158 research outputs found
Findings from aCGH in patients with congenital diaphragmatic hernia (CDH): A possible locus for Fryns syndrome (Am J Med Genet 140A:17–23, 2006)
No full textCongenital diaphragmatic hernia (CDH) is a common and often devastating birth defect that can occur in isolation or as part of a malformation complex. Considerable progress is being made in the identification of genetic causes of CDH. We applied array-based comparative genomic hybridization (aCGH) of approximately 1Mb resolution to 29 CDH patients with prior normal karyotypes who had been recruited into our multi-site study. One patient, clinically diagnosed with Fryns syndrome, demonstrated a de novo 5Mb deletion at chromosome region 1q41-q42.12 that was confirmed by FISH. Given prior reports of CDH in association with cytogenetic abnormalities in this region, we propose that this represents a locus for Fryns syndrome, a Fryns syndrome phenocopy, or CDH
Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism
No full textFirst published online in 2009Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan-Fryns and FG syndromes), nonspecific X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361(*), in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan-Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse.F. Laumonnier, C. Shoubridge, L.S. Nguyen, H. Van Esch, T. Kleefstra, S. Briault, J.P. Fryns, B. Hamel, J. Chelly, H.H. Ropers, N. Ronce, S. Blesson, C. Moraine, J. Gécz and M. Raynau
The concurrence of the blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) and Langer type of mesomelic dwarfism in the same patient. Evidence of the location of Langer type of mesomelic dwarfism at 3q22.3-q23?
No full textScreening for the Fragile X Syndrome: The Necessity of International Guidelines for Molecular Genetics Predictive Testing in General
No full texteditoria
Y-chromosome mosaicism with ring Y-chromosome/idic(Y)(p11.2) and “normal” ovarian development
No full textThe clinical phenotype in institutionalised adult males with X-linked mental retardation (XLMR).
No full textItem does not contain fulltextIn an institutionalised population of 471 mentally retarded adult residents (436 males and 35 females), 22 males (i.e. 5 % of the male population) had XLMR, accounting for 36.1 % of the residents diagnosed with a monogenic disorder (n = 61). Fragile X syndrome (FRAXA) was diagnosed in 16 residents, X-linked mental retardation with marfanoid habitus (Lujan-Fryns syndrome) in 2, and non-specific X-linked mental retardation (MRX) in 4 males. The 4 MRX-patients included 3 male sibs of a family, carrying a mutation in the IL-1 receptor accessory protein-like gene, and one male patient member of the MRX-44 family (linkage with LOD-score of 2.90). In the group of 215 males with idiopathic mental retardation (MR), family histories and pedigree data were compatible with XLMR in 35 males (35/215 = 16.3 %) from 32 families. Of these 35 males, 5.7 % were microcephalic with dysmorphic features and 5.7 % macrocephalic; micro-orchidism and macro-orchidism were each found in 11.4 %. One macrocephalic male had also macro-orchidism and dysmorphic features. In this study, the diagnosis of XLMR could thus be proposed in 57 males i.e. 13.1 % of the total male population. The clinical phenotype, behavioural problems and follow-up data in these different subgroups of XLMR are presented
Nonsyndromic x-linked mental retardation: where are the missing mutations?
No full textAnalysis of linkage intervals from 125 unrelated families with nonsyndromic X-linked mental retardation (NS-XLMR) has revealed that the respective gene defects are conspicuously clustered in defined regions of the human X-chromosome, with approximately 30% of all mutations being located on the proximal Xp. In 83% of these families, underlying gene defects are not yet known. Our observations should speed up the search for mutations that are still missing and pave the way for the molecular diagnosis of this common disorder.Hans-Hilger Ropers, Maria Hoeltzenbein, Vera Kalscheuer, Helger Yntema, Ben Hamel, Jean-Pierre Fryns, Jamel Chelly, Michael Partington, Jozef Gecz and Claude Morain
Between facts and norms. An ethical analysis of the relationship between empirical and normative approaches in bioethics with a focus on carrier testing in minors.
