44 results on '"CGH-array"'
Search Results
2. Incidence, clinical features and perinatal outcome in anomalous fetuses with late-onset growth restriction: cohort study.
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Dall'Asta, A., Stampalija, T., Mecacci, F., Ramirez Zegarra, R., Sorrentino, S., Minopoli, M., Ottaviani, C., Fantasia, I., Barbieri, M., Lisi, F., Simeone, S., Castellani, R., Fichera, A., Rizzo, G., Prefumo, F., Frusca, T., and Ghi, T.
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EVALUATION research , *SMALL for gestational age , *FETAL growth retardation , *FETAL ultrasonic imaging , *ANEUPLOIDY , *LONGITUDINAL method , *GESTATIONAL age , *RESEARCH , *RESEARCH methodology , *APGAR score , *COMPARATIVE studies , *DISEASE incidence - Abstract
Objective: To describe the incidence, clinical features and perinatal outcome of late-onset fetal growth restriction (FGR) associated with genetic syndrome or aneuploidy, structural malformation or congenital infection.Methods: This was a retrospective multicenter cohort study of patients who attended one of four tertiary maternity hospitals in Italy. We included consecutive singleton pregnancies between 32 + 0 and 36 + 6 weeks' gestation with either fetal abdominal circumference (AC) or estimated fetal weight < 10th percentile for gestational age or a reduction in AC of > 50 percentiles from the measurement at an ultrasound scan performed between 18 and 32 weeks. The study group consisted of pregnancies with late-onset FGR and a genetic syndrome or aneuploidy, structural malformation or congenital infection (anomalous late-onset FGR). The presence of congenital anomalies was ascertained postnatally in neonates with abnormal findings on antenatal investigation or detected after birth. The control group consisted of pregnancies with structurally and genetically normal fetuses with late-onset FGR. Composite adverse perinatal outcome was defined as the presence of at least one of stillbirth, 5-min Apgar score < 7, admission to the neonatal intensive care unit (NICU), need for respiratory support at birth, neonatal jaundice and neonatal hypoglycemia. The primary aims of the study were to assess the incidence and clinical features of anomalous late-onset FGR, and to compare the perinatal outcome of such cases with that of fetuses with non-anomalous late-onset FGR.Results: Overall, 1246 pregnancies complicated by late-onset FGR were included in the study, of which 120 (9.6%) were allocated to the anomalous late-onset FGR group. Of these, 11 (9.2%) had a genetic syndrome or aneuploidy, 105 (87.5%) had an isolated structural malformation, and four (3.3%) had a congenital infection. The most frequent structural defects associated with late-onset anomalous FGR were genitourinary malformations (28/105 (26.7%)) and limb malformation (21/105 (20.0%)). Compared with the non-anomalous late-onset FGR group, fetuses with anomalous late-onset FGR had an increased incidence of composite adverse perinatal outcome (35.9% vs 58.3%; P < 0.01). Newborns with anomalous, compared to those with non-anomalous, late-onset FGR showed a higher frequency of need for respiratory support at birth (25.8% vs 9.0%; P < 0.01), intubation (10.0% vs 1.1%; P < 0.01), NICU admission (43.3% vs 22.6%; P < 0.01) and longer hospital stay (median, 24 days (range, 4-250 days) vs 11 days (range, 2-59 days); P < 0.01).Conclusions: Most pregnancies complicated by anomalous late-onset FGR have structural malformations rather than genetic abnormality or infection. Fetuses with anomalous late-onset FGR have an increased incidence of complications at birth and NICU admission and a longer hospital stay compared with fetuses with isolated late-onset FGR. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]- Published
- 2022
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3. 16p11.2 microdeletion syndrome: a case report
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D. Dell’Edera, C. Dilucca, A. Allegretti, F. Simone, M. G. Lupo, C. Liccese, and R. Davanzo
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Developmental delay ,Intellectual disability ,CGH-array ,Submicroscopic chromosomal changes ,16p11.2 microdeletion syndrome ,Medicine - Abstract
Abstract Background The recurrent ∼ 600 kb 16p11.2 microdeletion is among the most commonly known genetic etiologies of autism spectrum disorder, overweightness, and related neurodevelopmental disorders. Case presentation Our patient is a 2-year-old white girl from the first pregnancy of a non-consanguineous healthy young white couple (father 33-years old and mother 29-years old). Our patient and her parents’ DNA were analyzed by comparative genomic hybridization-array platform. Comparative genomic hybridization-array analysis highlighted a ∼ 600 kb deletion in 16p11.2 region. It has a segregant nature, since it was found in the mother and in her 2-year-old daughter. The microdeletion was confirmed by fluorescence in situ hybridization analysis. Conclusions The presented clinical case is worthy of note since the observed microdeletion is often associated with a clinical phenotype tending to overweightness, but the proband (female) was hospitalized due to poor height and weight development, and anorexia. Moreover, the segregant nature of the observed genomic abnormality has to be noted, as well as the phenotypic variability between the mother and daughter. The case described here enriches the phenotypical spectrum linked to the 16p11.2 microdeletion. For these reasons, in the presence of a suspected genetic pathology it is fundamental to study the proband from the clinical point of view, to extend the clinical observation to the parents, and to provide a good family anamnesis. In this way, it is possible to reveal the presence of a familial genetic pathology whose phenotypical outcomes can be highly variable among the members of a family.
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- 2018
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4. Genomic changes of chromosomes 8p23.1 and 1q21: Novel mutations in malignant mesothelioma.
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Serio, Gabriella, Vimercati, Luigi, Pennella, Antonio, Gentile, Mattia, Cavone, Domenica, Buonadonna, Antonia Lucia, Scattone, Anna, Fortarezza, Francesco, De Palma, Angela, and Marzullo, Andrea
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MESOTHELIOMA , *ASBESTOS & health , *PERITONEAL cancer , *UBIQUITINATION , *DEFENSINS - Abstract
Highlights • Peritoneal malignant mesothelioma is a rare malignancy caused by asbestos exposure. • a-CGH was performed to identify genetic imbalances of peritoneal mesothelioma. • Loss of function of ubiquitination and defensins and mesothelioma carcinogenesis. Abstract Introduction Malignant mesothelioma is an aggressive malignancy of the thoracic cavity caused by prior asbestos exposure. In the peritoneum the mesothelioma is an extremely rare condition. In the present preliminary study, high-resolution array-comparative genomic hybridization (a-CGH) was performed to identify genetic imbalances in a series of malignant peritoneal mesothelioma cases. Materials and methods Between 1990 and 2008, among the cases recorded in the Apulia Mesothelioma Register, we found 22 peritoneal mesothelioma cases. CGH-array was performed on samples from all patients. Results The CGH-array analysis revealed multiple chromosomal imbalances. Interestingly, deletion at 8p23.1 was observed in 12 cases. Furthermore, another novel deletion at 1q21 was present in 11. Often, 1q21 and 8p23.1 losses were present in the same patient (7 cases). Losses of BAP1 and CDKN2A loci were not detected. Discussion The region at 8p23.1 contains the beta-defensin gene cluster (DEF) and 1q21 contains ubiquitin conjugating enzyme E2 (UBE2Q1). We hypotesized that the loss of function of ubiquitination, as well as of the defensins, could play an important role in the initial development and subsequent progression of mesothelioma. [ABSTRACT FROM AUTHOR]
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- 2018
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5. Clinical and Molecular Cytogenetic Characterisation of Children with Developmental Delay and Dysmorphic Features / Klinična in Molekularna Citogenetska Obravnava Otrok Z Razvojnim Zaostankom in Displastičnimi Znaki
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Bertok Sara, Žerjav Tanšek Mojca, Kotnik Primož, Battelino Tadej, Volk Marija, Pecile Vanna, Cleva Lisa, Gasparini Paolo, Kovač Jernej, and Hovnik Tinka
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copy number variations ,cgh-array ,snp-array ,fish ,variacije v številu kopij ,cgh-mikromreže ,snp-mikromreže ,Public aspects of medicine ,RA1-1270 - Abstract
Uvod. Razvojni zaostanek in displastične znake ugotavljamo pri 1-3% otrok. Molekularne citogenetske tehnike z visoko ločljivostjo (CGH- in SNP-mikromreže) so v zadnjih letih postale ključna preiskava v rutinski klinični diagnostiki pri preiskovancih z razvojnim zaostankom, displastičnimi znaki in drugimi nepravilnostmi. Metode in rezultati. V prispevku želimo prikazati klinične prednosti molekularnega citogenetskega pristopa v diagnostičnem postopku dveh otrok z razvojnim zaostankom, displastičnimi znaki in drugimi nepravilnostmi. Potrditev kromosomske preureditve z metodo FISH je potrebna za opredelitev točne kromosomske lokacije in mehanizma nastanka kromosomske nepravilnosti. Zaključek. V prispevku predstavljamo dva tipa kromosomskih nepravilnosti, ki smo jih ugotovili in potrdili z različnimi molekularnimi metodami. Poudariti želimo pomen potrjevanja in analize pri starših za opredelitev izvora nastanka kromosomske preureditve. Rezultati genetske preiskave so ključni pri genetskem svetovanju prizadetim posameznikom in njihovim družinam.
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- 2015
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6. Microarray-based comparative genomic hybridization analysis in neonates with congenital anomalies: detection of chromosomal imbalances
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Luiza Emy Dorfman, Júlio César L. Leite, Roberto Giugliani, and Mariluce Riegel
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Defeitos congênitos ,Anomalias congênitas ,Triagem seletiva de recém-nascidos ,Anomalias cromossômicas ,Citogenética molecular ,CGH-array ,Pediatrics ,RJ1-570 - Abstract
OBJECTIVE: To identify chromosomal imbalances by whole-genome microarray-based comparative genomic hybridization (array-CGH) in DNA samples of neonates with congenital anomalies of unknown cause from a birth defects monitoring program at a public maternity hospital. METHODS: A blind genomic analysis was performed retrospectively in 35 stored DNA samples of neonates born between July of 2011 and December of 2012. All potential DNA copy number variations detected (CNVs) were matched with those reported in public genomic databases, and their clinical significance was evaluated. RESULTS: Out of a total of 35 samples tested, 13 genomic imbalances were detected in 12/35 cases (34.3%). In 4/35 cases (11.4%), chromosomal imbalances could be defined as pathogenic; in 5/35 (14.3%) cases, DNA CNVs of uncertain clinical significance were identified; and in 4/35 cases (11.4%), normal variants were detected. Among the four cases with results considered causally related to the clinical findings, two of the four (50%) showed causative alterations already associated with well-defined microdeletion syndromes. In two of the four samples (50%), the chromosomal imbalances found, although predicted as pathogenic, had not been previously associated with recognized clinical entities. CONCLUSIONS: Array-CGH analysis allowed for a higher rate of detection of chromosomal anomalies, and this determination is especially valuable in neonates with congenital anomalies of unknown etiology, or in cases in which karyotype results cannot be obtained. Moreover, although the interpretation of the results must be refined, this method is a robust and precise tool that can be used in the first-line investigation of congenital anomalies, and should be considered for prospective/retrospective analyses of DNA samples by birth defect monitoring programs.
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- 2015
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7. Incidence, clinical features and perinatal outcome in anomalous fetuses with late-onset growth restriction: cohort study
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A. Dall'Asta, T. Stampalija, F. Mecacci, R. Ramirez Zegarra, S. Sorrentino, M. Minopoli, C. Ottaviani, I. Fantasia, M. Barbieri, F. Lisi, S. Simeone, R. Castellani, A. Fichera, G. Rizzo, F. Prefumo, T. Frusca, T. Ghi, Dall'Asta, A, Stampalija, T, Mecacci, F, Ramirez Zegarra, R, Sorrentino, S, Minopoli, M, Ottaviani, C, Fantasia, I, Barbieri, M, Lisi, F, Simeone, S, Castellani, R, Fichera, A, Rizzo, G, Prefumo, F, Frusca, T, and Ghi, T
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CGH-array ,aneuploidy ,congenital malformation ,fetal growth restriction ,perinatal outcome ,respiratory complication ,Fetal Growth Retardation ,Radiological and Ultrasound Technology ,Incidence ,Infant, Newborn ,Obstetrics and Gynecology ,Infant ,Gestational Age ,General Medicine ,Ultrasonography, Prenatal ,Cohort Studies ,Fetus ,Reproductive Medicine ,Pregnancy ,Settore MED/40 ,Infant, Small for Gestational Age ,Humans ,Radiology, Nuclear Medicine and imaging ,Female - Abstract
Objective: To describe the incidence, clinical features and perinatal outcome of late onset growth restriction (FGR) associated with genetic syndromes or aneuploidy, structural malformation, or congenital infection. Methods: Retrospective multicenter cohort study conducted at four tertiary maternity hospitals in Italy. We included singleton pregnancies between 32+0 and 36+6 weeks of gestation with either abdominal circumference or estimated fetal weight
- Published
- 2022
8. Apport de l'analyse chromosomique sur puce à ADN (ACPA) dans le diagnostic étiologique de l'insuffisance ovarienne prématurée.
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Hyon, Capucine
- Abstract
Copyright of Biologie Aujourd'hui is the property of EDP Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2017
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9. A CGH array study in nonsyndromic (primary) autism patients: deletions on 16p13.11, 16p11.2, 1q21.1, 2q21.1q21.2, and 8p23.1.
