431 research outputs found
To tell or not to tell? A systematic review of ethical reflections on incidental findings arising in genetics contexts
No full textAny test that produces visual images or digital or genetic sequences will tend to produce incidental findings because more will be visible than what was originally sought. We conducted a systematic review of the ethical reasons presented in the literature for and against the disclosure of incidental findings arising in clinical and research genetics contexts. A search of electronic databases resulted in 13 articles included for systematic review. Articles presented reasons for and against disclosure, and reasons for proceeding with caution when making decisions about disclosure. One major recommendation of the reviewed articles is in favor of qualified disclosure: incidental findings with confirmed clinical utility where there is the possibility of treatment or prevention should be disclosed, with exceptions. A second type of recommendation is that disclosure should proceed with caution, especially in the context of new genetic technologies and genetic testing involving minors. It is also recommended that the number of possible incidental findings be limited even before genetic testing is carried out. Such a policy, which we advocate, would show preference for non-disclosure.European Journal of Human Genetics advance online publication, 27 June 2012; doi:10.1038/ejhg.2012.130.sponsorship: This work was supported by FWO Flanders, project number G029107 and G.0594.09. K Devriendt is senior clinical investigator of the FWO-Vlaanderen and of the K.O.O.R U.Z.Leuven. We thank the anonymous reviewers for their valuable comments and suggestions. (FWO Flanders|G029107, FWO Flanders|G.0594.09)status: Publishe
Genetica van de hartontwikkeling bij de mens. De identificatie van genen betrokken in het ontstaan van aangeboren hartafwijkingen
No full textChromosome investigations are still an important part of the genetic inv estigations in children with congenital heart defects (CHDs). For this, chromosomes from dividing white blood cells are investigated under a mic roscope to check if certain chromosomes or parts of chromosomes are pres ent in too many or too little copies. In the present work we have invest igated whether submicroscopic chromosome imbalances are a frequent cause for CHDs. We introduced a novel genome-wide copy number profiling techn ique (aCGH) and showed that it enables a reliable detection of suc h imbalances at a resolution far surpassing the resolution of microscopi c chromosome investigations. The application of this technique in patien ts with a syndromic CHD greatly enhances the chance of finding an etiolo gical diagnosis. More precisely, in 20% of them, a disease-causing submi croscopic chromosome imbalance can be demonstrated. The correct delineat ion of chromosome aberrations by aCGH also entails a more accurate chara cterization of the genotype of the patient, permitting a more personaliz ed, specific genetic diagnosis. A diagnosis is of the utmost importance for the follow-up of the patients and their families, as it allows more correct counseling of patient and parents regarding recurrence risks and the mental and physical development that can be expected. In some cases it also impacts treatment of the patients as complications associated w ith certain genetic conditions can be prevented or managed from a subcli nical stage (e.g. hearing loss or cardiac complications). We showed that the application of higher-resolution platforms enables the genome-wide identification of indel mutations of single genes (e.g. in FOXC1 or ATRX ), but that this increased resolution is accompanied by an unexpected co mplexity in the evaluation of their causality. The identification of submicroscopic indels in the DNA of syndromic CHD patients pinpoints regions that contain a gene responsible for heart dev elopment. We detected many imbalances that affect genes known to cause C HDs. Accordingly, imbalances identified in this way that do not affect k nown genes for CHDs pinpoint novel candidate regions. The use of advance d database mining strategies like ENDEAVOUR aids in ranking and selectin g valuable candidate genes from these loci, and we showed that there is room for improvement by tailoring these tools to the needs of the underl ying clinical or scientific question. We have used expression analyses i n zebrafish embryos to identify the most valuable candidates from a grou p of high-ranked candidate genes. Genes that showed a specific expressio n in the developing zebrafish heart were considered good candidate genes . Only 2 out of 24 candidate genes displayed such a pattern: BMP4 and HAND2. Both genes are excellent candidates as they were already know n to be involved in mammalian heart development through studies in mice. In one person with a CHD we detected a deletion on the long arm of chrom osome 6. In this region, our algorithm identified TAB2 as the best candi date gene for causing heart defects. This gene is deleted in multiple pa tients with CHDs, is located in the critical deletion region and is rank ed first as a candidate gene amongst over 100 genes from the region. Los s of a copy of this gene is described to be associated with a high morta lity in newborn mice, and we have shown that it is associated with devel opmental defects in zebrafish. Although we could not identify pathogenic mutations in a group of 100 patients with isolated heart defects, other s did find a disruption of this gene in 3 members of a small family that have heart defects. This shows that loss of a copy of TAB2 is a rare ca use of CHDs.status: Publishe
