Views of patients and parents of children with genetic disorders on population-based expanded carrier screening.

OBJECTIVE: Faster and cheaper next generation sequencing technologies have enabled expansion of carrier screening for recessive disorders, potentially facilitating population-based implementation regardless of ancestry or family history. Little is known, however, about the attitudes regarding population-based carrier screening among families with genetic disorders. This study assessed views among parents and patients with a recessive disorder and parents of children with Down syndrome (DS) on expanded carrier screening (ECS). METHOD: In total, 85 patients with various recessive disorders, 110 parents of a child with a recessive disorder and 89 parents of a child with DS participated in an online survey in the Netherlands. Severity of recessive disorders was classified as mild/moderate or severe/profound. RESULTS: The majority of the (parents of) patients with a recessive disorder had a positive attitude towards population-based ECS, including screening for their own or their child's disorder. DS parents were significantly less positive towards ECS. Subgroup analyses showed that the severity of the disorder, rather than being a patient or parent, influences the attitudes, beliefs and intention to participate in ECS. CONCLUSION: Our findings have important implications for future implementation initiatives as they demonstrate the different perspectives from people with experiential knowledge with genetic disorders.

A prospective study on rapid exome sequencing as a diagnostic test for multiple congenital anomalies on fetal ultrasound.

OBJECTIVE: Conventional genetic tests (quantitative fluorescent-PCR [QF-PCR] and single nucleotide polymorphism-array) only diagnose ~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 ~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.

TRIDENT-2: National Implementation of Genome-wide Non-invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands.

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)-96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13-were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up.

A validated PROM in genetic counselling: the psychometric properties of the Dutch version of the Genetic Counselling Outcome Scale.

Patient empowerment has been identified as a key outcome goal in genetic counselling, and a patient reported outcome measure (PROM) has been developed to measure empowerment in genetic services: the Genetic Counselling Outcome Scale (GCOS). Here we validate the GCOS for a large and diverse Dutch study sample of 2194 patients referred to two clinical genetic centres for counselling about a wide range of conditions (heart disease, neurological disorders, cancer, congenital syndromes, intellectual disability and prenatal pathology). Our results suggest that the GCOS consists of a hierarchical 6-factor structure, with a main scale for empowerment and six subscales: uncertainty about heredity, hope, negative emotions, knowledge about the condition, knowledge about genetic services and uncertainty about the treatment. Six of the original 24 GCOS items were removed due to low factor loadings and small inter-item correlations. Internal consistency and test-retest reliability of the main scale and most subscales were satisfactory. Convergent validity was confirmed by moderate positive and moderate/strong negative associations between the GCOS main scale and other validated outcome measures. Responsiveness was comparable to that of other validated outcome measures. We saw significant improvement in the GCOS main scale and all the subscales after the first genetic counselling session. This study contributes to the international validation process of the GCOS, with the ultimate goal of using this instrument as a PROM, with empowerment as an outcome measure, to evaluate and improve the quality of genetic counselling in various clinical genetics settings.

The impact of national prenatal screening on the time of diagnosis and outcome of pregnancies affected with common trisomies, a cohort study in the Northern Netherlands.

BACKGROUND: To evaluate the impact of the introduction of prenatal screening on time of detection and pregnancy outcome for trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13). METHODS: We performed a retrospective, population-based cohort study in the Northern Netherlands including 503 trisomy cases born between 2005 and 2012. Screening tests and invasive procedures, timing of diagnosis and pregnancy outcome were compared between the period before (2005-2006) and after introduction (2007-2012) using X 2 tests. RESULTS: There was an increase in proportion of women who had a prenatal screening and/or invasive test, from 62% in 2005-2006 to 84% in 2010-2012 (p < 0.01), while the proportion of prenatally diagnosed cases did not change (60% overall). In women < =35 years 47% of the cases were diagnosed prenatally vs 73% in women >35 years (p < 0.01). More T13/T18 cases were diagnosed <24 weeks after introduction (62% vs 84%; p < 0.01). In T13/T18 intra-uterine death decreased (26% vs 15%), while terminations increased: 55% vs 72%. CONCLUSION: The introduction of prenatal screening had limited impact on the time of detection and outcome of the most common trisomies. The introduction of the 20-week anomaly scan has resulted in more trisomy cases diagnosed <24 weeks and a shift from fetal death to terminations.

