12 research outputs found
Genetically isolated populations: Implications for genetic care
No full textGenetically isolated populations exist worldwide. They provide unique opportunities for genetic studies that may eventually lead to useful clinical applications. This thesis concerns such genetic studies in a young genetically isolated population in the Netherlands. We identified the genetic causes of two autosomal recessive disorders (fetal akinesia deformation sequence and XX female gonadal dysgenesis) and studied the phenotypic variation of another autosomal recessive disorder (retinitis pigmentosa type 12). Furthermore, we implemented a preconception outpatient clinic offering carrier screening for multiple severe recessive disorders in this population. Approximately one-third of the individuals visiting the clinic turned out to be a carrier of at least one of the disorders and 1 in 25 couples were a carrier couple with a 1-in-4 risk of affected offspring. We evaluated the carrier screening offer by taking questionnaires and conducting interviews. Attendees were highly familiar with the disorders, demonstrated no major psychological outcomes, experienced no stigmatization, and were very satisfied after testing. All identified carrier couples made reproductive decisions based on their test results. Although genetically isolated populations may differ in various aspects from other populations and not all research findings may be representative for an outbred population, investigations in isolated populations are helpful in understanding causes of genetic disorders and provide important lessons for further successful and responsible implementation of preconception (expanded) carrier screening and other genetic services in the general population
Iris heterochromia: A variable feature in Verloes-Koulischer-oral-acral syndrome [6]
No full textSCOPUS: le.jinfo:eu-repo/semantics/publishe
Prenatal diagnosis of a trisomy 7/trisomy 13 mosaicism
No full textAbstract Double aneuploidy mosaicism of two different aneuploidy cell lines is rare. We describe for the first time a double trisomy mosaicism, involving chromosomes 7 and 13 in a fetus presenting with multiple congenital anomalies. No evidence for chimerism was found by DNA genotyping. The origin of both trisomies are consistent with isodisomy of maternal origin. Therefore, it is most likely that the double trisomy mosaicism arose from two independent events very early in embryonic development. The trisomy 7 and 13 cells were shown to be of maternal origin.</p
Noninvasive prenatal diagnosis of Huntington disease: detection of the paternally inherited expanded CAG repeat in maternal plasma
No full textItem does not contain fulltextOBJECTIVE: With a shift towards noninvasive testing, we have explored and validated the use of noninvasive prenatal diagnosis (NIPD) for Huntington disease (HD). METHODS: Fifteen couples have been included, assessing a total of n = 20 pregnancies. Fetal paternally inherited CAG repeat length was determined in total cell-free DNA from maternal plasma using a direct approach by PCR and subsequent fragment analysis. RESULTS: All fetal HD (n = 7) and intermediate (n = 3) CAG repeats could be detected in maternal plasma. Detection of repeats in the normal range (n = 10) was successful in n = 5 cases where the paternal repeat size could be distinguished from maternal repeat patterns after fragment analysis. In all other cases (n = 5), the paternal peaks coincided with the maternal peak pattern. All NIPD results were concordant with results from routine diagnostics on fetal genomic DNA from chorionic villi. CONCLUSION: In this validation study, we demonstrated that all fetuses at risk for HD could be identified noninvasively in maternal plasma. Additionally, we have confirmed results from previously described case reports that NIPD for HD can be performed using a direct approach by PCR. For future diagnostics, parental CAG profiles can be used to predict the success rate for NIPD prior to testing. (c) 2015 John Wiley & Sons, Ltd
Targeted carrier screening for four recessive disorders: high detection rate within a founder population
No full textIn a genetically isolated community in the Netherlands four severe recessive genetic disorders occur at relatively high frequency (pontocerebellar hypoplasia type 2 (PCH2), fetal akinesia deformation sequence (FADS), rhizomelic chondrodysplasia punctata type 1 (RCDP1), and osteogenesis imperfecta (OI) type IIB/III. Over the past decades multiple patients with these disorders have been identified. This warranted the start of a preconception outpatient clinic, in 2012, aimed at couples planning a pregnancy. The aim of our study was to evaluate the offer of targeted genetic carrier screening as a method to identify high-risk couples for having affected offspring in this high-risk subpopulation. In one year, 203 individuals (92 couples and 19 individuals) were counseled. In total, 65 of 196 (33.2%) tested individuals were carriers of at least one disease, five (7.7%) of them being carriers of two diseases. Carrier frequencies of PCH2, FADS, RCDP1, and OI were 14.3%, 11.2%, 6.1%, and 4.1% respectively. In individuals with a positive family history for one of the diseases, the carrier frequency was 57.8%; for those with a negative family history this was 25.8%. Four PCH2 carrier-couples were identified. Thus, targeted (preconception) carrier screening in this genetically isolated population in which a high prevalence of specific disorders occurs detects a high number of carriers, and is likely to be more effective compared to cascade genetic testing. Our findings and set-up can be seen as a model for carrier screening in other high-risk subpopulations and contributes to the discussion about the way carrier screening can be offered and organized in the general populatio
Coming to terms with the National Socialist Past in teamWorx's TV Event Movies: 'Dresden' (2006), 'Nicht alle waren Mörder' (2006) and 'Die Flucht' (2007).