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GÜMÜŞLÜ, Kudret Esen, SAVLI, Hakan, SÜNNETÇİ, Deniz, ÇİNE, Naci, KARA, Bülent, EREN KESKİN, Seda, and AKKOYUNLU, Ramis Ufuk
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DEVELOPMENTAL disabilities , *AUTISTIC people , *GENOMES , *IN situ hybridization , *CARCINOGENESIS - Abstract
Background/aim: To detect specific molecular changes of DNA level in primary autism patients by using whole genome CGH array technology. Materials and methods: A cohort of 35 primary autism patients received clinical genetic testing by using an oligonucleotide-based CGH array platform to test for submicroscopic genomic deletions and duplications. Fluorescent in situ hybridization was performed in seven patients for confirmation of the results. Results: We found 16p13.11 deletion in thirteen patients, 16p11.2 deletion in twelve patients, 1q21.1 deletion in ten patients, 2q21.1q21.2 deletion in eight patients, and 8p23.1 deletion in seven patients. Conclusion: Our study indicates that genes in 16p13.11, 16p11.2, 1q21.1, 2q21.1q21.2, and 8p23.1 loci are potential predisposition and new suspicious regions for primary autism. Deletions in these regions should be investigated in further studies to understand pathogenesis of primary autism. [ABSTRACT FROM AUTHOR]
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- 2015
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10. Microarray-based comparative genomic hybridization analysis in neonates with congenital anomalies: detection of chromosomal imbalances.
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Dorfmana, Luiza Emy, Leite, Júlio César L., Giugliani, Roberto, and Riegel, Mariluce
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NEWBORN infants ,HUMAN abnormalities ,KARYOTYPES ,CHROMOSOME abnormalities ,CYTOGENETICS - Abstract
Copyright of Jornal de Pediatria is the property of Sociedade Brasileira de Pediatria and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2015
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11. Clinical characteristics in patients with interstitial deletions of chromosome region 12q21-q22 and identification of a critical region associated with keratosis pilaris.
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Al‐Maawali, Almundher, Marshall, Christian R., Scherer, Stephen W., Dupuis, Lucie, Mendoza‐Londono, Roberto, and Stavropoulos, Dimitri J.
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We report on a male patient with a submicroscopic 1.21 Mb de novo deletion at 12q21.33-q22 with global developmental delay, characteristic facial features, and keratosis pilaris. Thus far, five other cases with a 12q de novo deletion including this segment have been reported; our case represents the smallest de novo deletion within this chromosome region. High resolution SNP microarray analysis showed a deletion of RefSeq genes BTG1 and LOC256021, and partial deletion of DCN. We propose that BTG1 is a critical gene for the development of the distinctive keratosis pilaris observed in patients with interstitial deletion of 12q21-q22, and suggest candidate genes that may contribute to dysmorphic features and global developmental delay. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2014
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12. Deciphering the Invdupdel(8p) Genotype–Phenotype Correlation: Our Opinion
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Tiziana Timpanaro, Andrea Bartuli, Laura Sciuto, Alessia Arena, Annamaria Sapuppo, Santiago Presti, Manuela Lo Bianco, Davide Vecchio, Giulia Messina, Agata Fiumara, Sarah Sciuto, Lidia Marino, Piero Pavone, and Marina Macchiaiolo
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Proband ,Opinion ,Chromosomal rearrangement ,Bioinformatics ,Genotype phenotype ,lcsh:RC321-571 ,Correlation ,03 medical and health sciences ,inversion ,0302 clinical medicine ,FISH ,Gene duplication ,chromosome 8 ,Medicine ,deletion ,Cognitive impairment ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,030304 developmental biology ,CGH-array ,0303 health sciences ,business.industry ,General Neuroscience ,Inverted duplication ,duplication ,genomic rearrangement ,Correlation analysis ,8p23.1 sub-band ,business ,030217 neurology & neurosurgery ,invdupdel(8p) - Abstract
The 8p inverted duplication/deletion is a rare chromosomal rearrangement clinically featuring neurodevelopmental delay, mild to severe cognitive impairment, heart congenital defects and brain abnormalities. Patients affected also present typical facial dysmorphisms and skeletal malformations, and it is thought that the composite clinical picture may fall into the chromosomal rearrangement architecture. With the major aim of better framing its related clinical and diagnostic paths, we describe a patient carrying a de novo invdupde[8p] whose clinical features have not been described so far. Hence, through an extensive genotype–phenotype correlation analysis and by reviewing the dedicated scientific literature, we compared our patient’s features with those reported in other patients, which allows us to place our proband’s expressiveness in an intermediate area, widening the scope of the already known invdupde[8p] genotype–phenotype relationship.
- Published
- 2020
13. Is there a link between genomic complexity and clinical outcome in uterine smooth muscle tumors?
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Croce, Sabrina, STAR, ABES, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Mojgan Devouassoux Shisheboran, and Frédéric Chibon
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Leiomyosarcoma ,CGH-array ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Leiomyoma ,Array-CGH ,Uterus ,CINSARC ,STUMP ,Léiomyome à Noyaux Bizarres ,Bizarre Nuclei leiomyoma ,Léïomyosarcome ,Utérus ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Léïomyome - Abstract
Sarcomas with complex genomics such as leiomyosarcomas (LMS) are characterized by an altered genome in the absence of a known recurrent "driver" genomic event. According to their clinical outcome, smooth muscle uterine tumours are divided into leiomyomas (LM) and LMS, and as spindle, epithelioid and myxoid variants with distinct diagnostic criteria depending on their morphology. The morphologic criteria are efficient but with some exceptions. In these cases, the tumour should be termed « smooth muscle tumour with uncertain malignant potential” (STUMP) and only the outcome can confirm its benign or malignant nature. Moreover, for some LM variants such as Bizarre Nuclei leiomyoma (BN-LM), the diagnosis may be particularly difficult. Even though BN-LM has a favourable outcome, it can harbour a complex genomic profile. The analysis of the complexity of a tumour’s genomic profile based on its Genomic Index (GI) obtained with the CINSARC (Complexity INdex in SARComas) signature has demonstrated its prognostic value, not only in genomically complex soft tissue sarcomas but also in GIST. We hypothesized that, as in soft tissue sarcomas, the degree of genomic complexity in uterine smooth muscle tumours correlates with their clinical outcome. The aim of this PhD dissertation using array-CGH and the CINSARC signature by Nanostring was to study the genomic profile of several series of benign and malignant uterine tumours and STUMP tumours with spindle, epithelioid and Bizarre Nuclei variants and to correlate the results with clinical outcome. In our first paper, we demonstrated that the genomic complexity of uterine smooth muscle tumours is related to their clinical outcome and that genomic analysis by array-CGH is a useful diagnostic tool complementary to the morphological approach. We subsequently demonstrated in a larger series of 70 tumours that the GI at the threshold of 10 splits STUMP into two groups: those without recurrence and with a similar behaviour to LM, and a second group with a rate of recurrence and death akin to LMS but more indolent. We demonstrated the prognostic value of the CINSARC Nanocind® signature by Nanostring technology on 60 formalin-fixed, paraffin-embedded uterine LMS for overall and disease-free survival. These results were confirmed even on stage I LMS, for which the efficacy of adjuvant chemotherapy remains to be proven. The CINSARC Nanocind® signature could be a useful tool for randomization in future clinical trials evaluating the benefit of adjuvant treatment on uterine LMS, in particular at an early stage. We also analysed the genomic profiles of 69 BN-LM by array-CGH and demonstrated that BN-LM is an entity different from LM and LMS. We identified 3 distinct BN-LM subtypes: an FH-deficient group, a group associated to TP53 alterations with chromosomal instability. And a third without recurrent alterations. Our results highlight the importance of integrating genomic data into the morphological and clinical context. Finally, we validated the GI threshold on a genomic platform (AGILENT 180K) different from the original one (AGILENT 60K) and We explored genomic profiles also for the epithelioid variant. Thus, genomic complexity correlates with outcome so genome profile analysis is a diagnostic tool complementary to morphology for distinguishing benign tumours from tumours with a risk of recurrence. The CINSARC signature may allow better patient management, especially in stage I LMS., Les sarcomes à génomique complexe sont caractérisés par un génome remanié en l’absence d’un évènement génomique récurrent connu et les léïomyosarcomes (LMS) font partie de ce groupe. Les tumeurs musculaires lisses utérines se divisent selon l’évolution clinique en léiomyomes (LM) et LMS et selon la morphologie en fusocellulaires, épithélioïdes et myxoïdes avec des critères diagnostiques distincts. Si ces critères sont suffisants pour un diagnostic lésionnel correct dans la majorité des cas, ils ne permettent pas la distinction entre un LM et un LMS dans un faible pourcentage de tumeurs. Dans ces cas la tumeur est dénommée « tumeur musculaire lisse utérine à potentiel de malignité incertain » (STUMP) posant un problème de prise en charge clinique. Certains variants comme le léiomyome à Noyaux Bizarres (LM-BN) pose un véritable problème diagnostique. D’évolution clinique bénigne, il présente un profil génomique hétérogène pouvant être complexe. L’analyse de la complexité du profil génomique basée sur le calcul du Genomic Index (GI) issu de la signature CINSARC (Complexity INdex in SARComas) a démontré sa valeur pronostique dans les sarcomes des tissus mous à génomique complexe, mais également dans les GIST. Notre hypothèse est qu’à l’instar des sarcomes des tissus mous le degré de complexité génomique est corrélé à l’évolution clinique dans les tumeurs musculaires lisses utérines. Le but de ce travail de thèse était d’étudier sur plusieurs tumeurs musculaires lisses utérines, bénignes, malignes et STUMP, de type fusiforme et les variantes à noyaux bizarres et épithélioïdes, le profil génomique par CGH-array et la signature d’expression CINSARC en utilisant la technique de Nanostring, en corrélation avec l’évolution clinique. Une première étude publiée a permis de confirmer que la complexité génomique est liée à l’évolution des tumeurs musculaires lisses utérines et peut être un outil diagnostique complémentaire à l’analyse morphologique. Nous avons testé cette hypothèse sur une série de 70 tumeurs musculaires lisses utérines et démontrer que le GI au seuil de 10 distingue les tumeurs sans récidive (LM) des tumeurs avec risque accru de récidive et d’évolution létale (LMS) en démembrant la catégorie de STUMP. Avec l’application de la signature CINSARC au matériel fixé en formol, par technologie Nanostring nous avons démontré sur une série de 60 LMS que cette signature est pronostique en survie globale et libre de maladie. De plus la signature CINSARC NANOCIND a montré sa valeur pronostique dans les LMS utérins de stade I pour lesquels la chimiothérapie adjuvante est discutée, sans efficacité prouvée. La signature CINSARC Nanocind® se propose comme un outil de randomisation dans les essais cliniques à venir. Nous avons par ailleurs analysé les profiles génomiques par array-CGH d’une série de 69 LM-BN et démontré que le LM-BN est une entité séparée du LM et du LMS identifiant 3 sous-types distincts de LM-BN : un groupe FH-déficient, un associé aux altérations de TP53 avec un génome plus remanié et un groupe sans altérations récurrentes. Notre étude souligne l´importance de l’intégration des données génomiques au contexte morphologique et clinique. Pour terminer nous avons validé le seuil du GI sur une plateforme génomique (AGILENT 180K) différente de celle d’origine (AGILENT 60K) et nous avons exploré le GI dans le variant à cellules épithélioïdes. Ainsi, la complexité génomique est corrélée à l’évolution clinique et l’étude du profil génomique des tumeurs musculaires lisses de l’utérus est utilisable en pratique quotidienne dans les lésions où la morphologie seule ne permet pas la distinction d’une tumeur bénigne d’une tumeur avec un potentiel évolutif, à condition d’intégrer ces données dans le contexte clinique et morphologique. La signature CINSARC dans les LMS de stade I peut permettre une meilleure prise en charge des patientes
- Published
- 2020
14. 16p11.2 microdeletion syndrome: a case report
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F Simone, C. Liccese, R. Davanzo, C. Dilucca, Maria Giovanna Lupo, Domenico Dell’Edera, and Arianna Allegretti
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Male ,Parents ,0301 basic medicine ,Proband ,Developmental delay ,Developmental Disabilities ,Submicroscopic chromosomal changes ,Intellectual disability ,lcsh:Medicine ,Case Report ,Chromosome Disorders ,030105 genetics & heredity ,Child ,In Situ Hybridization ,In Situ Hybridization, Fluorescence ,media_common ,Genetics ,CGH-array ,Daughter ,medicine.diagnostic_test ,General Medicine ,Microdeletion syndrome ,Phenotype ,16p11.2 microdeletion syndrome ,Autism spectrum disorder ,Child, Preschool ,Female ,Chromosome Deletion ,Abnormality ,Human ,Adult ,media_common.quotation_subject ,Chromosomes ,Fluorescence ,03 medical and health sciences ,Thinness ,medicine ,Humans ,Autistic Disorder ,Preschool ,Pair 16 ,business.industry ,lcsh:R ,medicine.disease ,Etiology ,business ,Chromosomes, Human, Pair 16 ,Intellectual Disability ,Fluorescence in situ hybridization - Abstract
Background The recurrent ∼ 600 kb 16p11.2 microdeletion is among the most commonly known genetic etiologies of autism spectrum disorder, overweightness, and related neurodevelopmental disorders. Case presentation Our patient is a 2-year-old white girl from the first pregnancy of a non-consanguineous healthy young white couple (father 33-years old and mother 29-years old). Our patient and her parents’ DNA were analyzed by comparative genomic hybridization-array platform. Comparative genomic hybridization-array analysis highlighted a ∼ 600 kb deletion in 16p11.2 region. It has a segregant nature, since it was found in the mother and in her 2-year-old daughter. The microdeletion was confirmed by fluorescence in situ hybridization analysis. Conclusions The presented clinical case is worthy of note since the observed microdeletion is often associated with a clinical phenotype tending to overweightness, but the proband (female) was hospitalized due to poor height and weight development, and anorexia. Moreover, the segregant nature of the observed genomic abnormality has to be noted, as well as the phenotypic variability between the mother and daughter. The case described here enriches the phenotypical spectrum linked to the 16p11.2 microdeletion. For these reasons, in the presence of a suspected genetic pathology it is fundamental to study the proband from the clinical point of view, to extend the clinical observation to the parents, and to provide a good family anamnesis. In this way, it is possible to reveal the presence of a familial genetic pathology whose phenotypical outcomes can be highly variable among the members of a family.