Population-based preconception carrier screening: how potential users from the general population view a test for 50 serious diseases.

With the increased international focus on personalized health care and preventive medicine, next-generation sequencing (NGS) has substantially expanded the options for carrier screening of serious, recessively inherited diseases. NGS screening tests not only offer reproductive options not previously available to couples, but they may also ultimately reduce the number of children born with devastating disorders. To date, preconception carrier screening (PCS) has largely targeted single diseases such as cystic fibrosis, but NGS allows the testing of many genes or diseases simultaneously. We have developed an expanded NGS PCS test for couples; simultaneously it covers 50 very serious, early-onset, autosomal recessive diseases that are untreatable. This is the first, noncommercial, population-based, expanded PCS test to be offered prospectively to couples in a health-care setting in Europe. So far, little is known about how potential users view such a PCS test. We therefore performed an online survey in 2014 among 500 people from the target population in the Netherlands. We enquired about their intention to take an expanded PCS test if one was offered, and through which provider they would like to see it offered. One-third of the respondents said they would take such a test were it to be offered. The majority (44%) preferred the test to be offered via their general practitioner (GP) and 58% would be willing to pay for the test, with a median cost of [euro ]75. Our next step is to perform an implementation study in which this PCS test will be provided via selected GPs in the Northern Netherlands.

Online genetic counseling from the providers' perspective: counselors' evaluations and a time and cost analysis.

Telemedicine applications are increasingly being introduced in patient care in various disciplines, including clinical genetics, mainly to increase access to care and to reduce time and costs for patients and professionals. Most telegenetics reports describe applications in large geographical areas, showing positive patients' and professionals' satisfaction. One economic analysis published thus far reported lower costs than in-person care. We hypothesized that telegenetics can also be beneficial from the professional's view in relatively small geographical areas. We performed a pilot study in the Northern Netherlands of 51 home-based online counseling sessions for cardiogenetic and oncogenetic cascade screening, and urgent prenatal counseling. Previously, we showed patient satisfaction, anxiety, and perceived control of online counseling to be comparable to in-person counseling. This study focuses on expectations, satisfaction, and practical evaluations of the involved counselors, and the impact in terms of time and costs. Most counselors expected disadvantages of online counseling for themselves and their patients, mainly concerning insufficient non-verbal communication; few expected advantages for themselves. Afterwards, counselors additionally raised the disadvantage of insufficient verbal communication, and reported frequent technical problems. Their overall mean telemedicine satisfaction itemscore was 3.38 before, and 2.95 afterwards, being afterwards slightly below the minimum level we set for a satisfactory result. We estimated reduced time and costs by online counseling with about 8% and 10-12%, respectively. We showed online genetic counseling to be effective, feasible and cost-efficient, but technical improvements are needed to increase counselors' satisfaction.

Telegenetics use in presymptomatic genetic counselling: patient evaluations on satisfaction and quality of care.

In recent years, online counselling has been introduced in clinical genetics to increase patients' access to care and to reduce time and cost for both patients and professionals. Most telegenetics reports so far evaluated online oncogenetic counselling at remote health centres in regions with large travelling distances, generally showing positive patient outcomes. We think online counselling--including the use of supportive tools that are also available during in-person counseling--of presymptomatic patients in their homes can also be feasible and valuable for patients in relatively small regions. We performed a single-centre pilot study of online genetic counselling for 57 patients who were presymptomatic cardiogenetic (n=17), presymptomatic oncogenetic (n=34) and prenatal (3 couples). One-third of presymptomatic patients we approached consented to online counselling. Patient evaluations of practical aspects, satisfaction and psychological outcomes were assessed and compared with a matched control group. Patients managed to fulfil the preparations, were significantly more satisfied with their counsellor and counselling session than controls and were satisfied with the online counselling more than they expected to be beforehand. Psychological outcomes (decreased anxiety and increased control) did not differ with control patients. Technical problems occurred in almost half of online sessions. Nonetheless, online counselling in patients' homes proved to be feasible and was appreciated by a substantial part of presymptomatic patients at our genetics centre in the Netherlands. Based on these outcomes, we conclude online counselling can be a valuable addition to existing counselling options in regular patient care.

