136 research outputs found

    Determining Group Structure from Sets of Irreducible Character Degrees

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    Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon heritable disease presenting with syncope or sudden cardiac death. Two genes involved in calcium homeostasis, the ryanodine receptor gene and the calsequestrin 2 (CASQ2) gene, have been implicated in this disease. We describe a young man presenting with exercise-induced syncope, clinically diagnosed as CPVT. Genetic analysis revealed two mutations, p.Y55C (C.164A>G) and p.P308L (c.923C>T), in the CASQ2 gene. Subsequent familial analysis indicates a compound heterozygous form of inheritance. (PACE 2008; 31:916-919). © 2008, The Authors. Journal compilation © 2008, Blackwell Publishing, Inc

    Long-Term Follow-Up Study on the Uptake of Genetic Counseling and Predictive DNA Testing in Inherited Cardiac Conditions

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    BACKGROUND: Inherited cardiac conditions present with a wide range of symptoms and may even result in sudden cardiac death. Relatives of probands with a confirmed pathogenic genetic variant are advised predictive DNA testing to enable prevention and treatment. In 2 previous cohort studies of 115 probands with a pathogenic variant, family uptake of genetic counseling was assessed in the first year(s) after test result disclosure to the proband. This study assesses uptake in these cohorts in the 14 to 23 years following disclosure. METHODS: Uptake was determined retrospectively using patient records. First-degree relatives, and second-degree relatives of a deceased first-degree relative suspected of having an inherited cardiac condition, were considered eligible. RESULTS: Of 717 eligible relatives (598 first-degree and 119 second-degree relatives), 60% attended genetic counseling. Most of them (68.6%) attended genetic counseling in the first year. A total of 98.4% of counseled relatives pursued predictive DNA testing. A total of 49.2% was identified as carrier. Median time between disclosure to the proband and counseling of relatives was 6 months (range: 0-187 months). Attending genetic counseling was observed more frequently in first-degree relatives, female relatives, primary arrhythmia syndromes, relatives with manifest inherited cardiac condition, relatives without children and families with sudden cardiac death in first-degree relatives <40 years. CONCLUSIONS: During median follow-up of 16 years, 60.0% of relatives attended genetic counseling, with 41.0% in the first year. Our results may suggest that some relatives are not or inadequately informed or that barriers against genetic counseling are present. Further research is needed into interventions facilitating family communication, increasing awareness among families and healthcare professionals, and lowering thresholds for genetic counseling

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

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    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

    Low rate of cardiac events in first-degree relatives of diagnosis-negative young sudden unexplained death syndrome victims during follow-up

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    BACKGROUND: Sudden unexplained death syndrome (SUDS) in young individuals often results from inherited cardiac disease. Accordingly, comprehensive examination in surviving first-degree relatives unmasks such disease in approximately 35% of the families. It is unknown whether individuals from diagnosis-negative families are at risk of developing manifest disease or cardiac events during follow-up.OBJECTIVE: This study aimed to study the prognosis of first-degree relatives of young SUDS victims, in whom the initial cardiologic and genetic examination did not lead to a diagnosis.METHODS: We retrieved vital status of surviving first-degree relatives from 83 diagnosis-negative families who presented to our cardiogenetics department between 1996 and 2009 because of SUDS in ≥1 relatives aged 1-50 years. Moreover, we contacted relatives who previously visited our center for detailed information.RESULTS: We obtained detailed information (median follow-up 6.6 years; interquartile range 4.7-9.6 years) in 340 of 417 first-degree relatives (81.5%) from 77 of 83 families (92.8%). Vital status, available in 405 relatives (97.1%), showed that 20 relatives (4.9%) died during follow-up, including 1 natural death before the age of 50. This girl belonged to a family with multiple cases of idiopathic ventricular fibrillation and SUDS, including another successfully resuscitated sibling during follow-up. Two hundred thirty-four of 340 first-degree relatives (68.8%) underwent cardiologic examination. Of these, 76 (32.5%) were reevaluated. Inherited cardiac disease was diagnosed in 3 families (3.6%).CONCLUSION: In first-degree relatives of young SUDS victims with no manifest abnormalities during the initial examination, the risk of developing manifest inherited cardiac disease or cardiac events during follow-up is low. This does not apply to families with obvious familial SUDS.</p