- Published
- 2018
15. Rare germline large rearrangements in the BRCA1/ 2 genes and eight candidate genes in 472 patients with breast cancer predisposition.
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Rouleau, E., Jesson, B., Briaux, A., Nogues, C., Chabaud, V., Demange, L., Sokolowska, J., Coulet, F., Barouk-Simonet, E., Bignon, Y., Bonnet, F., Bourdon, V., Bronner, M., Caputo, S., Castera, L., Delnatte, C., Delvincourt, C., Fournier, J., Hardouin, A., and Muller, D.
- Abstract
Hereditary breast cancers account for up to 5-10 % of breast cancers and a majority are related to the BRCA1 and BRCA2 genes. However, many families with breast cancer predisposition do not carry any known mutations for BRCA1 and BRCA2 genes. We explored the incidence of rare large rearrangements in the coding, noncoding and flanking regions of BRCA1/ 2 and in eight other candidate genes- CHEK2, BARD1, ATM, RAD50, RAD51, BRIP1, RAP80 and PALB2. A dedicated zoom-in CGH-array was applied to screen for rearrangements in 472 unrelated French individuals from breast-ovarian cancer families that were being followed in eight French oncogenetic laboratories. No new rearrangement was found neither in the genomic regions of BRCA1/ 2 nor in candidate genes, except for the CHEK2 and BARD1 genes. Three heterozygous deletions were detected in the 5′ and 3′ flanking regions of BRCA1. One large deletion introducing a frameshift was identified in the CHEK2 gene in two families and one heterozygous deletion was detected within an intron of BARD1. The study demonstrates the usefulness of CGH-array in routine genetic analysis and, aside from the CHEK2 rearrangements, indicates there is a very low incidence of large rearrangements in BRCA1/ 2 and in the other eight candidate genes in families already explored for BRCA1/ 2 mutations. Finally, next-generation sequencing should bring new information about point mutations in intronic and flanking regions and also medium size rearrangements. [ABSTRACT FROM AUTHOR]
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- 2012
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16. BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors.
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Samuelson, Emma, Karlsson, Sara, Partheen, Karolina, Nilsson, Staffan, Szpirer, Claude, and Behboudi, Afouz
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BREAST cancer , *TUMORS , *ETIOLOGY of diseases , *COMPARATIVE genomic hybridization , *CANCER treatment - Abstract
Background: Development of breast cancer is a multistage process influenced by hormonal and environmental factors as well as by genetic background. The search for genes underlying this malignancy has recently been highly productive, but the etiology behind this complex disease is still not understood. In studies using animal cancer models, heterogeneity of the genetic background and environmental factors is reduced and thus analysis and identification of genetic aberrations in tumors may become easier. To identify chromosomal regions potentially involved in the initiation and progression of mammary cancer, in the present work we subjected a subset of experimental mammary tumors to cytogenetic and molecular genetic analysis. Methods: Mammary tumors were induced with DMBA (7,12-dimethylbenz[a]anthrazene) in female rats from the susceptible SPRD-Cu3 strain and from crosses and backcrosses between this strain and the resistant WKY strain. We first produced a general overview of chromosomal aberrations in the tumors using conventional kartyotyping(G-banding) and Comparative Genome Hybridization (CGH) analyses. Particular chromosomal changes were then analyzed in more details using an in-house developed BAC (bacterial artificial chromosome) CGH-array platform. Results: Tumors appeared to be diploid by conventional karyotyping, however several sub-microscopic chromosome gains or losses in the tumor material were identified by BAC CGH-array analysis. An oncogenetic tree analysis based on the BAC CGH-array data suggested gain of rat chromosome (RNO) band 12q11, loss of RNO5q32 or RNO6q21 as the earliest events in the development of these mammary tumors. Conclusions: Some of the identified changes appear to be more specific for DMBA-induced mammary tumors and some are similar to those previously reported in ACI rat model for estradiol-induced mammary tumors. The later group of changes is more interesting, since they may represent anomalies that involve genes with a critical role in mammary tumor development. Genetic changes identified in this work are at very small scales and thus may provide a more feasible basis for the identification of the target gene(s). Identification of the genes underlying these chromosome changes can provide new insights to the mechanisms of mammary carcinogenesis. [ABSTRACT FROM AUTHOR]
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- 2012
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17. Les nouvelles technologies d’analyse du génome : quelles utilisations en diagnostic prénatal
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Vialard, F. and Molina Gomes, D.
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PRENATAL diagnosis , *MEDICAL technology , *CYTOGENETICS , *GENOMES , *DNA , *FETUS , *CYTODIAGNOSIS - Abstract
Abstract: Array-CGH emergence allowed important diagnosis progress, and a better care of patients in postnatal. So, there is a great temptation to use it also in prenatal diagnosis. The point of view objective is to make a rapid overview of cytogenetic diagnosis evolution during the last 50 years, and to show all questions raised by the use of array-CGH, and problems that could arise in prenatal diagnosis. While array-CGH just comes in genetic laboratories, new diagnosis approaches emerged like whole genome sequencing or non-invasive prenatal diagnosis. The 2nd objective will be to review all these techniques for a probably close future. [ABSTRACT FROM AUTHOR]
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- 2011
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18. De novo 15q21.1q21.2 deletion identified through FBN1 MLPA and refined by 244K array-CGH in a female teenager with incomplete Marfan syndrome
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Faivre, Laurence, Van Kien, Philippe Khau, Callier, Patrick, Ruiz-Pallares, Nathalie, Baudoin, Corinne, Plancke, Aurélie, Wolf, Jean-Eric, Thauvin-Robinet, Christel, Durand, Edith, Minot, Delphine, Dulieu, Véronique, Metaizeau, Jean-Damien, Leheup, Bruno, Coron, Fanny, Bidot, Samuel, Huet, Frédéric, Jondeau, Guillaume, Boileau, Catherine, Claustres, Mireille, and Mugneret, Francine
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MARFAN syndrome , *GLYCOPROTEINS , *MOLECULAR genetics , *DISEASES in teenagers , *COMPARATIVE genomic hybridization , *INTELLECTUAL disabilities , *MICROSATELLITE repeats , *PATIENTS - Abstract
Abstract: Interstitial deletions involving the 15q21.1 band are very rare. Only 4 of these cases have been studied using molecular cytogenetic techniques in order to confirm the deletion of the whole FBN1 gene. The presence of clinical features of the Marfan syndrome (MFS) spectrum associated with mental retardation has been described in only 2/4 patients. Here we report on a 16-year-old female referred for suspicion of MFS (positive thumb and wrist sign, scoliosis, joint hyperlaxity, high-arched palate with dental crowding, dysmorphism, mitral insufficiency with dystrophic valve, striae). She had therefore 3 minor criteria according to the Ghent nosology. She also had speech disabilities but could follow normal school training. Direct sequencing of the FBN1, TGFBR1 and TGFBR2 genes was negative. MLPA revealed a genomic deletion of the whole FBN1 gene, confirmed by loss of heterozygosity of maternal alleles for several microsatellite markers surrounding the FBN1 gene. The deletion was confirmed by FISH using a FBN1 probe and was not found in the parents. Array-CGH permitted to define a 2.97 Mb deletion, which was the smallest 15q microdeletion including FBN1. Contrary to the other published observations, our proband does not exhibit mental retardation, but neuropsychological evaluations revealed an attention deficit as well as a deficit in information-processing speed. Haploinsufficiency of FBN1 is likely to contribute to the presence of MFS features. However, attenuated features could be explained because disturbances of TGF-β signalling associated with FBN1 mutations do not exert full phenotypic effect through simple haploinsufficiency. Phenotypic variability in other patients with interstitial deletions including 15q21.1 band may reflect differences in deletion size and/or cys/trans modifying factors. [Copyright &y& Elsevier]
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- 2010
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19. Puces à ADN (CGH-array) : application pour le diagnostic de déséquilibres cytogénétiques cryptiques
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Andrieux, J.
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GENETICS , *EMBRYOLOGY , *MENDEL'S law , *BIOLOGY - Abstract
Abstract: Cytogenetics allows detection of genomic anomalies between 10 and 15Mb (classical cytogenetics) and between 3 and 5Mb (high-resolution cytogenetics). These pangenomic techniques are associated with more accurate analyses, single probe interstitial FISH and subtelomeric studies. Array-CGH (aCGH) allows high resolution pangenomic analyses. BAC/PAC and oligonucleotides array-CGH have transformed the field of genetics and are useful for constitutional, hematological and solid tumors cytogenetics. Array-based comparative pangenomic hybridization resolutions vary in size (range, several kilobases to 1Mb). With the more recent improvements, aCGH is becoming the “missing link” between cytogenetics and molecular diagnostics. Despite copy number variations (CNV) and without replacing karyotype, aCGH detects cryptic quantitative anomalies anywhere in the genome and becomes day after day more useful. [Copyright &y& Elsevier]
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- 2008
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20. Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array.
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Nakaya, K., Yamagata, H. D., Arita, N., Nakashiro, K.-i., Nose, M., Miki, T., and Hamakawa, H.
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ORAL cancer , *COMPARATIVE genomic hybridization , *TUMOR suppressor genes , *CADHERINS , *POLYMERASE chain reaction , *SQUAMOUS cell carcinoma - Abstract
Homozygous deletions (HD) provide an important resource for identifying the location of candidate tumor suppressor genes. To identify the tumor suppressor gene in oral cancer, we employed high-resolution comparative genomic hybridization (CGH)-array analysis. We identified a homozygous loss of FAT (4q35), a new member of the human cadherin superfamily, from genome-wide screening of copy number alterations in one primary oral cancer. This result was evaluated by genomic polymerase chain reaction in 13 oral cancer cell lines and 20 primary oral cancers and Southern blot in the cell lines. We found frequent exonic HD of FAT in the cell lines (3/13, 23%) and in primary oral cancers (16/20, 80%). FAT expression was absent in these cell lines. Homozygous deletion hot spots were observed in exon 1 (9/20, 45%) and exon 4 (7/20, 35%). Moreover, loss of gene expression was identified in other types of squamous cell carcinoma. The methylation status of the FAT CpG island in squamous cell carcinomas correlated negatively with its expression. Our results identify mutations in FAT as an important factor in the development of oral cancer and indicate the importance of FATs function in some squamous cell carcinomas.Oncogene (2007) 26, 5300–5308; doi:10.1038/sj.onc.1210330; published online 26 February 2007 [ABSTRACT FROM AUTHOR]
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- 2007
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21. ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation.