No full textAlhoewel de bioethiek sinds haar ontstaan een multidisciplinair onderzoe ksveld is, heeft ze zich vooral ontwikkeld als een normatieve discipline, geankerd in de disciplines van filosofie en theologie. De recente opkomst van empirische studies waarbij bioethische thema's on derzocht worden, plaatst de bioethiek voor fundamentele en methodol ogische vragen. Wat is immers de plaats van empirisch onderzoek in ethis che reflectie en besluitvorming en hoe is een dialoog of integratie tuss en empirische en normatieve benaderingen mogelijk? Dit onderzoeksproject heeft vijf concrete onderzoeksdoelstellingen uitgewerkt. Ten eerste ste lt dit onderzoeksproject als doel inzicht te krijgen in de aard en evolu tie van empirische studies in bioethiek. Ten tweede heeft dit onder zoeksproject als doel om vanuit een historisch perspectief de relat ies tussen empirische wetenschappen en bioethiek te onderzoeken. Te n derde wil dit onderzoeksproject onderzoek op welke manier resulta ten van empirisch onderzoek geïntegreerd kunnen worden in het ethische b esluitvormingsproces. Ten vierde wil dit onderzoeksproject de rol v an evidence-based medicine bestuderen voor ethische reflectie. Tens lotte wil dit onderzoeksproject bestuderen hoe in de ethische discussie over dragerschapstests bij minderjarigen de verhouding tussen empirisch onderzoek en normatieve benaderingen interfereert. Dit doctoraatsonderzoek heeft tot zes onderzoeksartikelen geleid, waarva n er reeds vier gepubliceerd zijn of aanvaard voor publicatie. Twee arti kelen zijn nog in review. Hierbij volgt de abstract van deze onderzoeksa rtikelen. 1) Empirical research in bioethics. A quantitative analysis Submitted for review Objectives: The objective of this research is to analyze the evolu tion and nature of published empirical research in the fields of medical ethics and bioethics. Design: Retrospective quantitative stu dy of nine peer reviewed journals in the field of bioethics and medical ethics (Bioethics, Cambridge Quarterly of Healthcare Ethic s, Hastings Center Report, Journal of Clinical Eth ics, Journal of Medical Ethics, Kennedy Institute of Ethics Journal, Nursing Ethics, and Theoretical Medicine and Bioethics). Results: In total 4029 articles published between 1990 and 2003 were retrieved from the nine bioethical journals under study. Over this period of time, 435 (10.8%) studies used an empirical design. The highest percentage of empirical research artic les appeared in Nursing Ethics (n=145, 39.51%), followed by the Jou rnal of Medical Ethics (n=128, 16.75%) and the Journal of Clinical Ethic s (n=93, 15.37%). These three journals together account for 84.13% of al l empirical research in bioethics published in this period. The results of the chi-square test for two independent samples for the entire datase t indicate that the period 19972003 presented a higher number of empiri cal studies (n=309) than did the period 19901996 (n=126). This increase is statistically significant (χ2=49.0264, p<.0001). Most empirical studies employed a quantitative paradigm (64.6%, n=281). The main topic of research was prolongation of life and euthanasia (n=68, e.g., artifi cial feeding, DNR orders, persistent vegetative state, and euthanasia).& nbsp;Conclusions: We concluded that the proportion of empiric al research steadily increased from 5.38% in 1990 to 15.36% in 2003. Wit hout a doubt, the importance of empirical methods in medical ethics and bioethics can only be expected to increase. 2) The birth of the empirical turn in bioethics P. Borry, P. Schotsmans, K. Dierickx, Bioethics 2005; 19 (1): 49-71. Since its origin, bioethics has attracted the collaboration of few socia l scientists, and social scientific methods of gathering empirical data have remained unfamiliar to ethicists. Recently, however, the clouded re lations between the empirical and normative perspectives on bioethics ap pear to be changing. Three reasons explain why there was no easy and con sistent input of empirical evidence into bioethics. Firstly, interdiscip linary dialogue runs the risk of communication problems and divergent ob jectives. Secondly, the social sciences were absent partners since the b eginning of bioethics. Thirdly, the meta-ethical distinction between is and ought created a natural border between the disciplines. Now, b ioethics tends to accommodate more empirical research. Three hypotheses explain this emergence. Firstly, dissatisfaction with a foundationalist interpretation of applied ethics created a stimulus to incorporate empir ical research in bioethics. Secondly, clinical ethicists became engaged in empirical research due to their strong integration in the medical set ting. Thirdly, the rise of the evidence-based paradigm had an influence on the practice of bioethics. However, a problematic relationship cannot simply and easily evolve into a perfect interaction. A new and positive climate for empirical approaches has arisen, but the original difficult ies have not disappeared. 