30 research outputs found
Novel deletion variants of 9q13–q21.12 and classical euchromatic variants of 9q12/qh involve deletion, duplication and triplication of large tracts of segmentally duplicated pericentromeric euchromatin
No full textLarge-scale copy number variation that is cytogenetically visible in normal individuals has been described as euchromatic variation but needs to be distinguished from pathogenic euchromatic deletion or duplication. Here, we report eight patients (three families and two individuals) with interstitial deletions of 9q13-q21.12. Fluorescence in situ hybridisation with a large panel of BACs showed that all the deleted clones were from extensive tracts of segmentally duplicated euchromatin, copies of which map to both the long and short arms of chromosome 9. The variety of reasons for which these patients were ascertained, and the phenotypically normal parents, indicates that this is a novel euchromatic variant with no phenotypic effect. Further, four patients with classical euchromatic variants of 9q12/qh or 9p12 were also shown to have duplications or triplications of this segmentally duplicated material common to both 9p and 9q. The cytogenetic boundaries between the segmentally duplicated regions and flanking unique sequences were mapped to 9p13.1 in the short arm (BAC RP11-402N8 at 38.7 Mb) and to 9q21.12 in the long arm (BAC RP11-88I18 at 70.3 Mb). The BACs identified in this study should in future make it possible to differentiate between clinically significant deletions or duplications and euchromatic variants with no established phenotypic consequence
The search for tourette syndrome genes : a conceptual and experimental approach
No full textDissertation (PhD) -- University of Stellenbosch, 1999.ENGLISH SUMMARY: Tourette syndrome has been reported in most populations throughout the world.
Overall, there appears to be similar clinical phenomenology and psychopathology,
which may serve as an indication of the biological nature for the condition.
The diagnosis of Tourette syndrome represents a challenge for physicians because of
clinical heterogeneity and often-present comorbidity with other known
neurobehavioural conditions. Due to these clinical overlaps Tourette syndrome may
serve as a model disorder for investigating the relationship between various
neurological and behavioral domains of childhood reflecting either the expression of a
common biological pathway or a common genetic background. The understanding of
the genetic basis of Tourette syndrome is therefore of special importance, because it
may provide useful insights for the study of other developmental disorders. However,
the lack of objective biological markers of clinical manifestation together with a
possible high phenocopy rate, unclear mode of inheritance, incomplete penetrance,
and frequent bilinear transmission of predisposing genes represent major obstacles for
those attempting to elucidate the genetic basis of Tourette syndrome.
The research presented in this document is a result of six years' effort of the author
and her collaborators to generate cytogenetic and molecular genetic data contributing
to a better understanding of genetic and environmental factors affecting the
phenotypic expression of Tourette syndrome. Theoretical and experimental results of
this collaborative effort are assembled in seven articles (four published, three
currently submitted for a publication) and a general introductory section relating to
the problems, methods and methodology described and utilized in data collection for
the individual papers.
Taken as a whole, while the study of chromosome fragile site expression in Tourette
syndrome probands yielded equivocal results leading to a number of rather speculative but interesting interpretations, the results of subsequent molecular genetic
studies are far clearer.
The three most valuable outcomes of these studies for future genetic investigations in
Tourette syndrome gene-mapping efforts in the Afrikaner population, and complex
genetic traits in general, are:
I. The evidence for association/linkage of at least three genomic regions with
Tourette syndrome in the Afrikaner population, with two of the regions (11q23
and 8q22) being suggestively linked to Tourette syndrome by others in different
populations and employing different analytical methods.
2. The evidence for extended background linkage disequilibrium in the general
Afrikaner population (> 5 cM) which further strengthens existing experimental
data demonstrating the suitability of this population for gene-mapping efforts
involving complex traits.
3. The proof based on real rather than computer-simulated data that sequential and
semiparametric methods of analysis could be sufficiently powerful to generate
cumulative evidence for positive linkage with the trait in the regions which
repeatedly yielded both highly significant as well as suggestively significant
disease-marker associations in the initial set of samples.AFRIKAANSE OPSOMMING: Tourettesindroom is 'n algemene oorerflike neurobiologiese probleem wat in verskeie
bevolkingsgroepe vanoor die wereld beskryf is. As gevolg van identiese
fenomenologie en psigopatologie ten spyte van omgewingsverskille, is dit aanduidend
van 'n sterk biologiese grondslag vir die toe stand.
Die teenwoordigheid van kliniese meersoortigheid en die verhoogde voorkoms van 'n
verskeidenheid komorbiede probleme by 'n subgroep van individue met
Tourettesindroom, veroorsaak dikwels probleme met die akkurate identifisering
hiervan. Dit skep egter ook geleenthede vir die bestudering by kinders, van verskeie
neurologiese en gedragsmanifestasies gebaseer op 'n gemene genetiese substraat.