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Takada, Hisashi, Imoto, Issei, Tsuda, Hitoshi, Nakanishi, Yukihiro, Ichikura, Takashi, Mochizuki, Hidetaka, Mitsufuji, Shoji, Hosoda, Fumie, Hirohashi, Setsuo, Ohki, Misao, and Inazawa, Johji
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TUMOR suppressor genes , *CANCER genetics , *ONCOGENES , *METHYLATION , *CELL fusion , *CANCER treatment , *GENE therapy , *TUMORS - Abstract
Array-based comparative genomic hybridization (CGH-array) has a powerful potential for high-throughput identification of genetic aberrations in cell genomes. We identified a homozygous loss of ADAM23 (2q33.3) in the course of a program to screen a panel of gastric cancer (GC) cell lines (1/32, 3.1%) for genomic copy-number aberrations using our custom-made CGH-array. Infrequent homozygous deletion of ADAM23 was also seen in primary gastric tumors (1/39, 2.6%). ADAM23 mRNA was expressed in normal stomach tissue, but not in the majority of GC cell lines without homozygous deletion of this gene. Expression of ADAM23 mRNA was restored to gene-silenced GC cells after treatment with 5-aza 2′-deoxycytidine. The methylation status of the ADAM23 CpG island, which showed promoter activity, correlated inversely with its expression. Methylation of this CpG island was observed both in GC cell lines and in primary GC tissues; in primary tumors with a hypermethylated CpG island, expression of ADAM23 was lower than in adjacent noncancerous tissues. Moreover, restoration of ADAM23 in GC cells reduced their numbers in colony-formation assays. These results suggest that genetic or epigenetic silencing by hypermethylation of the ADAM23 CpG-rich promoter region leads to loss of ADAM23 function, which may be a factor in gastric carcinogenesis.Oncogene (2005) 24, 8051–8060. doi:10.1038/sj.onc.1208952; published online 15 August 2005 [ABSTRACT FROM AUTHOR]
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- 2005
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22. Techniques d'exploration chromosomique en prénatal : mises au point et applications
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BRUN, Stéphanie, U 1211 Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (MRGM), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux, Didier Lacombe, Caroline Rooryck Thambo, Lacombe, Didier, Rooryck Thambo, Caroline, Le Caignec, Cédric, Vayssière, Christophe, Horovitz, Jacques, and Dallay, Dominique
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Chromosomal Microarray Analysis ,IUGR intra uterin growth restriction ,Non Invasive Prenatal Screening ,Array-CGH ,CGH-Array ,Prenatal diagnosis ,Diagnostic Prenatal Non Invasif ,Trisomy ,Fetal fraction ,Semiconductor sequencing ,Retard de croissance intra uterin ,ADNlc ,Medecine foetale ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
ObjectivePrenatal diagnosis allows to detect fetal pathologies in-utero. The goal of this work was both technical development and application of the chromosomal exploration technics in prenatal diagnosis. First, we aimed to validate and evaluate the performance metrics of the highthroughput semiconductor sequencing platform, Ion Proton®, in non-invasive prenatal genetic screening (NIPS) for common fetal aneuploidies in a clinical setting and, then to evaluate the diagnostic utility of prenatal diagnosis using the chromosomal microarray analysis (CMA) for fetuses presenting with isolated or associated intrauterine growth restriction (IUGR). Methods : First, regarding NIPS, a prospective cohort study including 2505 pregnant women from eight academic genetics laboratories (695 high risk pregnancies for trisomy 21 (risk ≥1/250 or with ultrasound anomalies) in a validation study, and 1810 such pregnancies, without ultrasound anomalies, in a real-life NIPS clinical setting) was conducted. An outcome was available for all cases in the validation cohort and for 521 in the clinical cohort. Cell-free DNA from plasma samples was sequenced using the Ion Proton sequencer, and sequencing data were analyzed using the open-access software, WISECONDOR. Performance metrics for detection 10 of trisomies 21, 18 and 13 were calculated based on either fetal karyotype result or clinical data collected at birth. We also evaluated the failure rate and compared three methods of fetal fraction quantification (RASSF1A assay, and DEFRAG and SANEFALCON software). Then, regarding the CMA study, we retrospectively included all fetuses with IUGR referred for prenatal testing and studied by rapid fluorescence in situ hybridization (FISH), karyotype, and CMA. Results :In the NIPS study, results from both cohorts were consistent and their gestational age was not significantly different, so their data were combined to increase the sample size for analysis. Sensitivities and specificities, respectively, were as follows: for trisomy 21, 98.3% (95% CI, 93.5–99.7%) and 99.9% (95% CI, 99.4–100%); for trisomy 18, 96.7% (95% CI, 80.9–99.8%) and 100% (95% CI, 99.6–100%); and for trisomy 13, 94.1% (95% CI, 69.2–99.7%) and 100% (95% CI, 99.6–100%). Our failure rate was 1.2% initially and as low as 0.6% after retesting some of the failed samples. Fetal fraction estimation by the RASSF1A assay was consistent with DEFRAG results, and both were adequate for routine diagnosis. Among the 162 IUGR fetuses (78 associated and 84 isolated IUGR) included in the CMA study, 15 had an abnormal FISH result: 10 associated and five isolated fetal IUGRs. Among the 143 fetuses studied by CMA, 10 (7%) presented pathogenic copy number variations (CNVs). All 10 were in the associated fetal IUGR group (10/65 or 15.4%; 95% confidence interval [CI]: 8.4%‐26.2%) versus 0/78 in the isolated fetal IUGR group (95% CI: 0%‐5.6%). Six fetuses (4.2%) carried variants of unknown significance (VOUS) (three associated and three isolated fetal IUGRs). Conclusion: We described one of the largest studies evaluating Ion Proton-based NIPS and the first clinical study reporting pregnancy outcome in a large series of patients. This platform is highly efficient in detecting the three most common trisomies. Our protocol is robust and can be implemented easily in any medical genetics’ laboratory. Our second study highlighted the added value of CMA in the case of associated fetal IUGR with an incremental yield of 6.1% (4/65) over karyotyping. No pathogenic CNVs were reported in the isolated fetal IUGR group. Could NIPS supplant CMA in isolated fetal IUGR? The development of the NIPS test has reduced prenatal invasive testing and therefore its complications [...].; ObjectifLe diagnostic prénatal (DPN) a pour but de détecter des pathologies foetales in utero. L’objectif de ce travail était de mettre au point et d’appliquer les techniques d’exploration chromosomique en prénatal. Nous avons, tout d’abord, validé et évalué une plateforme de séquençage basée sur la technologie des semi-conducteurs, Ion Proton®, pour le dépistage prénatal non-invasif (DPNI) des principales aneuploïdies en routine clinique, puis évalué l’intérêt de l’Analyse Chromosomique sur Puces à ADN (ACPA) dans le diagnostic prénatal des retards de croissance intra-utérin (RCIU) foetaux. Matériel et Méthodes Nous avons inclus prospectivement 2505 patientes enceintes analysées par huit laboratoires hospitalo-universitaires de génétique : 695 grossesses à haut risque pour la trisomie 21 (risque ≥1/250 ou avec anomalie échographique) dans une étude de validation de la technique du test ADN libre circulant (ADNlc), et 1810 grossesses à risque, sans anomalie échographique, en routine clinique. Les issues de grossesses étaient toutes disponibles dans l’étude de validation et pour 521 grossesses dans l’étude en routine clinique. L’ADNlc extrait d’échantillons plasmatiques était séquencé, puis les données étaient analysées à l’aide du logiciel WISECONDOR. Les résultats des tests ADNlc étaient comparés aux caryotypes foetaux ou 7 aux données à la naissance. Nous avons aussi évalué le taux d’échec et comparé trois méthodes d’évaluation de la fraction foetale (FF) (RASSF1A, DEFRAG et SANEFALCON). Nous avons rétrospectivement inclus tous les foetus référés pour un prélèvement invasif pour RCIU et étudié les résultats de technique d’hybridation in situ en fluorescence (FISH), caryotypes et ACPA. Résultats Les résultats des deux cohortes de l’étude sur l’ADNlc étaient cohérents et les âges gestationnels n’étaient pas significativement différents ; les données ont été combinées afin d’étoffer la cohorte à analyser. Respectivement, la sensibilité et la spécificité étaient de : 98.3% (95% IC, 93.5–99.7%) et 99.9% (95% IC, 99.4–100%) pour la trisomie 21; 96.7% (95% IC, 80.9–99.8%) et 100% (95% IC, 99.6–100%) pour la trisomie 18 ; et 94.1% (95% IC, 69.2–99.7%) et 100% (95% IC, 99.6–100%) pour la trisomie 13. Le taux de non rendus était de 1.2% initialement puis après réanalyse de 0.6%. L’estimation de la FF avec les méthodes RASSF1A et DEFRAG étaient comparables, toutes deux compatibles avec une utilisation en routine clinique. Parmi les 162 foetus RCIU (78 associés et 84 isolés) inclus dans l’étude ACPA, 15 avaient une FISH pathologique : 10 RCIU associés et cinq RCIU isolés. Parmi 143 foetus étudiés par ACPA, 10 (7%) présentaient un variant du nombre de copies (CNV), tous étaient des RCIUs associés (10/65 soit 15.4%; 95 IC: 8.4%‐26.2%), versus 0/78 dans le groupe RCIUs isolés (95% IC: 0%‐5.6%). Six foetus (4.2%) ont présenté des variants de signification inconnue (VSI) (trois RCIU associés et trois RCIU isolés). Conclusion : Notre étude évaluant le test ADNlc utilisant la technologie des semi-conducteurs est la première étude clinique à rapporter les issues de grossesses dans une population aussi large. La plateforme est performante pour le DPNI des principales aneuploïdies. Notre protocole robuste est facilement applicable en routine clinique. Notre étude souligne une augmentation de rendement diagnostique de l’ACPA de 6.1% (4/65) par rapport au caryotype pour le DPN des foetus présentant un RCIU associé. Aucun CNV pathogène n’a été mis en évidence dans le groupe RCIU isolé. L’ADNlc pourrait-il supplanter l’ACPA dans cette population de RCIU isolé ? Le développement du test ADNlc a permis de limiter le nombre de prélèvements invasifs et donc leurs complications [...].
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- 2019
23. 16p11.2 microdeletion syndrome: a case report
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Dell’Edera, D., Dilucca, C., Allegretti, A., Simone, F., Lupo, M. G., Liccese, C., and Davanzo, R.
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- 2018
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24. Genomic changes of chromosomes 8p23.1 and 1q21: Novel mutations in malignant mesothelioma
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Andrea Marzullo, Angela De Palma, Antonia Lucia Buonadonna, Domenica Cavone, Antonio Pennella, Mattia Gentile, Luigi Vimercati, Francesco Fortarezza, Anna Scattone, and Gabriella Serio
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Pulmonary and Respiratory Medicine ,Adult ,Male ,Mesothelioma ,Cancer Research ,Lung Neoplasms ,medicine.disease_cause ,Malignancy ,Chromosomes ,03 medical and health sciences ,0302 clinical medicine ,CDKN2A ,medicine ,80 and over ,Humans ,030212 general & internal medicine ,neoplasms ,CGH-array ,Peritoneum ,Aged ,Aged, 80 and over ,Chromosomes, Human, Pair 1 ,Chromosomes, Human, Pair 8 ,Comparative Genomic Hybridization ,Female ,Middle Aged ,Ubiquitin-Conjugating Enzymes ,Chromosome Aberrations ,Mutation ,Loss function ,BAP1 ,business.industry ,respiratory system ,medicine.disease ,Oncology ,030220 oncology & carcinogenesis ,Peritoneal mesothelioma ,Cancer research ,Pair 1 ,Pair 8 ,business ,Comparative genomic hybridization ,Human - Abstract
Introduction Malignant mesothelioma is an aggressive malignancy of the thoracic cavity caused by prior asbestos exposure. In the peritoneum the mesothelioma is an extremely rare condition. In the present preliminary study, high-resolution array-comparative genomic hybridization (a-CGH) was performed to identify genetic imbalances in a series of malignant peritoneal mesothelioma cases. Materials and methods Between 1990 and 2008, among the cases recorded in the Apulia Mesothelioma Register, we found 22 peritoneal mesothelioma cases. CGH-array was performed on samples from all patients. Results The CGH-array analysis revealed multiple chromosomal imbalances. Interestingly, deletion at 8p23.1 was observed in 12 cases. Furthermore, another novel deletion at 1q21 was present in 11. Often, 1q21 and 8p23.1 losses were present in the same patient (7 cases). Losses of BAP1 and CDKN2A loci were not detected. Discussion The region at 8p23.1 contains the beta-defensin gene cluster (DEF) and 1q21 contains ubiquitin conjugating enzyme E2 (UBE2Q1). We hypotesized that the loss of function of ubiquitination, as well as of the defensins, could play an important role in the initial development and subsequent progression of mesothelioma.