Maximising the efficiency of clinical screening programmes: balancing predictive genetic testing with a right not to know.

We explored the dilemma between patients' right not to know their genetic status and the efficient use of health-care resources in the form of clinical cancer screening programmes. Currently, in the Netherlands, 50% risk carriers of heritable cancer syndromes who choose not to know their genetic status have access to the same screening programmes as proven mutation carriers. This implies an inefficient use of health-care resources, because half of this group will not carry the familial mutation. At the moment, only a small number of patients are involved; however, the expanding possibilities for genetic risk profiling means this issue must be addressed because of potentially adverse societal and financial impact. The trade-off between patients' right not to know their genetic status and efficient use of health-care resources was discussed in six focus groups with health-care professionals and patients from three Dutch university hospitals. Professionals prefer patients to undergo a predictive DNA test as a prerequisite for entering cancer screening programmes. Professionals prioritise treating sick patients or proven mutation carriers over screening untested individuals. Participation in cancer screening programmes without prior DNA testing is, however, supported by most professionals, as testing is usually delayed and relatively few patients are involved at present. Reducing the number of 50% risk carriers undergoing screening is expected to be achieved by: offering more psychosocial support, explaining the iatrogenic risks of cancer screening, increasing out-of-pocket costs, and offering a less stringent screening programme for 50% risk carriers.

Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience.

AIMS: With more than 40 dilated cardiomyopathy (DCM)-related genes known, genetic analysis of patients with idiopathic DCM is costly and time-consuming. We describe the yield from genetic analysis in DCM patients in a large Dutch cohort. METHODS AND RESULTS: We collected cardiological and neurological evaluations, family screenings, and genetic analyses for 418 index patients with idiopathic DCM. We identified 35 (putative) pathogenic mutations in 82 index patients (20%). The type of DCM influenced the yield, with mutations found in 25% of familial DCM cases, compared with 8% of sporadic DCM cases and 62% of cases where DCM was accompanied by neuromuscular disease. A PLN founder mutation (43 cases) and LMNA mutations (19 cases, 16 different mutations) were most prevalent and often demonstrated a specific phenotype. Other mutations were found in: MYH7, DES, TNNT2, DMD, TPM1, DMPK, SCN5A, SGCB (homozygous), and TNNI3. After a median follow-up of 40 months, the combined outcome of death from any cause, heart transplantation, or malignant ventricular arrhythmias in patients with a mutation was worse than in those without an identified mutation (hazard ratio 2.0, 95% confidence interval 1.4-3.0). This seems to be mainly attributable to a high prevalence of malignant ventricular arrhythmias and end-stage heart failure in LMNA and PLN mutation carriers. CONCLUSION: The yield of identified mutations in DCM index patients with clinical clues, such as associated neuromuscular disease or familial occurrence, is higher compared with those without these clues. For sporadic DCM, specific clinical characteristics may be used to select cases for DNA analysis.

Clinical and genetic characterization of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy caused by a plakophilin-2 splice mutation.

OBJECTIVES: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by fibrofatty replacement of cardiomyocytes. In around 50% of index patients, a genetic predisposition is demonstrated. The purpose of this study was to examine a plakophilin-2 (PKP2) splice site mutation, c.2489+4A>C, identified in 4 separately ascertained Dutch ARVD/C families. METHODS: Genealogical studies and comprehensive screening of 5 desmosomal genes were undertaken. Reverse transcriptase PCR (RT-PCR) and subsequent sequencing was performed. RESULTS: An A-to-C change (c.2489+4A>C) near the splice donor site of intervening sequence 12 of PKP2 was found in all 4 families. Based on pedigree data and haplotype sharing, a common ancestor should be situated more than 7 generations ago. RT-PCR demonstrated the presence of aberrant messenger RNA. Clinical manifestations ranged from severe disease to nonpenetrance in elderly mutation carriers. CONCLUSIONS: This founder mutation in PKP2 is predicted to lead to the presence of a dysfunctional PKP2 protein, whereas most truncating mutations are expected to lead to loss of protein. Mutation carriers displayed a wide range of disease severity, suggesting that PKP2 mutations alone are not sufficient to cause disease, which results in the variable expression and incomplete penetrance characteristic of ARVD/C mutations.