Insig in die genetiese-omgewings wisselwerking by Tourettesindroom baan dus die
weg vir begrip van ander ontwikkelingsprobleme wat ook by kinders aangetref word.
Die afwesigheid van 'n betroubare biologiese merker of merkers vir hierdie kliniese
entiteit, die algemene voorkoms van fenokopiee, komplekse oorerwingspatroon,
onvolledige penetrasie en algemene verskynsel van oorerwing vanaf beide ouers,
verteenwoordig 'n aantal formidabele struikelblokke ten opsigte van die analise van
die genetiese basis van Tourettesindroom.
TS word as een van die komplekse oorerflike toestande beskou, wat beteken dat daar
duidelike oorerflike faktore by betrokke is, maar dat die oorerwing nie-mendelies van
aard is. Die gebruiklike reduksionistiese benaderings wat so suksesvol was vir die
analise van die enkelgeentoestande, werk nie meer onder hierdie omstandighedenie,
en vir die rede word verskeie nie-parametriese of semiparametriese modelle ingespan.
Die gedokumenteerde resultate verteenwoordig die navorsing uitgevoer tesame met
plaaslike en oorsese medewerkers op hierdie gebied gedurende die laaste ses jaar. Die
teoretiese en eksperimentele resultate word weergegee in sewe publikasies.
Hiertydens is sitogenetiese en molekulere gegewens versamel in 'n poging om die
genetiese en omgewingsfaktore onderliggend tot die ekspressie van Tourettesindroom te bepaal. Die teoretiese en eksperimentele resultate van hierdie poging word
weergegee in sewe publikasies, waarvan vier reeds gepubliseer is, en 'n algemene
inleidende afdeling wat die probleme en metodes bespreek soos tydens die
versameling en analise van die data ervaar is.
Die resultate word in twee afdelings aangebied: eerstens is daar die teoretisering ten
opsigte van die bevinding van chromosomale breekbaarheid, wat aangedui is om
verhoog te wees in die Tourette groep. Die betekenis van hierdie bevinding is tans
nog onduidelik, en as gevolg van resolusieverskille nie direk met die DNA bevindings
korreleerbaar nie. Hierdie merkerareas moet egter deurgaans in gedagte gehou word
as moontlik aanwysend van die ligging van kandidaatgene vir Tourettesindroom.
Die belangrikste gedeelte behandel egter die benadering tot die totale genoomsifiing,
sowel as die veilgheidsmaatreels ingebou deur die heranalise van verskeie subgroepe
en gevolglike replisering van resultate.
Die mees waardevolle implikasies van hierdie navorsing ten opsigte van die
uitstippeling van die pad vorentoe vir Tourettesindroom geenkartering by die
Afrikaner, en komplekse oorerflike toestande in die algemeen, sluit die volgende in:
1. Die bewyse gevind vir die bevestiging van 3 genomiese streke soos
oorspronklik deur die eerste fase assosiasiestudies aangetoon by die
manifestering van Tourettesindroom in die Afrikaner, en waar ten minste twee
van die gebiede (11q23 en 8q22) ook deur ander navorsers in ander
bevolkingsgroepe met hierdie toestand gekoppel is;
2. Die kwantifisering van die stand van koppelings-disekwilibrium by 'n aantal
lokusse in die Afrikaner genepoel van < 5cM. Hierdie gegewens versterk die
gedagtes met betrekking tot die geskiktheid van hierdie bevolkingsgroep vir
geenkarteringspogings vir komplekse toestande;
3. Die bewys, gebaseer op reele in stede van gemodelleerde data, dat
opeenvolgende, semiparametriese analisemetodes oor voldoende statistiese
krag beskik om kumulatiewe getuienis te verskaf vir positiewe koppeling van
TS met streke wat ook in die oorspronkilke siektemerker assosiasiestudies
betekenisvolle resultate gelewer het.Doctora
A de novo 4q34 interstitial deletion of at least 9.3 Mb with no discernible phenotypic effect
No full textCytogenetically visible imbalances without phenotypic effect are still rare despite the extent of large-scale copy number variation in the normal population revealed by array CGH. Here we report on a phenotypically normal 30-year-old female with a de novo, cytogenetically visible, interstitial deletion of band 4q34. She was referred following three successive miscarriages, one of which was an intra-uterine death with subendocardial fibroelastosis and dilated cardiomyopathy. There was no other notable medical or family history, she was of normal intelligence and had no dysmorphic features. FISH and Array CGH with a customized 1 Mb BAC array showed that the deletion is a minimum of 9.3 and a maximum of 10.7 Mb in size, between 173 Mb in 4q34.1 and 182 Mb in 4q34.3. The deletion contains only 23 known coding genes giving a low average gene density of 2 genes/Mb. This case further illustrates that (1) sizeable imbalances can be associated with apparent phenotypic normality, (2) gene density is a better guide to possible phenotypic consequences than aberration size, and (3) it is not always safe to assume that de novo imbalances will be causal
Identification of Genetic Markers Associated with Gilles de la Tourette Syndrome in an Afrikaner Population