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- 2018
25. Microarray-based comparative genomic hybridization analysis in neonates with congenital anomalies: detection of chromosomal imbalances
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Júlio César Loguercio Leite, Mariluce Riegel, Roberto Giugliani, and Luiza Emy Dorfman
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Male ,Defeitos congênitos ,Congenital anomalies ,Array-CGH ,Microarray ,Array‐CGH ,Citogenética molecular ,Biology ,Genomic databases ,Congenital Abnormalities ,Molecular cytogenetics ,chemistry.chemical_compound ,Neonatal Screening ,Anomalias congênitas ,Triagem seletiva de recém-nascidos ,Humans ,Triagem seletiva de recém‐nascidos ,Clinical significance ,Pediatrics, Perinatology, and Child Health ,Copy-number variation ,Oligonucleotide Array Sequence Analysis ,Retrospective Studies ,Chromosome Aberrations ,CGH-array ,Genetics ,Comparative Genomic Hybridization ,Chromosomal abnormalities ,lcsh:RJ1-570 ,Infant, Newborn ,lcsh:Pediatrics ,Anomalias cromossômicas ,Monitoring program ,Birth defects ,chemistry ,Karyotyping ,Pediatrics, Perinatology and Child Health ,Newborn selective screening ,Female ,CGH‐array ,DNA ,Comparative genomic hybridization - Abstract
Objective: To identify chromosomal imbalances by whole-genome microarray-based comparative genomic hybridization (array-CGH) in DNA samples of neonates with congenital anomalies of unknown cause from a birth defects monitoring program at a public maternity hospital. Methods: A blind genomic analysis was performed retrospectively in 35 stored DNA samples of neonates born between July of 2011 and December of 2012. All potential DNA copy number variations detected (CNVs) were matched with those reported in public genomic databases, and their clinical significance was evaluated. Results: Out of a total of 35 samples tested, 13 genomic imbalances were detected in 12/35 cases (34.3%). In 4/35 cases (11.4%), chromosomal imbalances could be defined as pathogenic; in 5/35 (14.3%) cases, DNA CNVs of uncertain clinical significance were identified; and in 4/35 cases (11.4%), normal variants were detected. Among the four cases with results considered causally related to the clinical findings, two of the four (50%) showed causative alterations already associated with well-defined microdeletion syndromes. In two of the four samples (50%), the chromosomal imbalances found, although predicted as pathogenic, had not been previously associated with recognized clinical entities. Conclusions: Array-CGH analysis allowed for a higher rate of detection of chromosomal anomalies, and this determination is especially valuable in neonates with congenital anomalies of unknown etiology, or in cases in which karyotype results cannot be obtained. Moreover, although the interpretation of the results must be refined, this method is a robust and precise tool that can be used in the first-line investigation of congenital anomalies, and should be considered for prospective/retrospective analyses of DNA samples by birth defect monitoring programs. Resumo: Objetivo: Identificar desequilíbrios cromossômicos por meio da hibridização genômica comparativa baseada em microarranjos (CGH-array) em amostras de DNA de neonatos com anomalias congênitas de causa desconhecida de um programa de monitoramento de defeitos congênitos em uma maternidade pública. Métodos: Uma análise genômica cega foi realizada retrospectivamente em 35 amostras armazenadas de DNA de neonatos nascidos entre julho de 2011 e dezembro de 2012. Todas as possíveis variações no número de cópias (CNVs) de DNA foram comparadas com as relatadas em bases de dados genômicos públicas, e sua relevância clínica foi avaliada. Resultados: De um total de 35 amostras testadas, foram detectados 13 desequilíbrios genômicos em 12/35 casos (34,3%). Em 4/35 casos (11,4%), os desequilíbrios cromossômicos poderiam ser definidos como patogênicos; em 5/35 (14,3%) deles foram identificadas CNVs de DNA de relevância clínica incerta; e, em 4/35 (11,4%), foram detectadas variações normais. Dentre os quatro casos com resultados considerados relacionados causalmente aos achados clínicos, 2/4 (50%) apresentaram alterações causais já relacionadas a síndromes de microdeleção bem definidas. Em 2/4 amostras (50%), os desequilíbrios cromossômicos encontrados, embora preditivos como patogênicos, não estavam relacionados anteriormente a entidades clínicas reconhecidas. Conclusões: A análise de CGH-array permitiu maior taxa de detecção de anomalias cromossômicas, e essa determinação é valiosa principalmente em neonatos com anomalias congênitas de etiologia desconhecida ou em casos em que os resultados do cariótipo não podem ser obtidos. Além disso, embora a interpretação dos resultados deva ser refinada, esse método é uma ferramenta robusta e precisa que pode ser usada na investigação de primeira linha de anomalias congênitas e deve ser considerada em análises futuras/retrospectivas de amostras de DNA por programas de monitoramento de defeitos congênitos. Keywords: Birth defects, Congenital anomalies, Newborn selective screening, Chromosomal abnormalities, Molecular cytogenetics, Array-CGH, Palavras-chave: Defeitos congênitos, Anomalias congênitas, Triagem seletiva de recém-nascidos, Anomalias cromossômicas, Citogenética molecular, CGH-array
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- 2015
26. A de novo 17q21.2 duplication in a boy with developmental delay and dysmorphic features
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Poirsier-Violle, Céline, Abourra, Azzedine, Baumann, Clarisse, Perrin, Laurence, Capri, Yline, Mignot, Cyril, Passemard, Sandrine, Drunat, Séverine, and Verloes, Alain
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DEVELOPMENTAL delay , *FACIAL abnormalities , *MICROCEPHALY , *CHROMOSOME duplication , *BOYS , *MICROGNATHIA , *DISEASES - Abstract
Abstract: We report a boy with severe developmental delay, microcephaly and characteristic facial dysmorphism consisting in round face, hypertelorism, upslanted palpebral fissures, small nose, large mouth, micrognathia, sparse hair and eyelashes. Array-CGH revealed a de novo duplication of 103 kb within 17q21.2 not reported to date. The duplication includes 8 genes: DHX58, KAT2A, HSPB9, RAB5C, KCNH4, HCRT, GHDC and STAT5B. Three genes (KATA2, KCNH4, and STAT5B) may contribute to intellectual deficiency. Further observations will be necessary to confirm the specificity of the facial Gestalt. [Copyright &y& Elsevier]
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- 2013
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27. Évolution des techniques de diagnostic en génétique
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Vigouroux, A. and Chassaing, N.
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- 2009
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28. Exploration raisonnée d’un handicap mental
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Verloes, A.
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- 2008
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29. Deciphering the Invdupdel(8p) Genotype–Phenotype Correlation: Our Opinion.
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Lo Bianco, Manuela, Vecchio, Davide, Timpanaro, Tiziana A., Arena, Alessia, Macchiaiolo, Marina, Bartuli, Andrea, Sciuto, Laura, Presti, Santiago, Sciuto, Sarah, Sapuppo, Annamaria, Fiumara, Agata, Marino, Lidia, Messina, Giulia, and Pavone, Piero
- Subjects
- *
CHROMOSOMAL rearrangement , *SCIENTIFIC literature , *BRAIN abnormalities , *MILD cognitive impairment , *HEART abnormalities - Abstract
The 8p inverted duplication/deletion is a rare chromosomal rearrangement clinically featuring neurodevelopmental delay, mild to severe cognitive impairment, heart congenital defects and brain abnormalities. Patients affected also present typical facial dysmorphisms and skeletal malformations, and it is thought that the composite clinical picture may fall into the chromosomal rearrangement architecture. With the major aim of better framing its related clinical and diagnostic paths, we describe a patient carrying a de novo invdupde[8p] whose clinical features have not been described so far. Hence, through an extensive genotype–phenotype correlation analysis and by reviewing the dedicated scientific literature, we compared our patient's features with those reported in other patients, which allows us to place our proband's expressiveness in an intermediate area, widening the scope of the already known invdupde[8p] genotype–phenotype relationship. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
30. Characterization of Genetic Variants of Susceptibility to Epilepsy in Algerian families
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Chentouf, Amina, Faculté de Médecine d'Oran, Faculté de Médecine d'Oran, Université Oran 1, Pr Malika Chaouch, and CHENTOUF, Amina
- Subjects
CGH-array ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,séquençage exomique ,phenotype ,CNV ,pedigree ,polymorphisme ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,épilepsie ,génétique ,polymorphism ,phénotype ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,exome sequencing ,epilepsy ,genetics ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,mutation ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
A genetic component to epilepsy has been recognized since Antiquity and is well established through twin and familial aggregation studies, which provide convincing evidence for the heritability of epilepsy. Despite major advances in genetic studies, genetic epilepsies have not yet revealed all their secrets. This prospective study aimed to identify genetic variants of epilepsy, to document the genotype/phenotype correlations and inheritance patterns in multigenerational Algerian families. Genetic analyzes included exome sequencing, CGH-array and Southern blotting.We studied a family with a pair of monozygotic twins affected by temporal lobe epilepsy. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene encoding the galanin neuropeptide. This latter was found to act as a potent anticonvulsant and regulates epileptic seizures in animal models. However, until now its role in human epilepsy was not established. Functional analysis showed evidence that the mutant protein disrupts galanin signalling, and strongly supports GAL as the causal gene for the TLE in this family.We described a family with two siblings affected by temporal lobe epilepsy and psychiatric comorbidities. Exome sequencing identified a single nucleotide polymorphism in the RELN gene (rs55689103) whose mutations have been associated with epilepsy and schizophrenia.We identified two families with progressive myoclonus epilepsy type 1. Genetic studies by Southern blotting showed an expansion of dodecamer CCCCGCCCCGCG in EPM1 gene. In addition, two other families were analysed by CGH-array, but no pathogenic CNV was identified. The study of other multigenerational families would identify new genetic variants of epilepsy., L’existence d’une composante génétique dans l’épilepsie est connue depuis des années grâce aux études épidémiologiques de concordance entre jumeaux et d’agrégation familiale, qui fournissent des preuves convaincantes pour l'héritabilité de l'épilepsie. En dépit des avancées majeures des techniques d’exploration pangénomique, les épilepsies génétiques n’ont pas encore livré tous leurs secrets. Cette étude avait pour objectifs de caractériser des variants génétiques de vulnérabilité à l’épilepsie, d’étudier les modes de transmission et d’analyser les relations génotype/phénotype chez des familles Algériennes.Il s’agit d’une étude prospective menée au service de Neurologie du CHU d’Oran sur une période de 05 ans. Des familles multigénérationnelles comportant chacune au moins deux individus épileptiques ont participé à l’étude. Les analyses génétiques réalisées consistaient en un séquençage exomique de nouvelle génération, la technique de Southern Blot, et la recherche de variations du nombre de copies d’ADN (CNV) par la technique de CGH-array. Parmi les quarante familles ayant participé à l’étude, six ont bénéficié d’études génétiques. Ces études ont permis d’identifier une mutation de novo (p.A39E) dans le gène GAL codant pour le neuropeptide galanine chez des jumeaux monozygotes atteints d’épilepsie du lobe temporal (ELT). Le rôle du peptide Galanine dans la régulation du processus d’épileptogénèse a été démontré il y a plus de deux décennies sur des modèles animaux, mais à ce jour, aucune mutation GAL en rapport avec un phénotype épileptique n’avait été décrite chez l’Homme. Nous avons complété l’étude génétique par des analyses in silico qui ont confirmé l’hypothèse de causalité de la mutation identifiée, et corrélé le génotype au phénotype dans cette famille. Nos résultats pourraient avoir des retombées directes sur le développement de molécules antiépileptiques à base de galanine et de traitements par thérapie génique. Nous avons analysé une deuxième famille au phénotype d’ELT et comorbidités psychiatriques. Le séquençage exomique a mis en évidence un variant (rs55689103) du gène RELN déjà incriminé dans l’épilepsie et la schizophrénie. Nous avons identifié deux autres familles au phénotype d’épilepsie myoclonique progressive de type 1. L’étude génétique par Southern Blot a confirmé l’expansion du dodécamère CCCCGCCCCGCG dans le gène EPM1. Par ailleurs, deux autres familles ont été analysées par CGH-array, mais aucun CNV pathogène n’a été identifié par cette technique. L’étude d’autres familles multigénérationnelles permettrait d'identifier de nouveaux variants génétiques des épilepsies.
- Published
- 2016
31. Caractérisation de variants génétiques de vulnérabilité à l'épilepsie chez des familles Algériennes
- Author
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Chentouf, Amina, CHENTOUF, Amina, Faculté de Médecine d'Oran, Faculté de Médecine d'Oran, Université Oran 1, and Pr Malika Chaouch
- Subjects
CGH-array ,séquençage exomique ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,phenotype ,CNV ,pedigree ,polymorphisme ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,épilepsie ,génétique ,polymorphism ,phénotype ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,exome sequencing ,epilepsy ,genetics ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,mutation ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
A genetic component to epilepsy has been recognized since Antiquity and is well established through twin and familial aggregation studies, which provide convincing evidence for the heritability of epilepsy. Despite major advances in genetic studies, genetic epilepsies have not yet revealed all their secrets. This prospective study aimed to identify genetic variants of epilepsy, to document the genotype/phenotype correlations and inheritance patterns in multigenerational Algerian families. Genetic analyzes included exome sequencing, CGH-array and Southern blotting.We studied a family with a pair of monozygotic twins affected by temporal lobe epilepsy. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene encoding the galanin neuropeptide. This latter was found to act as a potent anticonvulsant and regulates epileptic seizures in animal models. However, until now its role in human epilepsy was not established. Functional analysis showed evidence that the mutant protein disrupts galanin signalling, and strongly supports GAL as the causal gene for the TLE in this family.We described a family with two siblings affected by temporal lobe epilepsy and psychiatric comorbidities. Exome sequencing identified a single nucleotide polymorphism in the RELN gene (rs55689103) whose mutations have been associated with epilepsy and schizophrenia.We identified two families with progressive myoclonus epilepsy type 1. Genetic studies by Southern blotting showed an expansion of dodecamer CCCCGCCCCGCG in EPM1 gene. In addition, two other families were analysed by CGH-array, but no pathogenic CNV was identified. The study of other multigenerational families would identify new genetic variants of epilepsy., L’existence d’une composante génétique dans l’épilepsie est connue depuis des années grâce aux études épidémiologiques de concordance entre jumeaux et d’agrégation familiale, qui fournissent des preuves convaincantes pour l'héritabilité de l'épilepsie. En dépit des avancées majeures des techniques d’exploration pangénomique, les épilepsies génétiques n’ont pas encore livré tous leurs secrets. Cette étude avait pour objectifs de caractériser des variants génétiques de vulnérabilité à l’épilepsie, d’étudier les modes de transmission et d’analyser les relations génotype/phénotype chez des familles Algériennes.Il s’agit d’une étude prospective menée au service de Neurologie du CHU d’Oran sur une période de 05 ans. Des familles multigénérationnelles comportant chacune au moins deux individus épileptiques ont participé à l’étude. Les analyses génétiques réalisées consistaient en un séquençage exomique de nouvelle génération, la technique de Southern Blot, et la recherche de variations du nombre de copies d’ADN (CNV) par la technique de CGH-array. Parmi les quarante familles ayant participé à l’étude, six ont bénéficié d’études génétiques. Ces études ont permis d’identifier une mutation de novo (p.A39E) dans le gène GAL codant pour le neuropeptide galanine chez des jumeaux monozygotes atteints d’épilepsie du lobe temporal (ELT). Le rôle du peptide Galanine dans la régulation du processus d’épileptogénèse a été démontré il y a plus de deux décennies sur des modèles animaux, mais à ce jour, aucune mutation GAL en rapport avec un phénotype épileptique n’avait été décrite chez l’Homme. Nous avons complété l’étude génétique par des analyses in silico qui ont confirmé l’hypothèse de causalité de la mutation identifiée, et corrélé le génotype au phénotype dans cette famille. Nos résultats pourraient avoir des retombées directes sur le développement de molécules antiépileptiques à base de galanine et de traitements par thérapie génique. Nous avons analysé une deuxième famille au phénotype d’ELT et comorbidités psychiatriques. Le séquençage exomique a mis en évidence un variant (rs55689103) du gène RELN déjà incriminé dans l’épilepsie et la schizophrénie. Nous avons identifié deux autres familles au phénotype d’épilepsie myoclonique progressive de type 1. L’étude génétique par Southern Blot a confirmé l’expansion du dodécamère CCCCGCCCCGCG dans le gène EPM1. Par ailleurs, deux autres familles ont été analysées par CGH-array, mais aucun CNV pathogène n’a été identifié par cette technique. L’étude d’autres familles multigénérationnelles permettrait d'identifier de nouveaux variants génétiques des épilepsies.