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

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.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study.

BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. METHODS AND RESULTS: One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V(1) to V(3), especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations). CONCLUSIONS: Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives.

Cardiogenetic screening of first-degree relatives after sudden cardiac death in the young: a population-based approach.

AIMS: To investigate the yield of cardiogenetic screening of relatives of young sudden cardiac death (SCD) and sudden unexplained death (SUD) victims in a population-based setting. METHODS AND RESULTS: A population-based study was carried out between 2000 and 2006. Records of the hospital, death declaration certificates, and resuscitation records were reviewed for SCD and SUD cases (1-40 years). Information on autopsy results and cardiogenetic screening of the victims' first-degree relatives was collected. Relatives were invited for additional cardiogenetic screening when this had not yet been performed. The search led to 16 cases of SCD/SUD and 4 cases of aborted SCD/SUD. Causes of SCD/SUD were myocardial infarction (n = 3), arrhythmogenic right ventricular cardiomyopathy (ARVC) (n = 2), long-QT syndrome (n = 1), hypertrophic cardiomyopathy (n = 2), left ventricular hypertrophy due to aortic stenosis (n = 1), and unknown cause of death (n = 7). Causes of aborted SCD/SUD were myocardial infarction (n = 2), idiopatic ventricular fibrillation (n = 1), and the Brugada syndrome (n = 1). The cardiogenetic screening of 37 relatives of 12 victims led to a diagnosis of Brugada syndrome in 3 relatives and the suspicion of ARVC in 2 relatives. The yield of screening of these relatives was 14% (95% confidence interval: 3-25%). CONCLUSION: In the usual care, relatives of (aborted) SCD and SUD victims are often not referred for cardiogenetic screening. Screening is often not performed according to a systematic approach, and the detection rate of inherited diseases in relatives of (aborted) SCD and SUD victims in a population-based setting, although substantial, is lower than expected based on previous studies.

Desmin mutations as a cause of right ventricular heart failure affect the intercalated disks.

BACKGROUND: Mutations in the gene encoding desmin (DES), an intermediate filament protein, underlie a heterogeneous phenotype, which is referred to as desmin-related myopathy (DRM). Right ventricular involvement including an arrhythmogenic right ventricular cardiomyopathy (ARVC)(-like) phenotype has occasionally been described in DES mutation-carrying patients. OBJECTIVE: To determine the effects of a DES missense mutation on the structure of different intercalated disk proteins, to evaluate right ventricular involvement in DES mutation carriers, and to establish the role of DES mutations in ARVC(-like) phenotypes. METHODS: We evaluated the clinical phenotype in two families carrying two different DES mutations. One family was diagnosed with DRM, with an ARVC(-like) phenotype in one patient, while the other family presented with a severe biventricular cardiomyopathy. Additional immunohistochemistry of desmosomal proteins was performed in myocardial tissue from two patients of the last family. The DES gene was screened for mutations in 50 ARVC(-like) patients. RESULTS: Except for two different DES mutations (p.N342D and p.R454W) in two families with DRM and severe biventricular cardiomyopathy, respectively, we did not find additional DES mutations in ARVC(-like) patients. In addition to desmin aggregates, immunohistochemistry demonstrated a decreased amount of desmoplakin and plakophilin-2 at the intercalated disk in p.R454W mutation carriers. CONCLUSIONS: We confirmed that either an ARVC-like phenotype or a severe cardiomyopathy with right ventricular involvement are possible, yet infrequent, cardiac phenotypes in DRM. Moreover, we demonstrated that the DES mutation p.R454W affects the localization of desmoplakin and plakophilin-2 at the intercalated disk, suggesting a link between desmosomal cardiomyopathies (mainly affecting the right ventricle) and cardiomyopathies caused by DES mutations.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy diagnostic task force criteria: impact of new task force criteria.