Structural chromosomal rearrangements in autism spectrum disorders
No full textAutisme spectrum stoornis (ASS) is een heterogene groep van aandoeningen met deficits in sociale interactie, communicatie en taalontwikkeling, en kenmerken van stereotiep en repetitief gedrag. Hoewel ASS een sterk genetische basis heeft, zijn bij de meerderheid van de patiënten de genetische oorzaken en overervingsmodellen nog niet opgehelderd. Slechts 10-15% van de patiënten hebben een enkelvoudig genetische oorzaak, zoals een puntmutatie of chromosomale herschikking, vb. een gebalanceerde translocatie. Vaak zijn deze monogene oorzaken gekoppeld aan een syndromale vorm van ASS. Recent onderzoek heft aangetoond dat zeldzame kopij nummer varianten geassocieerd zijn aan ASS. Deze factoren kunnen beschouwd worden als belangrijke risicofactoren met matig tot groot effect. De meeste chromosomale herschikkingen en mutaties zijn echter niet recurrent, wat snelle vooruitgang in het onderzoek naar autisme genetica bemoeilijkt. Chromosomale herschikkingen vormen echter een ideaal uitgangspunt voor de ontdekking van nieuwe genen in ASS. In dit doctoraatsonderzoek werden de breekpunten van complexe de novo schijnbaar gebalanceerde herschikkingen gekarakteriseerd bij 4 ASS patiënten. Aldus werden verscheidene positionele kandidaatgenen geïdentificeerd aan de breekpunten. Bijkomend werden ook cryptische breekpunt-geassocieerde deleties gevonden bij 2 patiënten. Voor 2 synaptische genen, CDH11 and CNTN3, werd bijkomende genetische en biologische evidentie gevonden voor hun betrokkenheid bij ASS. Daarom werden ze werden geselecteerd voor mutatieanalyse en/of associatiestudies. Voor CDH11 werd bijkomende genetische evidentie gevonden voor de betrokkenheid in ASS. Daarnaast identificeerden we ook een nieuw kandidaatgen, FAM120C, door studie van een complexe submicroscopische X-gebonden deletie. Verder onderzoek op dit gen is momenteel bezig. Ook voor DISC1, een gen geassocieerd aan schizophrenie, werd bijkomende genetische evidentie gevonden voor de betrookkenheid in ASS. Tenslotte leidde onderzoek van een familiale 118kb microdeletie in de recurrente 16p11.2 CNV regio, tot een verkleining van de kritische ASS regio van 27 naar 5 genen: SEZ6L2, MVP, CDIPT, ASPHD1 and KCTD13. Met behulp van familie- en associatiestudies, hebben we getracht de verschillende genetische varianten onder te brengen in een frequentie-effect spectrum. Ook worden de moeilijkheden die optreden bij genetische adviesverlening besproken, met name het ontrafelen van het precieze overervingsmechanisme. Aangezien de meeste varianten uniek zijn voor 1 patiënt of familie, blijft het een zeer grote uitdaging om hun effectgrootte te voorspellen.In de laatste jaren is duidelijk geworden dat CNVs belangrijke risicofactoren zijn in ASS. Hoewel deze bevindingen zeer nuttig kunnen zijn bij het stellen van een diagnose, is de tijd nog niet rijp voor de implementatie van deze CNVs in a priori risicopredictie.status: Publishe
Chromosomale varianten in aangeboren hartafwijkingen
No full textCopy number variation in congenital heart defects The aim of this thesis was to advance our insight on copy number variation in thegenesis of congenital heart defects. The body of current knowledge on the genetics of CHD is scattered across publications, text books and genomic databases. To enhance the identification of chromosomal regions and genes recurrently linked to congenital heart defects, we developed a Wiki-based portal for standardized and curated integration of clinical and molecular data on CHD, termed CHDWiki, which is described in Part I of this thesis. In the first chapter we elaborate on the developmental process underlying CHDWiki, and we discuss on howthis Wiki knowledge and analysis portal can serve the broad community that is studying CHDs, ranging from the pediatric cardiologist and clinical geneticist to the basic investigator of cardiogenesis (Part I, Chapter 1 ) . Subsequently, all submicroscopic imbalances recurrently related to CHDs, compiled in CHDWiki, were evaluated in a systemic way todelineate overlapping imbalanced regions critical for heart development. We aimed to identify novel candidate genes for CHD within these regions, using computational gene prioritization tools. We provide an overviewof these results in chapter 2 (Part I, Chapter 2 ), and we elaborate on the delineation of 3 novel chromosomal CHD-related syndromes in chapter 3: the 16p13.3 microduplication syndrome, a novel recurrent 22q11 deletion and deletions on 10q22q23 (Part I, Chapter 3 ). Array comparative genomic hybridization is already widely used in a clinical setting for the diagnosis of individuals with congenital malformations . The interpretation of CNVs is challenging as infrequent disease-causing copy number changes