- Published
- 2016
32. Microarray testing (CGH-ARRAY) alterations in individuals with autism spectrum disorders
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Visconti P, ROCHAT, MAGALI JANE, Resca F, Maestrini E, Maretti M, Scaduto MC, Posar A., Visconti, P, Rochat, Mj, Resca, F, Maestrini, E, Maretti, M, Scaduto, Mc, and Posar, A.
- Subjects
Genetic ,Autism Spectrum Disorder ,CGH-Array - Published
- 2016
33. Rare germline large rearrangements in the BRCA1/2 genes and eight candidate genes in 472 patients with breast cancer predisposition
- Author
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Rouleau, E., Jesson, B., Briaux, A., Nogues, C., Chabaud, V., Demange, L., Sokolowska, J., Coulet, F., Barouk-Simonet, E., Bignon, Y. J., Bonnet, F., Bourdon, V., Bronner, M., Caputo, S., Castera, L., Delnatte, C., Delvincourt, C., Fournier, J., Hardouin, A., Muller, D., Peyrat, J. P., Toulas, C., Uhrhammer, N., Vidal, V., Stoppa-Lyonnet, D., Bieche, I., and Lidereau, R.
- Published
- 2012
- Full Text
- View/download PDF
34. Impact de l’analyse chromosomique par puce à ADN (ACPA) sur les représentations maternelles et l’état émotionnel des mères
- Author
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Decherf, Margaux, Université Paris Descartes - École de sages-femmes Baudelocque (UPD ESF Baudelocque), Université Paris Descartes - Paris 5 (UPD5), Sylvie Viaux-Savelon, and École de sages-femmes Baudelocque (ESF Baudelocque)
- Subjects
Maternal stress ,MESH: Trouble de l'adaptation ,Prenatal diagnosis ,Anxiety ,[SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics ,MESH: Mother-child relation ,Stress maternel ,Caryotype ,MESH: Relations mère-enfant ,MESH: Caryotype ,Attachement mère-fœtus ,Mother-fetus attachment ,CGH-array ,MESH: Relations mère ,Diagnostic prénatal ,Dépression ,MESH: Karyotype ,MESH: Maternal-fetal relation ,Relation mère-enfant ,ACPA ,Anomalies échographiques ,MESH: Foetus ,MESH: Prenatal diagnosis ,Abnormal ultrasound findings ,[SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics ,MESH: Adjustment disorders ,Mother-infant relation ,MESH: Diagnostic prénatal ,Anxiété - Abstract
Impact of array comparative genomic hybridization (CGH-array) on maternal representations and emotional status.New techniques of chromosomal analysis by CGH-array, performed after the discovery of anomalies at the foetal ultrasound, have complicated the challenges of prenatal diagnosis.Objective: To Assess the impact of the chromosomal analysis by CGH-array focusing on the mother's emotional response and their representations of themselves and their future child.Method: This is a cross-sectional study based on semi-structured interviews in the immediate postpartum period. We have compared 3 groups of women. One composed by 10 women presenting soft markers at the time of foetal echography who were then explored by CGH Array which delivered normal results. A second group of 10 women without any anomalies whatsoever. The third one including 18 women for whom it was found signs (soft markers) at the time of foetal echography during their pregnancy in 2007, before the introduction of the CGH-array and whose child at birth was healthy. Two variables were analyzed: the maternal representations throw IRMAG (Interview of maternal representations of attachment), the mother's emotional situation throw the analysis of anxiety (Covi scale and auto questioning of Spielberger) and the degree of depression (Raskin Depression Rating Scale).Results: Comparatively with the witness group, patients of the CGH-array group had significantly higher scores of depression (Raskin scale 3,8 vs 2), less rich representations (IRMAG scale 2,5 vs 3,8), a less structured discussion (3 vs 4,1), less fantasies (2,1 vs 3,5) and a more important social dependence (3 vs 2). Their anxiety, as their ability to adapt to the situation, their intensity of investment and the differentiation of the child were not significantly different compared with the witness group. Compared to the 2007 group that has not benefited from the CGH-array, patients of the CGH-array group had similar scale of anxiety and depression levels. We didn't found any differences in the consistence of their talking, in the richness of their perceptions, in their social dependence, and in the raising of fantasies. The intensity of investment and differentiation (3.2 vs 2.4) of the child, however, were significantly higher in the CHG-array group than in the group who did not have this type of prenatal diagnosis.Conclusion: Prenatal diagnosis with CHG-array comes with an increase in depressive traits and an alteration of maternal representations after the birth of a child finally healthy. This impact don’t differ from what was observed in similar diagnostic situations before the introduction of this method.; Les nouvelles techniques d’analyse chromosomique par puce à ADN (ACPA), après la découverte d’une anomalie échographique fœtale, ont complexifié les enjeux du diagnostic anténatal (DAN).Objectif : évaluer l’impact du diagnostic prénatal par ACPA sur l’état émotionnel des mères et leurs représentations d’elles-mêmes et de leurs futurs enfants.Méthode : c’est une étude transversale par entretiens semi-structurés dans le post-partum immédiat. Nous avons comparé trois groupes de femmes. Un groupe de dix femmes avec la présence de signes d’appel échographiques fœtaux qui ont ensuite été explorés par ACPA et dont les résultats étaient normaux. Un deuxième groupe de dix femmes ayant eu une grossesse sans anomalie échographique fœtale dépistée. Enfin, un troisième groupe de dix-huit femmes pour qui il a été retrouvé des signes d’appel échographique en 2007 avant l’introduction de l’ACPA dans les méthodes de DAN et dont l’enfant à la naissance était bien portant. Deux variables ont été analysées : les représentations maternelles par l’IRMAG (l’Interview of Maternal Representations of Attachment) et l’état émotionnel des mères par l’analyse du niveau d’anxiété (échelle de Covi et auto-questionnaire « état » de Spielberger) et du niveau de dépression (échelle de Raskin).Résultats : en comparaison au groupe témoin, les patientes du groupe ACPA avaient un niveau de dépression significativement plus élevé (score de Raskin 3,8 vs 2), des représentations avec des perceptions plus pauvres (score à l’IRMAG 2,5 vs 3,8), un discours moins structuré (3 vs 4,1) avec moins d’émergence des fantaisies (2,1 vs 3,5) et une plus grande dépendance sociale (3 vs 2). Leur niveau d’anxiété ainsi que leur ouverture au changement, leur intensité d’investissement et de différenciation de l’enfant étaient similaires aux témoins. En comparaison au groupe de 2007 qui n’a pas bénéficié d’une ACPA, les patientes du groupe ACPA avaient des scores d’anxiété et de dépression similaires. Il n’a pas été trouvé de différence dans la richesse de leurs perceptions, la cohérence de leur discours, leur dépendance sociale et leur émergence des fantaisies. L’intensité de l’investissement et la différenciation (3,2 vs 2,4) de l’enfant étaient cependant significativement plus élevées dans le groupe ACPA que dans le groupe n’ayant pas eu ce type de DPN.Conclusion : Le diagnostic prénatal avec ACPA s’accompagne d’une augmentation des traits dépressifs et d’une altération des représentations maternelles après la naissance d’un enfant finalement bien portant. Cet impact n’est pas différent de ce qui était observé dans des situations diagnostiques analogues avant l’introduction de cette méthode.
- Published
- 2015
35. Clinical and Molecular Cytogenetic Characterisation of Children with Developmental Delay and Dysmorphic Features = Klinična in Molekularna Citogenetska Obravnava Otrok Z Razvojnim Zaostankom in Displastičnimi Znaki
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Vanna Pecile, Lisa Cleva, Tadej Battelino, Tinka Hovnik, Jernej Kovač, Paolo Gasparini, Mojca Žerjav Tanšek, Marija Volk, Primož Kotnik, Sara Bertok, Bertok, Sara, Žerjav Tanšek, Mojca, Kotnik, Primož, Battelino, Tadej, Volk, Marija, Pecile, Vanna, Cleva, Lisa, Gasparini, Paolo, Kovač, Jernej, and Hovnik, Tinka
- Subjects
CGH-array ,business.industry ,copy number variations ,SNP-array ,FISH ,Genetic counseling ,Public Health, Environmental and Occupational Health ,copy number variation ,Single-nucleotide polymorphism ,Computational biology ,Chromosomal rearrangement ,cgh-mikromreže ,Bioinformatics ,Phenotype ,variacije v številu kopij ,Medicine ,In patient ,Copy-number variation ,snp-mikromreže ,Public aspects of medicine ,RA1-1270 ,business ,SNP array ,Comparative genomic hybridization - Abstract
Introduction. Developmental delay and dysmorphic features affect 1 - 3 % of paediatric population. In the last few years molecular cytogenetic high resolution techniques (comparative genomic hybridization arrays and single-nucleotide polymorphism arrays) have been proven to be a first-tier choice for clinical diagnostics of developmental delay and dysmorphic features. Methods and results. In the present article we describe the clinical advantages of molecular cytogenetic approach (comparative genomic hybridization arrays and single nucleotide polymorphism arrays) in the diagnostic procedure of two children with developmental delay, dysmorphic features and additional morphological phenotypes. Additionally, we demonstrate the necessity of fluorescent in situ hybridization utilisation to identify the localisation and underlying mechanism of detected chromosomal rearrangement. Conclusions. Two types of chromosomal abnormalities were identified and confirmed using different molecular genetic approaches. Comparative genomic hybridization arrays and single nucleotide polymorphism arrays are hereby presented as important methods to identify chromosomal imbalances in patients with developmental delay and dysmorphic features. We emphasize the importance of molecular genetic testing in patients’ parents for the demonstration of the origin and clinical importance of the aberrations prior determined in the patients. The results obtained using molecular cytogenetic high resolution techniques methods are the cornerstone for proper genetic counselling to the affected families.