3) What is the role of empirical research in ethical reflection and decision-making? An ethical analysis P. Borry, P. Schotsmans, K. Dierickx, Med Health Care Phil&nbs p;2004; 7 (1): 41-53. The field of bioethics is increasingly coming into contact with empirica l research findings. In this article, we ask what role empirical researc h can play in the process of ethical clarification and decision-making. Ethical reflection almost always proceeds in three steps: the descriptio n of the moral question, the assessment of the moral question and the ev aluation of the decision-making. Empirical research can contribute at ea ch step of this process. In the description of the moral object, first o f all, empirical research has a role to play in the description of moral ly relevant facts. It plays a role in answering the "reality-revealing q uestions" (what, why, how, who, where and when), in assessing the conseq uences and in proposing alternative courses of action. Secondly, empiric al research plays a role in assessing the moral question. It must be ack nowledged that research possesses "the normative power of the factual", which can also become normative by suppressing other norms. However, ind uctive normativity should always be balanced out by a deductive form of normativity. Thirdly, empirical research also has a role to play in eval uating the decision-making process. It can rule out certain moral choice s by pointing out the occurrence of certain unexpected consequences or e ffects. It can also be useful, however, as a sociology of bioethics in w hich the discipline of bioethics itself becomes an object of research. 4) Evidence-based medicine and its role in ethical decision-mak ing P. Borry, P. Schotsmans, K. Dierickx, J Eval Clin Pract (accepted). The recent emergence of evidence-based medicine (EBM) presents medical e thics with the challenge of analyzing what is the current best medical e vidence in ethical decision-making. This article concludes that the use of the best available, most recently published research findings is a pr imary moral obligation. However, this does not automatically mean that t he use of these research findings will lead to better ethical decision-m aking. Research data can be distorted by methodological failings in the design and reporting of experiments, or by technical and commercial bias . Moreover, the introduction of norms, values, principles and ethical th eories can lead to other choices than those proposed by empirical resear ch findings. Ethical decision-making must be informed and legitimated by the best available medical research. Nevertheless, ethical decision-mak ing is still primarily a choice based on values and norms. 5) Attitudes towards carrier testing in minors: a systematic re view P. Borry, J.P. Fryns, P. Schotsmans, K. Dierickx, Genet Couns (acce pted). Objectives: The objective of this article is to review the at titudes of the different stakeholders (minors, healthcare professionals, parents and relatives of affected individuals) towards carrier testing in minors. Design: The databases Pubmed, Google Scholar, Psychinfo, Biological Abstracts, Francis, Anthropological Index online, Web of Science, and Sociological Abstracts were searched using key word s for the period 1990-2004. Studies were included if they were published in a peer reviewed journal in English and described the attitudes of mi nors, parents or healthcare professionals towards carrier testing in min ors in a family context. The results were presented in a summary form.&n bsp;Results: In total 20 relevant studies were retrieved (2 s tudies reported the attitudes of two stakeholders). Only one study repor ted the attitudes of adolescents, two studies reported the attitudes of adults who had undergone carrier testing in childhood. In total six stud ies have been retrieved discussing the parental attitudes towards carrie r testing in their children. Over all studies, most parents showed inter est in detecting their childrens carrier status and responded they want ed their child tested before the age of majority; some parents even befo re 12 years. Eight studies were retrieved that reported the attitudes of relatives of affected individuals. Most were in favor of carrier testin g before 18 years. Conclusion: The studies retrieved sug gest that most parents are interested in the carrier status of their chi ldren and want their children to be tested before they reach legal major ity (and some even in childhood). This can lead to tensions between pare nts and healthcare professionals regarding carrier testing in minors. Gu idelines of healthcare professionals advise to defer carrier testing on the grounds that children should be able to decide for themselves later in life to request a carrier test or not. 6) Carrier testing in minors: a systematic review of guidelines and position papers Submitted for review. Objectives: The objective of this article is to review all pu blished normative ethical and clinical guidelines concerning the genetic carrier testing of minors. Design: The databases Pubmed , Philosophers Index, Biological Abstracts, Web of Science, and Google Scholar were searched using keywords relating to the carrier testing of children. We also searched the websites of the national bioethics commit tees indexed on the websites of WHO and the German Reference Center for Ethics in the Life Sciences, the Human Genetics Societies of various nat ions indexed on the website of the International Federation of Human Gen etics Societies and related links, and the national medical associations indexed on the website of the World Medical Association. Result s: We retrieved 14 guidelines emanating from 24 different groups . All guidelines advanced the following preferences: (1) carrier testing should not be performed in children, and (2) testing should be deferred until the child can give proper informed consent to be tested. The guid elines varied in three areas: (a) the role of genetic services in ensuri ng that children are informed about their carrier status and associated risks when they are older; (b) exceptions to the general rule of withhol ding or deferring carrier testing; and (c) the communication of incident ally discovered carrier status. Conclusion: In the absen ce of compelling reasons, carrier testing of a child can reasonably be d eferred until the child has the intellectual capacity needed to discern if and when to be tested.status: Publishe
Human chromosome fragility
No full textFragile sites are heritable specific chromosome loci that exhibit an increased frequency of gaps, poor staining, constrictions or breaks when chromosomes are exposed to partial DNA replication inhibition. They constitute areas of chromatin that fail to compact during mitosis. They are classified as rare or common depending on their frequency within the population and are further subdivided on the basis of their specific induction chemistry into different groups differentiated as folate sensitive or non-folate sensitive rare fragile sites, and as aphidicolin, bromodeoxyuridine (BrdU) or 5-azacytidine inducible common fragile sites. Most of the known inducers of fragility share in common their potentiality to inhibit the elongation of DNA replication, particularly at fragile site loci. Seven folate sensitive (FRA10A, FRA11B, FRA12A, FRA16A, FRAXA, FRAXE and FRAXF) and two non-folate sensitive (FRA10B and FRA16B) fragile sites have been molecularly characterized. All have been found to represent expanded DNA repeat sequences resulting from a dynamic mutation involving the normally occurring polymorphic CCG/CGG trinucleotide repeats at the folate sensitive and AT-rich minisatellite repeats at the non-folate sensitive fragile sites. These expanded repeats were demonstrated, first, to have the potential, under certain conditions, to form stable secondary non-B DNA structures (intra-strand hairpins, slipped strand DNA or tetrahelical structures) and to present highly flexible repeat sequences, both conditions which are expected to affect the replication dynamics, and second, to decrease the efficiency of nucleosome assembly, resulting in decondensation defects seen as fragile sites. Thirteen aphidicolin inducible common fragile sites (FRA2G, FRA3B, FRA4F, FRA6E, FRA6F, FRA7E, FRA7G, FRA7H, FRA7I, FRA8C, FRA9E, FRA16D and FRAXB) have been characterized at a molecular level and found to represent relatively AT-rich DNA areas, but without any expanded repeat motifs. Analysis of structural characteristics of the DNA at some of these sites (FRA2G, FRA3B, FRA6F, FRA7E, FRA7G, FRA7H, FRA7I, FRA16D and FRAXB) showed that they contained more areas of high DNA torsional flexibility with more highly AT-dinucleotide-rich islands than neighbouring non-fragile regions. These islands were shown to have the potential to form secondary non-B DNA structures and to interfere with higher-order chromatin folding. Therefore, a common fragility mechanism, characterized by high flexibility and the potential to form secondary structures and interfere with nucleosome assembly, is shared by all the cloned classes of fragile sites. From the clinical point of view, the folate sensitive rare fragile site FRAXA is the most important fragile site as it is associated with the fragile X syndrome, the most common form of familial mental retardation, affecting about 1/4000 males and 1/6000 females. Mental retardation in this syndrome is considered as resulting from the abolition of the FMR1 gene expression due to hypermethylation of the gene CpG islands adjacent to the expanded methylated trinucleotide repeat. FRAXE is associated with X-linked non-specific mental retardation, and FRA11B with Jacobsen syndrome. There is also some evidence that fragile sites, especially common fragile sites, are consistently involved in the in vivo chromosomal rearrangements related to cancer, whereas the possible implication of common fragile sites in neuropsychiatric and developmental disorders is still poorly documented.status: Publishe
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