No full textThis thesis examines three made-for-television ‘Event Movies’ from the German production company teamWorx, made between 2006 and 2007 – Dresden (2006), Nicht alle waren Mörder (2006) and Die Flucht (2007) – within the context of contemporary debates of ‘Vergangenheitsbewältigung’ or ‘coming to terms with the past’ in Germany. It will deal with specific debates in memory of the National Socialist past, namely representations of Germans as victims of the Second World War and memory of the Holocaust. Although in recent years the importance of teamWorx’s television films has begun to be acknowledged by scholars in both Germany and the UK, this thesis represents the first attempt to analyse these three Event Movies as a unit and to explore in-depth the teamWorx company and its attitudes to historical film. As such, two interviews will be relied on throughout this thesis, with chairman of the board Nico Hofmann and Die Flucht’s director Kai Wessel.
In order to place the films within the context of contemporary debates on memory of the Nazi past in Germany, the thesis will undertake a filmic analysis of the Event Movies, supported by both the intentions of the filmmakers and critical responses in the contemporary press. Of primary importance for the thesis will be the twin concerns of the authenticity of teamWorx’s productions, as claimed by the filmmakers and the Event Movies’ borrowing of filmmaking devices from Hollywood genres, in particular the melodrama. Following this analysis it will be asked to what extent the Event Movies affect and reflect contemporary debates on the legacy of National Socialism and how these films contribute to the normalisation of the Nazi past in Germany
Coming to terms with the National Socialist Past in teamWorx's TV Event Movies: 'Dresden' (2006), 'Nicht alle waren Mörder' (2006) and 'Die Flucht' (2007)
No full textThis thesis examines three made-for-television ‘Event Movies’ from the German production company teamWorx, made between 2006 and 2007 – Dresden (2006), Nicht alle waren Mörder (2006) and Die Flucht (2007) – within the context of contemporary debates of ‘Vergangenheitsbewältigung’ or ‘coming to terms with the past’ in Germany. It will deal with specific debates in memory of the National Socialist past, namely representations of Germans as victims of the Second World War and memory of the Holocaust. Although in recent years the importance of teamWorx’s television films has begun to be acknowledged by scholars in both Germany and the UK, this thesis represents the first attempt to analyse these three Event Movies as a unit and to explore in-depth the teamWorx company and its attitudes to historical film. As such, two interviews will be relied on throughout this thesis, with chairman of the board Nico Hofmann and Die Flucht’s director Kai Wessel. In order to place the films within the context of contemporary debates on memory of the Nazi past in Germany, the thesis will undertake a filmic analysis of the Event Movies, supported by both the intentions of the filmmakers and critical responses in the contemporary press. Of primary importance for the thesis will be the twin concerns of the authenticity of teamWorx’s productions, as claimed by the filmmakers and the Event Movies’ borrowing of filmmaking devices from Hollywood genres, in particular the melodrama. Following this analysis it will be asked to what extent the Event Movies affect and reflect contemporary debates on the legacy of National Socialism and how these films contribute to the normalisation of the Nazi past in Germany
LONG-TERM FOLLOW-UP OF PATIENTS WITH RETINITIS PIGMENTOSA TYPE 12 CAUSED BY CRB1 MUTATIONS: A Severe Phenotype With Considerable Interindividual Variability
