mortem molecular genetic investigation can be of value in reaching a diagnosis and in determining the subsequent therapeutic options for immediate relatives.

The long QT syndrome is characterised by QT prolongation on the ECG, repeated syncope and sudden cardiac death. QT prolongation is the result of delayed repolarisation at the cellular level, secondary to dysfunctioning ion channels. Ventricular arrhythmias underlie syncope and death. At least six genes, all encoding (parts of) ion channels, are causally involved. A molecular diagnosis is often feasible and can be reached reasonably straightforwardly, based on the clinical (family) history and the ECG pattern.

DNA diagnostics were carried out in a family after the long QT interval syndrome had been diagnosed in one of its members. The psychic reactions to this testing were different from those seen in other hereditary diseases such as Huntington's disease. This was probably due to the sudden and unexpected occurrence of the arrhythmia. The family members in whom clinical and DNA diagnostics gave purely negative findings were not relieved, owing to solidarity with the affected relatives. Their partners did not understand this response. The anxiety and concern of the gene carriers had nothing to do with their own health status but with that of their carrier children. These parents were in need of educational counselling and advice. The results of clinical and DNA diagnostics affected the family relationships: in carriers the feeling of closeness grew, while the non-carriers were afraid of loss of family closeness.

Sudden cardiac death without ischaemic heart disease may be due to a hereditary heart disease with an autosomal dominant heredity. The occurrence, if any, of sudden death in such a family is a main indicator for the risk of sudden cardiac death in other family members. Cardiological and/or genetic investigation may reveal a hereditary disease in relatives without symptoms. Of some of these pathological conditions, the corresponding chromosomal localizations and sometimes the gene mutations have been identified. The psychic burden of family investigation and the socio-economic consequences (insurances, occupation, family relationships) are potentially heavy. Prophylactic treatment of asymptomatic persons in whom a gene mutation is established may comprise advice about lifestyle (e.g. avoidance of peak exercise in patients with hypertrophic cardiomyopathy), medication (e.g. beta-receptor blockers in patients with a long QT interval) or implantation of a pacemaker or internal defibrillator (e.g. in asymptomatic persons with the Brugada syndrome, a form of right bundle branch block). Presymptomatic investigation must be performed multidisciplinary.

Three people applied for genetic counselling, but during the consultations the clinical geneticist discovered other problems for which advice could have been given but was not asked. This caused a serious dilemma. The first person was a woman who wanted to know the risks of epilepsy for her potential offspring, but then it became clear that she appeared to have Huntington's disease in the family. The second person was a man who wanted to know about the genetic risks for his offspring of a borderline psychiatric disorder, but the geneticist, seeing that the partner had severe limb defects, wondered whether these were caused by a genetic disorder. The third patient was a pregnant woman who came asking about the risks caused by mental retardation in one of her ancestors, but who appeared to be a heavy drinker and user of cocaine and ecstasy. In dealing with such 'secondary' problems, it should be kept in mind that persons seeking advice must decide for themselves whether or not they want to be informed regarding these problems or not.

Congenital long RT syndrome (cLQTS) is electrocardiographically characterized by a prolonged RT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant (Romano Ward) or as an autosomal recessive disorder (Jervell and Lange-Nielsen syndrome). Mutations in at least five genes have been associated with the LQTS. Four genes, encoding cardiac ion channels, have been identified. The mast common forms of LQTS are due to mutations in the potassium-channel genes KCNQ1 and HERG, We have screened 24 Dutch LQTS families for mutations in KCNQ1 and HERG, Fourteen missense mutations were identified. Eight of these missense mutations were novel: three in KCNQ1 and five in HERG, Novel missense mutations in KCNQ1 were Y184S, S373P, and W392R and novel missense mutations in HERG were A558P, R582C, G604S, T613M, and F640L. The KCNQ1 mutation G189R and the HERG mutation R582C were detected in two families. The pathogenicity of the mutations was based on segregation in families, absence in control individuals, the nature of the amino acid substitution, and localization in the protein. Genotype-phenotype studies indicated that auditory stimuli as trigger of cardiac events differentiate LQTS2 and LQTS1, In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analyses for unequivocal diagnosis of patients with LQTS. Hum Mutat 13:301-310, 1999, (C) 1999 Wiley-Liss, Inc.