- Published
- 2015
36. Búsqueda e identificación de nuevas causas genéticas o epigenéticas de trastornos del neurodesarrollo
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Mayo de Andrés, Sonia, Martínez Castellano, Francisco, Orellana Alonso, Carmen, and Departament de Bioquímica i Biologia Molecular
- Subjects
CGH-array ,UNESCO::CIENCIAS DE LA VIDA::Genética ,Trastornos del espectro autista ,CIENCIAS DE LA VIDA::Genética [UNESCO] ,Genética Humana ,Trastornos del neurodesarrollo ,metilación del ADN ,Epigenética ,Genética Molecular ,Discapacidad intelectual - Abstract
Los trastornos del neurodesarrollo engloban desordenes cognitivos, de aprendizaje, comportamiento, comunicación y motores, que aparecen en edad temprana, como la discapacidad intelectual (DI) o los trastornos del espectro autista (TEA). Se trata de patologías complejas, debidas a alteraciones en el desarrollo del sistema nervioso central (SNC), que pueden presentan agregación familiar o asociarse a otras anomalías congénitas o rasgos dismórficos. Pese a que la causa de este tipo de trastornos en muchos casos es desconocida, existen claras evidencias sobre sus bases genéticas, con un gran número de síndromes descritos que cursan con DI asociados a diversas variantes en número de copias (CNVs) o alteraciones epigenéticas. El desarrollo del sistema nervioso, la plasticidad neuronal o la organización sináptica son procesos dinámicos modulados por la epigenética, que actúa de mediador entre el medio ambiente al que nos vemos expuestos y cuyo receptor principal es el SNC, y la información contenida en los genes. Las alteraciones de estos mecanismos pueden ser génicas, al afectar a la secuencia de genes que codifican para proteínas que participan en estos procesos; o epigenéticas, al producirse cambios en las señales epigenéticas sin alteración de la secuencia del ADN. En base a esto, el presente trabajo pretende contribuir al conocimiento de la etiología y al diagnóstico genético de los trastornos del neurodesarrollo. Por un lado, mediante la búsqueda de alteraciones genéticas relacionadas con este tipo de trastornos, tanto en genes implicados en la regulación epigenética, la diferenciación y el desarrollo del SNC, como en elementos del genoma que puedan intervenir en la regulación de la expresión génica, principalmente elementos ultraconservados (UCEs) y miRNAs. Y por otro lado, con la búsqueda de alteraciones epigenéticas, centrándonos en la metilación del genoma completo y de regiones candidatas de interés, tales como dominios sometidos a metilación diferencial. Para ello se han utilizado distintas aproximaciones en una serie de 395 pacientes con DI y/o TEA de etiología desconocida que presentan además anomalías congénitas, rasgos dismórficos y/o distintos antecedentes familiares que puedan estar relacionados con estos trastornos. En el rastreo del genoma en busca de alteraciones genéticas se ha empleado como herramienta el CGH-array, utilizando, tanto uno comercial (4X44K, G4426B, Agilent Technologies) como otro de diseño propio, específico para este trabajo, centrado en genes y regiones de interés en los trastornos del neurodesarrollo. Los resultados obtenidos por ambas estrategias fueron confirmados por diversas técnicas (marcadores microsatélites, MLPA, PCR cuantitativa o FISH). Además se realizó un rastreo de mutaciones en el gen candidato MYT1L, mediante heterodúplex, en una serie de 69 pacientes clínicamente seleccionada, confirmando los resultados obtenidos por secuenciación. Para el rastreo de cambios en la metilación global del genoma se realizó, en un total de 17 pacientes con alteración conocida en algún gen epigenético y 33 controles, un estudio piloto mediante HPLC, método de referencia para esta determinación. Para el rastreo en regiones específicas, en toda la serie de pacientes, se seleccionaron 4 loci sometidos a impronta (KCNQ1OT1, H19, SNRPN y MEG3) utilizando un protocolo basado en el tratamiento con enzima de restricción sensible a metilación y PCR múltiple semicuantitativa, confirmando los resultados obtenidos mediante marcadores microsatélite, para poder valorar posibles disomías uniparentales, o MS-MLPA. Los estudios genéticos realizados mediante array han permitido detectar 220 cambios de dosis en 152 pacientes, siendo 58 de ellos portadores de alguna CNV claramente causal. Entre el 29 y el 50 % de los pacientes con un cambio de dosis patológico tienen afectado algún gen de la maquinaria epigenética cuya alteración tiene repercusión clínica. Además se observó un enriquecimiento significativo en genes epigenéticos en CNVs patológicas, en contraposición con un empobrecimiento de este tipo de genes entre las CNVs benignas. Los resultados obtenidos confirman la importancia de los genes responsables de los procesos epigenéticos en el neurodesarrollo, y su sensibilidad a los cambios de dosis. Sin embargo, no se han detectado alteraciones causales que afecten exclusivamente a UCEs o miRNAs, aunque se ha obtenido un enriquecimiento significativo de estos elementos en CNVs patológicas, lo que sugiere que la desregulación de la expresión génica, mediada por este tipo de elementos, podría suponer un factor de predisposición para los trastornos del neurodesarrollo. Para intentar explicar los mecanismos que han dado lugar a las CNVs, detectadas en este trabajo, se hizo un análisis de las zonas de incertidumbre donde se localizan los puntos de rotura, observándose en esas regiones un enriquecimiento significativo en secuencias repetitivas, genes y lincRNAs. Estos elementos podrían participar en la formación de los reordenamientos cromosómicos de distintas formas. Las duplicaciones segmentarias y los elementos Alu, podrían intervenir directamente en los complejos mecanismos que generan estos reordenamientos (NAHR, NHEJ o FoSTeS). Por otra parte, las secuencias que se transcriben, pueden ser vulnerables a sufrir roturas, al descondensarse la cromatina y verse expuestos durante su transcripción, en etapas clave como la gametogénesis o estadios tempranos del desarrollo embrionario. Asimismo, el enriquecimiento en genes de los puntos de rotura podría favorecer la formación de genes quimera cuya contribución al fenotipo ayudaría a explicar las diferentes consecuencias fenotípicas de deleciones o duplicaciones aparentemente equivalentes. En este sentido, se ha estimado que en nuestra serie un 60 % de las deleciones con zona de incertidumbre inferior a 315 Kb podría formar un gen quimera, confirmándose además la formación de transcritos de fusión en los únicos tres casos estudiados experimentalmente. En cuanto a la aplicación de un diseño específico de array para los trastornos del neurodesarrollo, con una alta densidad de sondas en genes y regiones con valor clínico demostrado y una selección de sondas genómicas que permitan una buena resolución a lo largo de todo el genoma, nuestros resultados indican que se trata de una estrategia adecuada para detectar tanto alteraciones intragénicas como CNVs patológicas de mayor tamaño. No obstante, el número de alteraciones intragénicas patológicas detectadas es minoritario, mientras que las benignas representan un alto porcentaje, por lo que el rendimiento diagnóstico del array para este tipo de alteraciones puede ser bajo. Sin embargo, las CNVs intragénicas en genes candidatos de DI pueden ayudar a aclarar la contribución de estos genes en los trastornos del neurodesarrollo. Además, los distintos resultados obtenidos en relación al gen MYT1L, junto con la información disponible en la bibliografía permiten aseverar que su haploinsuficiencia causa discapacidad intelectual frecuentemente asociada a autismo, siendo la obesidad un rasgo mucho menos frecuente de lo que inicialmente se indicaba, que puede deberse a otros factores como la alteración de diferentes genes de la región. Por otro lado, los estudios de metilación global no permitieron encontrar diferencias significativas entre el grupo de pacientes con DI y alteración genética conocida en genes implicados en la regulación epigenética frente al grupo control de individuos sanos, probablemente debido a la multitud de factores endógenos, exógenos y de diseño experimental que pueden modificar estos valores, por lo que la utilidad clínica de esta estrategia como marcador de un trastorno de la maquinaria epigenética en pacientes con DI no ha sido validada. Sin embargo, el rastreo en loci conocidos sometidos a impronta ha permitido diagnosticar a 5 pacientes, mostrando además evidencias en dos de ellos de sendos nuevos síndromes de impronta, por lo que el estudio de los patrones de metilación de distintas regiones improntadas conocidas, en ADN obtenido de sangre periférica, puede servir de marcador de nuevos síndromes de impronta causados por alteraciones epigenéticas multi-loci. Con los resultados de este trabajo ha quedado demostrado que dentro de las causas genéticas responsables de los trastornos del neurodesarrollo, el fenotipo de los pacientes con DI idiopática puede deberse a una combinación de factores que incluyen, reordenamientos genómicos, mutaciones puntuales o alteraciones epigenéticas, lo que dificulta la valoración clínica inicial de estos pacientes y la orientación de los estudios genéticos pertinentes. Por lo que en estos casos, realizar una completa evaluación de estos factores, permite aumentar la probabilidad de llegar a un diagnóstico certero que posibilite un correcto asesoramiento a las familias. Neurodevelopmental disorders include cognitive, learning, behaviour, communication and motor disorders, which appear in early childhood, such as intellectual disability (ID) or autism spectrum disorders (ASD). These complex diseases, due to alterations in the developing central nervous system (CNS), may have familial aggregation or be associated with other congenital anomalies or dysmorphic features. Although the cause of these disorders is unknown in many cases, there is clear evidence of their genetic backgrounds, with a large number of described syndromes with ID associated to various copy number variants (CNVs) or epigenetic alterations. The development of the nervous system, neuronal plasticity or synaptic organization are dynamic processes modulated by epigenetic, which mediates between the environment to which we are exposed and whose primary receptor is the CNS, and the information contained in the genes. Alterations of these mechanisms can be genetics, since they affect the gene sequence encoding proteins involved in these processes; or epigenetics, when changes occur in the epigenetic signals without altering the DNA sequence. Based on these premises, this study aims to contribute to the understanding of the etiology and genetic diagnosis of neurodevelopmental disorders. On one hand, by finding genetic alterations related to these disorders, including both, genes involved in epigenetic regulation and CNS differentiation and development, as genomic elements that may contribute in regulation of gene expression, mainly ultra-conserved elements (UCEs) and miRNAs. On the other hand, by searching for epigenetic alterations, focusing on methylation, in whole-genome and in candidate regions of interest, such as differential methylation domains. For this purpose, different approaches have been used in a series of 395 patients with ID and/or ASD of unknown etiology who also have congenital anomalies, dysmorphic features and/or other family history that may be associated with these disorders. In the genome screening searching for genetic alterations, CGH-array has been used as a tool, using both a commercial one (4X44K, G4426B, Agilent Technologies) and a self-designed one, specific for this work, focused on genes and regions of interest in neurodevelopmental disorders. The results obtained by both strategies were confirmed by different techniques (microsatellite markers, MLPA, quantitative PCR or FISH). Also screening mutations in the candidate gene MYT1L was performed by heteroduplex in a series of 69 clinically selected patients, confirming the results obtained by sequencing. For the screening of global genome methylation changes a pilot study by HPLC was performed in a total of 17 patients with a known epigenetic gene alteration and 33 controls. For the screening of specific regions throughout the whole series of patients, 4 imprinted loci (KCNQ1OT1, H19, SNRPN y MEG3) were selected, using a treatment based on methylation sensitive restriction enzyme and semiquantitative multiplex PCR protocol. The results were confirmed by microsatellite markers, to assess possible uniparental disomies, or MS-MLPA. Genetic studies by array have revealed 220 CNVs in 152 patients, 58 of them being carriers of a clear causal CNV. Between 29 and 50% of the patients with a pathological dose change have affected some epigenetic gene whose alteration have clinical impact. Furthermore, a significant enrichment was observed in epigenetic gene in pathological CNVs as opposed to an impoverishment of such genes in benign CNVs. The results confirm the importance of the genes responsible for epigenetic processes in neurodevelopment, and its sensitivity to changes in dose. However, no causal alterations involving only UCEs or miRNAs have been detected, although it has obtained a significant enrichment of these elements in pathological CNVs, suggesting that dysregulation of gene expression, mediated by such elements, could be a factor of predisposition for neurodevelopmental disorders. To try to explain the mechanisms that have led to the CNVs detected in this work, an analysis of the areas of uncertainty where the breakpoints are located was performed, observed in these regions a significant enrichment in repetitive sequences, genes and lincRNAs. These may participate in the formation of chromosomal rearrangements in different ways. Segmental duplications and Alu elements may intervene directly in the complex mechanisms that generate these rearrangements (NAHR, or FoSTeS NHEJ). On the other hand, the transcribed sequences can be vulnerable to breakage, when the chromatin is uncondensed and be exposed during their transcription at key stages as gametogenesis or early stages of embryonic development. Also, the enrichment in genes at the breakpoints could promote the formation of chimeric genes whose phenotype contribution would help to explain the different phenotypic consequences of deletions or duplications apparently equivalent. In this regard, it is estimated that in our study 60% of the deletions with areas of uncertainty less than 315 Kb could form a chimeric gene, confirming also the formation of fusion transcripts in the only three cases studied experimentally. Regarding the application of the specific array design for neurodevelopmental disorders, with a high density of probes on genes and regions with proven clinical value and a selection of genomic probes that allow a good resolution over the entire genome, our results indicate that it is an appropriate strategy to detect both intragenic alterations as larger pathological CNVs. However, the number of pathological intragenic alterations detected is minority, while the benign ones represent a high percentage, so the diagnostic yield of the array for such changes may be low. However, intragenic CNVs in candidate genes for ID can help to clarify the contribution of these genes in neurodevelopmental disorders. In addition, the different results obtained in relation to MYT1L gene, together with the information available in the literature, allow asserting that their haploinsufficiency causes intellectual disability often associated with autism, being obesity a much less common trait than initially stated, which can be due to other factors such as the alteration of different genes in the region. On the other hand, global methylation studies didn’t allow to find significant differences between the group of patients with ID and genetic alteration in known genes involved in epigenetic regulation versus control group of healthy individuals, probably due to the large amount of endogenous, exogenous and experimental design factors that can modify these values. According to this, the clinical utility of this strategy as a marker of a disorder of the epigenetic machinery in patients with ID has not been validated. However, the screening of known imprinting loci has allowed the diagnosis of 5 patients, also showing evidence of two new imprinting syndromes, so that the study of methylation patterns in different known imprinted regions in DNA obtained from peripheral blood, can serve as a marker for new imprinting syndromes caused by epigenetic alterations multi-loci. With the results of this study it has been proved that within the genetic causes responsible for neurodevelopmental disorders, the phenotype of patients with idiopathic ID may be due to a combination of factors including, genomic rearrangements, point mutations or epigenetic alterations, hindering the initial clinical evaluation of these patients and the orientation of relevant genetic studies. So in these cases, a complete assessment of these factors can increase the likelihood of reaching an accurate diagnosis that enables proper counsel to families.
- Published
- 2015
37. Syndromale Formen geistiger Behinderung
- Author
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Gillessen-Kaesbach, G.