should be distinguished from the abundant copy number variations without obvious major clinical significance. In Part II of this thesis, we discuss some of the challenges that arise upon the introduction of aCGH as a diagnostic tool in a clinical cardiogenetic setting, and introduce an algorithm for CNV interpretation (Part II, Chapter 1 ). We applied aCGH studies in large cohorts with syndromic CHD (Part II, Chapter 2 ) and sporadic non-syndromic CHD (Part II, Chapter 3 ). Based on our experience as well as those of others described in the literature, we outline the state-of-the-art and attempt toanswer a number of outstanding questions, such as the yield of aCGH in different patient populations, the added value of higher resolution arrays, and the existence of predictive factors in syndromic cases. Studies addressing the role of somatic copy number variation (CNV) in the genesis of congenital heart defects are scarce. In Part III of this thesis, we explore the occurrence of CNV differences in monozygotic twins discordant for the presenece of a congenital heart defect,as an illustrative model for chromosomal mosaicism in CHD.status: Publishe
Pulmonale Arteriële Hypertensie in Congenitaal Hartlijden in België: Prevalentie, Incidentie, Predictoren en Preklinische Detectiemethoden van Pulmonale Hypertensie
No full textPulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) implicates considerable morbidity and mortality. Through the unique Belgian Registry on Adult CHD, we first want to identify the prevalence and incidence of PAH in CHD. Also predictors of the development of PAH and long-term outcome will be defined.
Secondly, we would like to track these CHD patients who were discharged from follow-up in the past, but still prone to develop PAH later in life. Based on local database analysis, we identified around 1000 unreported patients, who might impact substantially the true prevalence and incidence of PAH.
Our research group showed earlier that, although pulmonary artery pressures seem to be normal at rest after late atrial septal defect closure, an abnormal increase in pulmonary vascular resistance during exercise is found. We hypothesize that patients who present with such mild pulmonary vascular disease may develop PAH and have impaired prognosis. We aim to develop an early detection method of PAH and want to investigate whether selective pulmonary vasodilators may alter outcome of these patients.
Lastly, in collaboration with the Centre for Human Genetics, we aim to look for a genetic link between CHD patients and the development of PAH. Remarkably, some patients develop PAH and others do not. Therefore, we believe that not only hemodynamic, but also genetic factors determine this clinical variability. Genetic screening could then be used as an additional detection tool for PAH in a preclinical stage, with new opportunities for prevention or early treatment.
Our research hypothesis:
We believe that the combination of environmental risk factors and a genetic predisposition leads to the development of early PVD (detectable by bicycle stress echocardiography). This early PVD may evolve to morphometric changes of the right heart and/or PAH development, and in the longer run to complications as arrhythmias and right heart failure. Early detection and treatment of pulmonary vascular disease could neutralize or at least slow down this pathophysiological process and perhaps prevent the development of PAH and its associated morbidity and mortality.status: Publishe
Homozygous loss-of-function mutation in ALMS1 causes the lethal disorder mitogenic cardiomyopathy in two siblings
No full textTwo siblings from consanguineous parents of Turkish descent presented with isolated dilated cardiomyopathy, leading to early death in infancy. The diagnosis of mitogenic cardiomyopathy was made histologically.sponsorship: This work was made possible by grants by the Unrestricted Eddy Merckx Research Fund, the FU Leuven (GOA/12/015). K. Devriendt is a senior clinical investigator of the FWO-Flanders. (Unrestricted Eddy Merckx Research Fund, FU Leuven|GOA/12/015)status: Publishe
Measuring traits of autism spectrum disorders in families: A search for informative phenotypes
No full textAutism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders defined by impairments in social communication and social interaction and by a restricted and repetitive pattern of behaviour and interests with a strong genetic basis. Finding genetic causes of ASDs has been complicated by both genotypic and phenotypic heterogeneity. To overcome these kinds of problems in psychiatry genetics, the concept of endophenotypes, traits that are thought to be intermediate between genes and phenotype, was introduced. In 2007 this concept was broadened to (genetically) informative phenotypes, with three subtypes, each with specific characteristics and ways in which they can be genetically informative. These phenotypes can be of biological, cognitive or behavioural nature. Criteria that should be met for some of these subtypes are, e.g., that it should segregate with the disorder, that it can be measured reliably, and that is present in unaffected family members at a higher frequency than in the general population.