No full textSummaryBecause gene-mapping efforts, using large kindreds and parametric methods of analysis, for the neurologic disorder Tourette syndrome have failed, efforts are being redirected toward association studies in young, genetically isolated populations. The availability of dense marker maps makes it feasible to search for association throughout the entire genome. We report the results of such a genome scan using DNA samples from Tourette patients and unaffected control subjects from the South African Afrikaner population. To optimize mapping efficiency, we chose a two-step strategy. First, we screened pools of DNA samples from both affected and control individuals, using a dense collection of 1,167 short tandem-repeat polymorphisms distributed throughout the genome. Second, we typed those markers displaying evidence of allele frequency–distribution shifts, along with additional tightly linked markers, using DNA from each affected and unaffected individual. To reduce false positives, we tested two independent groups of case and control subjects. Strongest evidence for association (P values 10−2 to 10−5) were obtained for markers within chromosomal regions encompassing D2S1790 near the chromosome 2 centromere, D6S477 on distal 6p, D8S257 on 8q, D11S933 on 11q, D14S1003 on proximal 14q, D20S1085 on distal 20q, and D21S1252 on 21q
Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer
No full textThe somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the lifetime of the individual with cancer. Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures and a signature of localized hypermutation called kataegis. A germline copy number polymorphism involving APOBEC3A and APOBEC3B, which effectively deletes APOBEC3B, has been associated with modestly increased risk of breast cancer. Here we show that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers. The results suggest that the APOBEC3A-APOBEC3B germline deletion allele confers cancer susceptibility through increased activity of APOBEC-dependent mutational processes, although the mechanism by which this increase in activity occurs remains unknown
Learning of Exception Strategies in Assembly Tasks
No full textAssembly tasks performed with a robot often fail due to unforeseen situations, regardless of the fact that we carefully learned and optimized the assembly policy. This problem is even more present in humanoid robots acting in an unstructured environment where it is not possible to anticipate all factors that might lead to the failure of the given task. In this work, we propose a concurrent LfD framework, which associates demonstrated exception strategies to the given context. Whenever a failure occurs, the proposed algorithm generalizes past experience regarding the current context and generates an appropriate policy that solves the assembly issue. For this purpose, we applied PCA on force/torque data, which generates low dimensional descriptor of the current context. The proposed framework was validated in a peg-in-hole (PiH) task using Franka-Emika Panda robot.This is the author submitted version to ICRA 2020. For the publisher version, please access 10.1109/ICRA40945.2020.9197480
Male child with somatic mosaic Osteopathia Striata with Cranial Sclerosis caused by a novel pathogenic <i>AMER1</i> frameshift mutation
No full textAuthor Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language (Nature Communications, (2018), 9, 1, (4619), 10.1038/s41467-018-06014-6)
No full text\ua9 2019, The Author(s).The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1
Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency
No full textAbstractMitochondrial aminoacyl-tRNA synthetases (aaRSs) are essential enzymes in protein synthesis since they charge tRNAs with their cognate amino acids. Mutations in the genes encoding mitochondrial aaRSs have been associated with a wide spectrum of human mitochondrial diseases. Here we report the identification of pathogenic mutations (a partial genomic deletion and a highly conserved p. Asp325Tyr missense variant) in FARS2, the gene encoding mitochondrial phenylalanyl-tRNA synthetase, in a patient with early-onset epilepsy and isolated complex IV deficiency in muscle. The biochemical defect was expressed in myoblasts but not in fibroblasts and associated with decreased steady state levels of COXI and COXII protein and reduced steady state levels of the mt-tRNAPhe transcript. Functional analysis of the recombinant mutant p. Asp325Tyr FARS2 protein showed an inability to bind ATP and consequently undetectable aminoacylation activity using either bacterial tRNA or human mt-tRNAPhe as substrates. Lentiviral transduction of cells with wildtype FARS2 restored complex IV protein levels, confirming that the p.Asp325Tyr mutation is pathogenic, causing respiratory chain deficiency and neurological deficits on account of defective aminoacylation of mt-tRNAPhe