No full textPURPOSE: To examine the long-term clinical course and variability in a large pedigree segregating CRB1 type autosomal recessive retinitis pigmentosa. METHODS: An observational case study of 30 patients with CRB1 type autosomal recessive retinitis pigmentosa, homozygous for the CRB1 c.3122T > C; p.(Met1041Thr) mutation from a Dutch genetically isolated population in which the CRB1 gene was originally identified. The authors evaluated medical records, analyzed a questionnaire, and performed a comprehensive ophthalmic examination, including optical coherence tomography. RESULTS: Mean follow-up was 19 years (range 0-45 years, SD 15 years). With aging, patients showed progressive visual decline, deterioration of visual fields, increasing narrowing of the anterior chamber, increased prevalence of cataract, and an increase in the amount of intraretinal pigmentations. Fifty percent of patients had a visual acuity of ≤0.3 at Age 18 and of ≤0.1 at Age 35. Electroretinogram responses were severely reduced or absent already at a young age and optical coherence tomography showed increased retinal thickness with often cystoid maculopathy at young age, and thinning of the retina and disorientation of the photoreceptor layer in the late stages. The clinical course showed considerable interindividual variability, but intraindividual similarity between both eyes was the rule. CONCLUSION: The wide and variable clinical spectrum in patients with the same CRB1 mutation supports the hypothesis that the CRB1 type autosomal recessive retinitis pigmentosa-phenotype is modulated by other factors. The clinical variability will make it harder to evaluate the effect of (upcoming) therapies for retinitis pigmentosa, although because of the intraindividual similarity between both eyes, the contralateral eye can be used as an excellent internal control
Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis
No full textPontocerebellar hypoplasia (PCH) is a heterogeneous neurodegenerative disorder with a prenatal onset. Using whole-exome sequencing, we identified variants in the gene Coenzyme A (CoA) synthase (COASY) gene, an enzyme essential in CoA synthesis, in four individuals from two families with PCH, prenatal onset microcephaly, and arthrogryposis. In family 1, compound heterozygous variants were identified in COASY: c.[1549_1550delAG]; [1486-3 C>G]. In family 2, all three affected siblings were homozygous for the c.1486-3 C>G variant. In both families, the variants segregated with the phenotype. RNA analysis showed that the c.1486-3 C>G variant leads to skipping of exon 7 with partial retention of intron 7, disturbing the reading frame and resulting in a premature stop codon (p.(Ala496Ilefs*20)). No CoA synthase protein was detected in patient cells by immunoblot analysis and CoA synthase activity was virtually absent. Partial CoA synthase defects were previously described as a cause of COASY Protein-Associated Neurodegeneration (CoPAN), a type of Neurodegeneration and Brain Iron Accumulation (NBIA). Here we demonstrate that near complete loss of function variants in COASY are associated with lethal PCH and arthrogryposis
Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings
No full textItem does not contain fulltextIn recent studies on prenatal testing for Noonan syndrome (NS) in fetuses with an increased nuchal translucency (NT) and a normal karyotype, mutations have been reported in 9-16% of cases. In this study, DNA of 75 fetuses with a normal karyotype and abnormal ultrasound findings was tested in a diagnostic setting for mutations in (a subset of) the four most commonly mutated NS genes. A de novo mutation in either PTPN11, KRAS or RAF1 was detected in 13 fetuses (17.3%). Ultrasound findings were increased NT, distended jugular lymphatic sacs (JLS), hydrothorax, renal anomalies, polyhydramnios, cystic hygroma, cardiac anomalies, hydrops fetalis and ascites. A second group, consisting of anonymized DNA of 60 other fetuses with sonographic abnormalities, was tested for mutations in 10 NS genes. In this group, five possible pathogenic mutations have been identified (in PTPN11 (n=2), RAF1, BRAF and MAP2K1 (each n=1)). We recommend prenatal testing of PTPN11, KRAS and RAF1 in pregnancies with an increased NT and at least one of the following additional features: polyhydramnios, hydrops fetalis, renal anomalies, distended JLS, hydrothorax, cardiac anomalies, cystic hygroma and ascites. If possible, mutation analysis of BRAF and MAP2K1 should be considered