- Published
- 2009
- Full Text
- View/download PDF
38. Aplicación de nuevas tecnologías para la detección de reordenamientos genómicos en pacientes con retraso del neurodesarrollo y anomalías congénitas
- Author
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Monfort Membrado, Sandra, Martínez Castellano, Francisco, Orellana Alonso, Carmen, and Departament de Genètica
- Subjects
CGH-array ,discapacidad ,UNESCO::CIENCIAS DE LA VIDA::Genética ,CIENCIAS DE LA VIDA::Genética [UNESCO] ,FISH ,UNESCO::CIENCIAS MÉDICAS ,genética ,CIENCIAS MÉDICAS [UNESCO] - Abstract
El retraso del neurodesarrollo o discapacidad intelectual (DI) es una de las causas de minusvalías más frecuente en niños, afecta a cuatro de cada mil nacidos vivos en su forma más grave, aunque el retraso leve podría afectar a 1-3% de la población. La mayoría de los casos de DI son de origen desconocido. Las variantes de número de copias (CNVs) son una causa importante de discapacidad intelectual sindrómica. A lo largo de estos años se han desarrollado diferentes herramientas para el estudio genético de la discapacidad intelectual sindrómica, tales como la FISH (hibridación in situ fluorescente), el MLPA (multiplex ligation-dependent probe amplification) o la CGH-array (Hibridación genómica comparada sobre arrays). La hipótesis es que los reordenamientos genómicos son una causa importante de retraso del neurodesarrollo y anomalías congénitas. La aplicación de diferentes tecnologías nos va a permitir evaluar qué método es el más adecuado para su detección y aplicación en la práctica clínica. El objetivo general de este trabajo es evaluar la aplicabilidad de las diferentes tecnologías (FISH, MLPA y CGH-array) para la detección de reordenamientos genómicos desequilibrados en pacientes con retraso psicomotor y anomalías congénitas. Se ha estudiado una serie de 202 pacientes con retraso del neurodesarrollo asociado a anomalías congénitas, antecedentes familiares de DI y/o abortos de repetición, mediante FISH y MLPA de regiones subteloméricas y dos tipos de arrays genómicos (basado en BACs y en oligonucleótidos). Uno de los grandes retos de este trabajo ha sido la interpretación de la repercusión clínica de las CNVs detectadas. Inicialmente se utilizaron diferentes criterios, clasificando las CNVs en patológicas si habían surgido de novo o presentaban un tamaño mayor de 1Mb y polimórficas si habían sido heredadas de un progenitor sano o se habían descrito en población general. A lo largo de este trabajo, se ha puesto de manifiesto que no existen criterios únicos con validez universal para establecer el carácter patológico o polimórfico de las CNVs, hoy por hoy, la interpretación es muy dinámica, y está sujeta al conocimiento disponible en cada momento. La frecuencia de reordenamientos considerados patológicos detectados mediante FISH y MLPA ha sido similar, aproximadamente del 10%, siendo la técnica del MLPA la más indicada de las dos para el rastreo de reordenamientos subteloméricos, por ser más económica y menos laboriosa. Mediante la CGH-array se han detectado un mayor número de CNVs patológicas, un 12% mediante el array basado en BACs y un 25% mediante el array basado en oligonucleótidos. Por otra parte, el array de oligonucleótidos presenta una mayor especificidad, sensibilidad y posibilidad de automatización. Con estos resultados concluimos que la CGH-array basada en oligonucleótidos es la técnica más apropiada para la detección de reordenamientos genómicos desequilibrados en todo el genoma. El número de CNVs patológicas detectadas presentan una buena correlación con el tamaño del cromosoma, sugiriendo una distribución uniforme, salvo en los cromosomas X, 16 y 22 que presentan una mayor tasa de alteraciones en relación a su tamaño. Finalmente, para poder ofrecer un asesoramiento genético adecuado a las familias tras la detección de CNVs patológicas, es conveniente realizar estudios complementarios mediante la técnica del FISH para detectar reordenamientos genómicos equilibrados y translocaciones intersticiales en los progenitores. Neurodevelopmental delay or intellectual disability (ID) is one of the most common causes of disability in children (4/1000). The majority of ID cases have an unknown origin. Copy number variants (CNVs) are a cause of syndromic intellectual disability. In these last years, new tools have been developed for the genetic study of ID, such as FISH (fluorescence in situ hybridization), the MLPA (multiplex ligation -dependent probe amplification) or CGH-array (Comparative genomic hybridization arrays). The hypothesis is that genomic rearrangements are an important cause of neurodevelopmental delay and congenital anomalies. The application of different technologies will allow us to evaluate which method is best suited for detection and application in clinical practice. The objective of this work is evaluate the applicability of these technologies for detecting unbalanced genomic rearrangements in patients with syndromic ID. We have studied 202 patients with neurodevelopmental delay associated with congenital abnormalities, family history of ID and / or repeat abortions, by subtelomeric FISH and MLPA and two types of genomic arrays (based on BACs and oligonucleotides). One of the great challenges of this work was the clinical interpretation of the CNVs detected. Initially different simple criteria were used in classifying pathogenic CNVs if they had arisen de novo or had a size larger than 1Mb and polymorphic if they were inherited from a healthy parent or had been described in general population. In this work, it has been shown that there are no unique criteria with universal validity to establish the pathogenic or polymorphic character of CNVs. Today the interpretation is very dynamic and is subject to the knowledge available at the time. The pathogenic CNVs frequencies detected by FISH and MLPA were similar (10 %), but the MLPA technique was better for subtelomeric rearrangements screening, being cheaper and less laborious. By CGH-array was detected a greater number of pathogenic CNVs, 12% by BACs array and 25% by oligonucleotide array. Moreover, the oligonucleotides array was a higher specificity, sensitivity and automation possibility. With these results, we concluded that the CGH-array based on oligonucleotide is the most appropriate technique for the detection of genomic rearrangements unbalanced. A good correlation of the number of CNVs and the size of the chromosomes suggests a uniform distribution, except for chromosomes X, 16 and 22, which have a higher rate of changes in relation to its size. Finally, in order to offer appropriate genetic counseling to families following the detection of pathogenic CNVs, it is advisable to perform additional studies using FISH technique to detect genomic rearrangements and interstitial balanced translocations in parents.
- Published
- 2014
39. ANALISI DI CARCINOMI PAPILLIFERI TIROIDEI MEDIANTE CGH-ARRAY
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Passon, Nadia
- Subjects
Settore MED/03 - Genetica Medica ,CGH-ARRAY ,PTC ,TNIK ,CA12 ,DLEU2 ,CCND3 - Published
- 2013
40. Identification, par criblage génomique à haut débit, de Variations du Nombre de Copies impliquées dans les formes précoces de Maladie d'Alzheimer
- Author
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Legallic, Solenn, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and HAL-EPHE, Admin
- Subjects
CGH-array ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,peptide Aβ ,QMPSF ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,variations du nombre de copies ,[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,maladie d’Alzheimer à début précoce - Abstract
L’étude des formes rares de maladie d’Alzheimer (MA) s’est avérée être une stratégie utile dans l’identification de gènes impliqués dans le déterminisme de la MA. Cette stratégie a permis d’identifier les mutations des gènes APP, PSEN1 et PSEN2 dans 77% des formes autosomiques dominantes à début précoce de MA (ADEOAD). Les variations du nombre de copies (CNVs) sont définies comme « des segments d’ADN d’au moins 1 kb pour lesquels des différences du nombre de copies ont été identifiées par comparaison entre deux génomes ». On estime à ce jour que plus de 30% des gènes sont soumis à des CNVs, et qu’un individu sur 10 porte un CNV de novo. Dans ce cadre, nous avons émis l’hypothèse que des variations du nombre de copies (CNVs) rares pouvaient être à l’origine de la pathologie chez certaines familles ADEOAD sans mutation identifiée dans les gènes connus, de même que chez des cas rares de MA sporadique à début précoce. En utilisant l’hybridation génomique comparative à haute-résolution, nous avons recherché la présence des CNVs rares chez 21 cas ADEOAD non-apparentés, sans altération sur les gènes connus, et 12 cas de MA sporadique, avec un âge de début avant 55 ans.Les analyses ont révélé la présence de 7 CNVs uniques (4 chez les ADEOAD et 3 chez les cas isolés) non retrouvés chez 1078 contrôles et 912 cas de MA à début tardif.De façon intéressante, 4 de ces 7 réarrangements touchent des gènes (KLK6, SLC30A3, MEOX2, and FPR2) codant des protéines fortement associées aux voies métaboliques et de signalisation du peptide β-amyloïde.Bien que ces CNVs soient des variants individuels rares et associés à des sous-groupes particuliers de patients, ces résultats renforcent le rôle causal, dans la MA, d’un groupe de gènes codant des molécules suspectées de longue date, de modifier le métabolisme ou la signalisation de l’Aβ, et pour lesquels des modèles animaux ou cellulaires ont déjà été développés.
- Published
- 2012
41. DÉTECTION DE RÉARRANGEMENTS CHROMOSOMIQUES PAR LA TECHNIQUE DE CGH ARRAY CHEZ DES PATIENTS ATTEINTS DE DÉFICIENCE INTELLECTUELLE SYNDROMIQUE
- Author
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Royer, Ghislaine, Service de Génétique Médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), École pratique des hautes études ( EPHE ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)
- Subjects
quotient intellectuel ,CGH-array ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,[ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,génome ,CNV ,diagnostic ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,[ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,[ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics ,déficience intellectuelle - Abstract
La déficience intellectuelle (DI) se définit comme un arrêt du développement mental caractérisé pardes facultés et un niveau global de l’intelligence réduits, survenant avant l’âge de 18 ans. Elle estévaluée à l’aide de tests du comportement adaptatif et de tests cognitifs standardisés mesurant lequotient intellectuel (QI). On parle de déficience intellectuelle sévère lorsque le QI est inférieur à 50 etde déficience intellectuelle légère modérée lorsque le QI est compris entre 50 et 70. Les étiologies sontvariées et se répartissent en 20% de facteurs environnementaux et 40 % de causes génétiques connues.En effet, les anomalies chromosomiques constituent la cause génétique la plus fréquente et sontretrouvées dans 15% des patients atteints de déficience intellectuelle sévère. Cependant dans plus de40% des cas les DI restent inexpliquées. L’exploration globale du génome a connu des avancéestechnologiques considérables ces dernières années, notamment avec l’utilisation de la techniqued’hybridation génomique comparative sur micro-réseau, la CGH-array. La technique consiste àhybrider simultanément l’ADN de patients avec des milliers de sondes constituées de séquenceschoisies dans le génome humain, sur des lames de verre, avec une résolution < 1 Mb. Lesperformances de résolution des puces ne cessent d’augmenter, et avec elles les difficultésd’interprétation des résultats obtenus. En effet, on observe dans le génome humain de nombreusesvariations de séquences de l’ADN (Copy Number Variations - CNV) et Copy Number Polymorphisms- CNP) dont l’effet phénotypique n’est pas connu. L’évaluation du caractère pathogène de cesanomalies est l’objet de nombreux travaux. Les performances de la CGH-array nous ont conduits àutiliser cette technique pour l’exploration d’une cohorte de patients reçus dans le service de génétiquede l’hôpital Necker-Enfants-Malades présentant une DI syndromique et pour lesquels aucun diagnosticn’avait encore été posé. Les remaniements détectés par CGH-array ont été confirmés par FISH dans lelaboratoire de cytogénétique. Cependant, les limites de résolution de la FISH sont atteintes notammentpour les duplications adjacentes de petite taille, ce qui nous a amenés à envisager des techniquesalternatives de biologie moléculaire, PCR semi-quantitative et QMPSF.Les résultats de ce travail confirment largement l’utilité de la CGH-array dans le diagnosticdes DI syndromiques et sont concordants avec les données de la littérature, ce qui a permis aulaboratoire de cytogénétique de substituer en première intention la technique de CGH-array auCaryotype Haute Résolution et d’envisager l’abandon du caryotype standard en première intentionpour l’exploration des DI syndromiques.
- Published
- 2011
42. Caractérisation de 10 marqueurs chromosomiques surnuméraires (MCS) : apport de l'hybridation génomique comparative sur microréseau (CHG-ARRAY)
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Egea, Grégory, Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Damien Sanlaville
- Subjects
MCS ,CGH-array ,Mosaïcisme ,FISH ,Retard mental ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences - Abstract
Lors de la réalisation d'un caryotype, la présence d'un fragment chromosomique surnuméraire dont on ne sait pas déterminer l'origine est parfois mise en évidence. Il s'agit d'un Marqueur Chromosomique Surnuméraire (MCS). Ces chromosomes additionnels de structure indéterminée font l'objet d'études approfondies car ils peuvent être associés à des phénotypes anormaux. La difficulté réside en l'identification et la caractérisation de ce MCS afin d'établir une corrélation génotype-phénotype. L'étude présentée dans ce travail, réalisée sur 10 patients présentant un retard mental et porteurs d'un MCS révélé sur leur caryotype mais non identifié en FISH, a eu pour objectif d'évaluer l'utilité de la CGH-array dans l'identification et la caractérisation des MCS. Cette technique a permis de caractériser précisément le MCS dans 8 cas sur 10. Ces 8 MCS étaient constitués d'euchromatine, et avec l'aide de la littérature, une corrélation génotypephénotype a pu être établie. En revanche, lorsque le MCS est en mosaïque faible (cas 1 et 4), il peut échapper à la détection en CGH-array. Des techniques alternatives doivent alors être utilisées.
- Published
- 2010
43. Analyse de réarrangements génomiques chez des patients atteints d'anomalies du développement embryonnaire : retard mental et malformations multiples congénitales; spectre oculo-auriculo-vertébral
- Author
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ROORYCK THAMBO, Caroline, Arveiler, Benoît, Lacombe, Didier, Dubus, Pierre, Odent, Sylvie, and Jonveaux, Philippe
- Subjects
CGH-array ,Anomalies du développement embryonnaire ,Duplication ,Retard mental ,Syndrome de Goldenhar ,Spectre oculo-auriculo-vertébral (OAVS) ,Puces à ADN ,Remaniements génomiques ,Délétion
44. Etude clinique et génétique de l’albinisme oculocutané : développement d’outils de diagnostic moléculaire et recherche de nouveaux gènes
- Author
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MORICE-PICARD, Fanny, Lacombe, Didier, Taieb, Alain, Montoliu, Lluis, Calvas, Patrick, and Vidaud, Michel
- Subjects
CGH-array ,Pigmentation ,Gène candidat ,Exome ,Albinisme oculocutané ,Mélanogenèse ,Remaniements géniques
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