In this doctoral dissertation, we describe different studies that aim at defining candidate informative phenotypes for ASDs, focusing on behavioural characteristics in participants with an ASD and their unaffected relatives. All the analyses were based on datanbsp;in 170 families with at least one childnbsp;an ASD.
A series of factor analyses on Developmental, Dimensional and Diagnostic Interview (3di) data from participants with an ASD results in a five dimensions solution (Chapter 2). The presence of these underlying constructs cannot be confirmed on 3di data of their unaffected siblings, and the same conclusion resulted from analyses on Social Responsiveness Scale (SRS) data. Based on these results, we conclude that clinical and research instruments that measure ASD traits result in different underlying symptom dimensions in ASD vs. non-ASD samples, and consequently, scores on separate symptom dimensions based on the clinical phenotype in ASD are not readily applicable as informative phenotypes in non-ASD samples (Chapter 3).
Another way of searching for informative phenotypes is by studying whether behavioural characteristics of individuals with an ASD are also present in their unaffected relatives. In Chapter 4 we report about atypical sensory processing in adolescents with an ASD using the Adolescent/Adult Sensory Profile. Their unaffected adolescent siblings show a level of sensation seeking that is intermediate between adolescents with an ASD and general population controls. We conclude that, although more research is definitely needed, Sensation Seeking may be a candidate genetically informative phenotype.
In a similar vein, we study quantitative autism traits (QAT) as measured by the Social Responsiveness Scale (SRS) of all participating family members. Based on comparisons of SRS total scores of participants with an ASD, their unaffected family members and general population controls, we demonstrate that fathers of children with an ASD show a higher level of QAT compared to controls (Chapter 5). In Chapter 6 we describe the association of QAT levels between family members. These results corroborate the assortative mating theory and possible intergenerational transmission of QAT from both fathers and mothers to their offspring. Combining our results and those of other studies, we can conclude that QAT measures, e.g., the SRS, may serve as a genetically informative phenotype.
In our general discussion, the methodological difficulties about the informative phenotype concept are thoroughly discussed. In short, we propose to use the umbrella term genetically informative phenotype, when studying behavioural characteristics in genetic research, since the use of subtypes leads to discussions about terminology, that may be contra productive for further research. Based on our analyses and results, but also on the questions we came across carrying out our studies, we also highlight important methodological issues for both researchers and clinicians. For ASD family studies, a thorough diagnostic screening of all family members appears to be very important since false allocation to an unaffected status can have major consequence on the results. For clinical practice, many questionnaires and interviews have been developed for screening and diagnostic assessment purposes. We discuss however, that clinicians should be aware that the context in which they are used, e.g., screening vs. diagnostic assessment in a psychiatric context vs. family research, can have great influence on their reliability.status: Publishe
Ethical signposts for clinical geneticists in secondary variant and incidental finding disclosure discussions
No full textWhile ethical and empirical interest in so-called secondary variants and incidental findings in clinical genetics contexts is growing, critical reflection on the ethical foundations of the various recommendations proposed is thus far largely lacking. We examine and critique the ethical justifications of the three most prominent disclosure positions: briefly, the clinical geneticist decides, a joint decision, and the patient decides. Subsequently, instead of immediately developing a new disclosure option, we explore relevant foundational ethical values and norms, drawing on the normative and empirical ethical literature. Four ethical signposts are thereby developed to help guide disclosure discussions. These are: respectful sharing of the clinician's expertise; transparent communication; epistemic modesty; and respect for the embedded nature of the patient. We conclude by considering the most common current disclosure positions in the light of the four ethical signposts.sponsorship: K. Devriendt and H. Van Esch are senior clinical investigators of the FWO-Vlaanderen and of the "Interuniversity Attraction Poles" programme of the Belgian federal scientific policy office, Project P7/43 "BeMGI." ("Interuniversity Attraction Poles" programme of the Belgian federal scientific policy office|P7/43 "BeMGI")status: Publishe
Genetische studies bij ontwikkelingsstoornissen van skelet en ledematen.