BACKGROUND: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) Diagnostic Task Force Criteria (TFC) proposed in 1994 are highly specific but lack sensitivity. A new international task force modified criteria to improve diagnostic yield. A comparison of diagnosis by 1994 TFC versus newly proposed criteria in 3 patient groups was conducted. METHODS AND RESULTS: In new TFC, scoring by major and minor criteria is maintained. Structural abnormalities are quantified and TFC highly specific for ARVD/C upgraded to major. Furthermore, new criteria are added: terminal activation duration of QRS > or = 55 ms, ventricular tachycardia with left bundle-branch block morphology and superior axis, and genetic criteria. Three groups were studied: (1) 105 patients with proven ARVD/C according to 1994 TFC, (2) 89 of their family members, and (3) 39 patients with probable ARVD/C (ie, 3 points by 1994 TFC). All were screened for pathogenic mutations in desmosomal genes. Three ARVD/C patients did not meet the new sharpened criteria on structural abnormalities and thereby did not fulfill new TFC. In 62 of 105 patients with proven ARVD/C, mutations were found: 58 in the gene encoding Plakophilin2 (PKP2), 3 in Desmoglein2, 3 in Desmocollin2, and 1 in Desmoplakin. Three patients had bigenic involvement. Ten additional relatives (11%) fulfilled new TFC: 9 (90%) were female, and all carried PKP2 mutations. No relatives lost diagnosis by application of new TFC. Of patients with probable ARVD/C, 25 (64%) fulfilled new TFC: 8 (40%) women and 14 (56%) carrying pathogenic mutations. CONCLUSIONS: In this first study applying new TFC to patients suspected of ARVD/C, 64% of probable ARVD/C patients and 11% of family members were additionally diagnosed. ECG criteria and pathogenic mutations especially contributed to new diagnosis. Newly proposed TFC have a major impact in increasing diagnostic yield of ARVD/C.

Uptake of genetic counselling and predictive DNA testing in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is a common autosomal dominant disease, associated with heart failure and arrhythmias predisposing to sudden cardiac death. After the detection of the causal mutation in the proband predictive DNA testing of relatives is possible (cascade screening). Prevention of sudden cardiac death in patients with a high risk by means of an implantable cardioverter defibrillator is effective. In 97 hypertrophic cardiomyopathy families with a sarcomere gene mutation we retrospectively determined uptake of genetic counselling and predictive DNA testing in relatives within 1 year after the detection of the causal mutation in the proband. Uptake of genetic counselling was 39% and did not differ significantly by proband's or relative's gender, nor by young age of the relative (< 18 years) or a family history positive for sudden cardiac death. In second-degree relatives, eligible for predictive DNA testing when the first-degree relative had died, uptake was 27.5% (P = 0.047). Uptake of predictive genetic testing was 39%; conditional uptake of predictive genetic testing was 99%. Uptake of genetic counselling in hypertrophic cardiomyopathy is comparable to uptake in oncogenetics. Conditional uptake of predictive DNA testing, however, is much higher. Because sudden cardiac death can be prevented uptake of genetic counselling in hypertrophic cardiomyopathy should be as high as possible. To achieve this research into the determinants of uptake is needed.

Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy.

BACKGROUND: Mutations in the plakophilin-2 gene (PKP2) have been found in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC). Hence, genetic screening can potentially be a valuable tool in the diagnostic workup of patients with ARVC. METHODS AND RESULTS: To establish the prevalence and character of PKP2 mutations and to study potential differences in the associated phenotype, we evaluated 96 index patients, including 56 who fulfilled the published task force criteria. In addition, 114 family members from 34 of these 56 ARVC index patients were phenotyped. In 24 of these 56 ARVC patients (43%), 14 different (11 novel) PKP2 mutations were identified. Four different mutations were found more than once; haplotype analyses revealed identical haplotypes in the different mutation carriers, suggesting founder mutations. No specific genotype-phenotype correlations could be identified, except that negative T waves in V(2) and V(3) occurred more often in PKP2 mutation carriers (P<0.05). Of the 34 index patients whose family members were phenotyped, 23 familial cases were identified. PKP2 mutations were identified in 16 of these 23 ARVC index patients (70%) with familial ARVC. On the other hand, no PKP2 mutations at all were found in 11 probands without additional affected family members (P<0.001). CONCLUSIONS: PKP2 mutations can be identified in nearly half of the Dutch patients fulfilling the ARVC criteria. In familial ARVC, even the vast majority (70%) is caused by PKP2 mutations. However, nonfamilial ARVC is not related to PKP2. The high yield of mutational analysis in familial ARVC is unique in inherited cardiomyopathies.