    Mortality of Inherited Arrhythmia Syndromes Insight Into Their Natural History

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    Background-For most arrhythmia syndromes, the risk of sudden cardiac death for asymptomatic mutation carriers is ill defined. Data on the natural history of these diseases, therefore, are essential. The family tree mortality ratio method offers the unique possibility to study the natural history at a time when the disease was not known and patients received no treatment. Methods and Results-In 6 inherited arrhythmia syndromes caused by specific mutations, we analyzed all-cause mortality with the family tree mortality ratio method (main outcome measure, standardized mortality ratio [SMR]). In long-QT syndrome (LQTS) type 1, severely increased mortality risk during all years of childhood was observed (1-19 years), in particular during the first 10 years of life (SMR, 2.9; 95% CI, 1.5-5.1). In LQTS type 2, we observed increasing SMRs starting from age 15 years, which just reached significance between age 30 and 39 (SMR, 4.0; 95% CI, 1.1-10.0). In LQTS type 3, the SMR was increased between age 15 and 19 years (SMR, 5.8; 95% CI, 1.2-16.9). In the SCN5A overlap syndrome, excess mortality was observed between age 10 and 59 years, with a peak between 20 and 39 years (SMR, 3.8; 95% CI, 2.5-5.7). In catecholaminergic polymorphic ventricular tachycardia, excess mortality was restricted to ages 20 to 39 years (SMR, 3.0; 95% CI, 1.3-6.0). In Brugada syndrome, excess mortality was observed between age 40 and 59 (SMR, 1.79; 95% CI, 1.2-2.4), particularly in men. Conclusions-We identified age ranges during which the mortality risk manifests in an unselected and untreated population, which can guide screening in these families. (Circ Cardiovasc Genet. 2012;5:183-189.

    Spectrophotometric, chemometric and chromatographic determination of naphazoline hydrochloride and chlorpheniramine maleate in the presence of naphazoline hydrochloride alkaline degradation product

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    AbstractFour accurate and sensitive methods were developed and validated for determination of naphazoline hydrochloride (NAP) and chlorpheniramine maleate (CLO) in the presence of naphazoline hydrochloride alkaline degradation product (NAP Deg). The first method is a spectrophotometric one , where NAP was determined by the fourth derivative (D4) spectrophotometric method by measuring the peak amplitude at 302nm, while CLO was determined by the second derivative of the ratio spectra (DD2) spectrophotometric method at 276.4nm. The second method is a chemometric-assisted spectrophotometric method in which partial least squares (PLS-1) and partial component regression (PCR) were used for the determination of NAP, CLO and NAP Deg using the information contained in their absorption spectra of ternary mixture. The third method is a TLC-densitometric one where NAP, CLO and NAP Deg were separated using HPTLC silica gel F254 plates using ethyl acetate:methanol:ammonia: (8:2:0.5, by volume) as the developing system followed by densitometric measurement at 245nm. The fourth method is HPLC method where NAP, CLO and NAP Deg were separated using ODS C18 column and a mobile phase consisting of 0.1M KH2PO4 (pH=7):methanol (55:45 v/v) delivered at 1.5mLmin−1 followed by UV detection at 265nm. The proposed methods have been successfully applied to the analysis of NAP and CLO in pharmaceutical formulations without interference from the dosage form additives and the results were statistically compared with a reported method

    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

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    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 chi(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 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

    Cognitive and affective outcomes of genetic counselling in the Netherlands at group and individual level:a personalized approach seems necessary

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    We performed a large outcome study at group and individual level in which the goals of genetic counselling were operationalized into cognitive and affective outcomes: empowerment, perceived personal control and anxiety. We then examined which socio-demographic and clinical variables were associated with changes in these outcomes. Data came from 1479 counselees who completed questionnaires (GCOS-18, PPC and STAI) at three time points: before the start of genetic counselling, after the first consultation and after the results of genetic counselling were disclosed. Results showed that at group level empowerment, perceived personal control and anxiety improved significantly after the whole genetic counselling process. Effect-sizes were medium for empowerment and small for the other outcomes. At individual level, 48% of counselees improved in empowerment, 21% in perceived personal control and 17% in anxiety. Around 10% of counselees worsened on all outcomes. Only 'reason for referral' and 'genetic test result' were significantly associated with changes in outcomes. This study demonstrated improvements among counselees in cognitive and affective outcomes after genetic counselling at group level. However, our results also suggest that there are opportunities for improvement at individual level, as many counselees remained stable and some even worsened on all outcomes. Routine outcome monitoring could help to explore the needs of counselees and could help to identify counselees who worsen.</p

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

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    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 €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

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

    No full text
    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
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