No full textAangeboren afwijkingen van skelet en ledematen komen voor bij 1/500 à 1/1000 pasgeborenen. De vorming en uitgroei van ledematen is een relatief recente ontwikkeling bij vertebraten. Dit verklaart waarom een groot aantal, reeds bestaande, moleculaire ontwikkelingsmechanismen hierbij werden overgenomen en ingeschakeld. Het is ook de uitleg voor het voorkomen van geassocieerde aangeboren afwijkingen bij meer dan 50 % van deze patiënten, en onderlijnt de noodzaak om deze groep van patiënten multidisciplinair te volgen.Sinds vele jaren is de ontwikkeling van de ledematen bij vertebraten een belangrijk model geweest voor onderzoek van morfogenese en organogenese in het algemeen, en dit onderzoek heeft geresulteerd in belangrijke nieuwe inzichten. In dit proefschrift hebben we verschillende klassieke en nieuwe technieken toegepast om een beter inzicht te krijgen in de moleculaire mechanismen van deze groep van aangeboren afwijkingen. Het uiteindelijke doel is een accurate klinische follow-up aan te bieden dankzij een correcte diagnose, die bovendien ook de mogelijkheid biedt voor adequate genetische counseling met de mogelijkheid van eventuele prenatale diagnostiek.Voor dit onderzoek hebben we een groep patiënten geselecteerd met complexe skeletale afwijkingen na een voorafgaandelijke grondige klinische en morfologische phenotypering.In het eerste deel van het proefschrift werden 2 patiënten die drager zijn van een zogenaamde gebalanceerde chromosomale herschikking, respectievelijk een translocatie en een inversie, verder moleculair onderzocht. Het betrof een persoon met een mesomelische skeletdysplasie, respectievelijk een persoon met Klippel-Feil syndroom. Onderzoek van de breukpunten betrokken in de chromosomale herschikkingen toonde geen disruptie van bekende genen, noch afwijkende expressie van geselecteerde genen die gelegen zijn in de nabijheid van de breukpunten. Verder onderzoek met nieuwe technologies zal hopelijk meer inzicht bijbrengen in de genotype/phenotype correlatie bij deze twee patiënten.In het tweede deel van dit proefschrift hebben we onderzoek verricht bij 58 personen met complexe aangeboren skeletafwijkingen met behulp van de zogenaamde microarray-CGH technologie. Als eersten konden we aantonen dat een microduplicatie/triplicatie ter hoogte van chromosoom 10q24 de moleculaire basis is van het zogenaamde Distal Limb Deficiency-Micrognathia syndroom. Verder onderzoek toonde dat deze 10q24 duplicatie/triplicatie eveneens teruggevonden wordt bij patiënten met syndromische vormen van kreefthand-kreeftvoet malformatie (SHFM3). De ernst van de lidmaatafwijking is bovendien gecorreleerd met de toename van het aantal genomische kopijen binnen deze locus.Een originele bijdrage is eveneens de aflijning van twee nieuwe syndromen binnen het zogenaamde Cenani-Lenz oligosyndactylie spectrum veroorzaakt door genomische herschikkingen in de GREMLIN1-FORMIN1 locus: 1) Een syndroom gekenmerkt door oligosyndactylie, radio-ulnaire synostose, gehoorverlies en nierafwijkingen;2) Een vorm van oligosyndactylie, gelijkend op Cenani-Lenz syndroom.Verder onderzoek is nodig om uit te maken in welke mate de GREM-1, respectievelijk FMN1, herschikkingen verantwoordelijk zijn voor deze phenotypes.In een finaal, derde onderzoeksdeel hebben we het klinisch phenotype bij patiënten met een 2q31 deletie verder gepreciseerd. We hebben aangetoond dat er geen aparte locus voor SHFM5 (kreefthand-kreeftvoet malformatie syndromische vorm 5) is, en dat enkel de HOXD genen betrokken zijn in de pathogenese van de variabele lidmaat defecten bij deze patiënten.Verder definieerden we de kritische loci voor het typische faciale voorkomen en de skeletafwijkingen, die resulteren in een klinisch herkenbaar 2q31.1 microdeletie syndroom. Verder onderzoek is nodig om uit te maken of 1 gen of meerdere genen (contigu gen deletie) verantwoordelijk is voor het specifiek faciale phenotype.In conclusie, bij 18,5 % van de onderzochte patiënten vonden we genetische afwijkingen die causaal zijn voor de skelet/lidmaatafwijkingen. De genetisch moleculaire oorzaak van het zogenaamde Distal Limb Deficiency-Micrognathia syndroom werd gevonden, en het klinische phenotype van het SHFM3 spectrum werd verder gedefinieerd. Tenslotte werden drie nieuwe syndromen afgelijnd:1) Het oligosyndactylie - radio-ulnaire synostose gehoorverlies nierafwijkingen syndroom;2) een vorm van oligosyndactylie gelijkend op Lenz-Cenani-syndroom en;3) het 2q31.1 microdeletie syndroom.status: Publishe
Genetica van Aangeboren Hartafwijkingen: Studies door Next-Generation Sequencing
No full textstatus: Publishe
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