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International audience; Objective: We aimed to gather fetal cases carrying a 7q11.23 copy number variation (CNV) and collect precise clinical data to broaden knowledge of antenatal features in these syndromes.Methods: We retrospectively recruited unrelated cases with 7q11.23 deletion, known as Williams-Beuren syndrome (WBS), or 7q11.23 duplication who had prenatal ultrasound findings. We collected laboratory and clinical data, fetal ultrasound, cardiac ultrasound and fetal autopsy reports from 18 prenatal diagnostic centers throughout France.Results: 40 fetuses with WBS were collected and the most common features were intra-uterine growth retardation (IUGR) (70.0%, 28/40), cardiovascular defects (30.0%, 12/40), polyhydramnios (17.5%, 7/40) and protruding tongue (15.0%, 6/40). Fetal autopsy reports were available for 11 cases and were compared with ultrasound prenatal features. Four cases of fetuses with 7q11.23 microduplication were collected and prenatal ultrasound signs were variable and often isolated.Conclusion: This work strengthens the fact that 7q11.23 CNVs are associated with a broad spectrum of antenatal presentations. IUGR and cardiovascular defects were the most frequent ultrasound signs. By reporting the biggest series of antenatal WBS, we aim to better delineate distinctive signs in fetuses with 7q11.23 CNVs.

Cytogenetic aberrations are found in 65% of adults and 75% of children with acute leukemia. Specific aberrations are used as markers for the prognostic stratification of patients. The current standard cytogenetic procedure for acute leukemias is karyotyping in combination with FISH and RT-PCR. Optical genome mapping (OGM) is a new technology providing a precise identification of chromosomal abnormalities in a single approach. In our prospective study, the results obtained using OGM and standard techniques were compared in 29 cases of acute myeloid (AML) or lymphoblastic leukemia (ALL). OGM detected 73% (53/73) of abnormalities identified by standard methods. In AML cases, two single clones and three subclones were missed by OGM, but the assignment of patients to cytogenetic risk groups was concordant in all patients. OGM identified additional abnormalities in six cases, including one cryptic structural variant of clinical interest and two subclones. In B-ALL cases, OGM correctly detected all relevant aberrations and revealed additional potentially targetable alterations. In T-ALL cases, OGM characterized a complex karyotype in one case and identified additional abnormalities in two others. In conclusion, OGM is an attractive alternative to current multiple cytogenetic testing in acute leukemia that simplifies the procedure and reduces costs.

Telomeres protect chromosome ends and control cell division and senescence. During organogenesis, telomeres need to be long enough to ensure the cell proliferation necessary at this stage of development. Previous studies have shown that telomere shortening is associated with growth retardation and congenital malformations. However, these studies were performed in newborns or postnatally, and data on telomere length (TL) during the prenatal period are still very limited. We measured TL using quantitative PCR in amniotic fluid (AF) and chorionic villi (CV) samples from 69 control fetuses with normal ultrasound (52 AF and 17 CV) and 213 fetuses (165 AF and 48 CV) with intrauterine growth retardation (IUGR) or congenital malformations diagnosed by ultrasound. The samples were collected by amniocentesis at the gestational age (GA) of 25.0 ± 5.4 weeks and by CV biopsy at 18.1 ± 6.3 weeks. In neither sample type was TL influenced by GA or fetal sex. In AF, a comparison of abnormal versus normal fetuses showed a significant telomere shortening in cases of IUGR (reduction of 34%, P

International audience; OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.

International audience

Objective Principal objective of this work was to analyse the cost effectiveness of different sequences of cytogenetic techniques from the hospital's point of view, after prenatal ultrasound has identified fetal malformations. Methods Cytogenetic tests were performed for each case in 3 strategies, and their results are reported and compared to one reference strategy. Two new simulated strategies were considered: chromosomal microarrays alone and a direct test + CMA. Main outcomes measures cost-effectiveness ratio. Results A single test result was positive in 234 of the 835 pregnancies studied (28%). CMA alone would have identified 239 abnormalities. In the simulated direct test + CMA sequence, the direct test alone would have been positive for 66.1% of the abnormalities identified. When testing was indicated for NT, reference strategy (Direct + karyotyping) costs 1 084.8 euros by positive test results. Strategies Direct + CMA and CMA alone cost respectively 992.7 and 550.0 euros by positive test results. For OUM indications, reference strategy costs 2 937.8 euros by positive test results. Strategies Direct + CMA and CMA alone cost respectively, 2 118.4 and 1 304.7 euros by positive test results. Conclusions CMA appears to be the most effective test for prenatal cytogenetic diagnosis of fetal abnormalities identified by ultrasound.

Background The 10q26 subtelomeric microdeletion syndrome is a rare and clinically heterogeneous disorder. The precise relationships between the causative genes and the phenotype are unclear. Case presentation We report two new cases of 860 kb deletion of 10q26.2 identified by array CGH in a fetus with intrauterine growth retardation and his mother. The deleted region encompassed only four coding genes, DOCK1, INSYN2, NPS and FOX12. The proband had dysmorphic facies characterized by a high forehead, malformed ears, a prominent nose, and retrognathia. He had bilateral club feet, clinodactily and mild psychomotor retardation. His mother had a short stature, microcephaly, a long face with a high forehead and bitemporal narrowing, arched and sparse eyebrows, strabismus, prominent nose and chin, a thin upper lip and large protruding ears, and mild intellectual disability. Conclusions This study presents the smallest 10q26.2 deletion so far identified, which further refines the minimal critical region associated with the 10q26 microdeletion syndrome. It focuses on three genes potentially responsible for the phenotype: DOCK1, which is the major candidate gene, and INSYN2 and NPS, which could be involved in cognitive functions.

Le syndrome microdeletionnel 10q26 correspond a un syndrome rare et cliniquement heterogene. La correlation genotype-phenotype reste aujourd’hui mal etablie. Nous rapportons deux nouvelles personnes (un garcon de 22 mois et sa mere) presentant une deletion 10q26.2 de 860 kb. L’ACPA avait ete realisee en prenatal en raison d’un retard de croissance intra-uterin. La region deletee contenait seulement 4 genes codants : DOCK1, INSYN2, NPS and FOX12. A la naissance, le proband presentait des particularites morphologiques faciales avec un front haut, des oreilles mal ourlees, un nez proeminent, et une retrognathie; ainsi que des pieds bots bilateraux et une clinodactylie. A l’âge de 22 mois, il presentait un retard psychomoteur global. Sa mere presentait une taille et un perimetre crânien a la limite inferieure de la normale, un visage allonge avec un front haut et une retraction bitemporale, des sourcils arques et clairsemes, un strabisme, un nez et un menton proeminents, une levre superieure fine et des oreilles larges et decollees. Elle a presente des difficultes d’apprentissage importantes. Cette deletion est la plus petite deletion decrite dans la litterature et permet d’affiner la region minimale critique du syndrome 10q26. Trois genes candidats pourraient participer au phenotype : le gene DOCK1, deja considere comme le gene candidat principal, et les genes INSYN2 and NPS qui pourraient etre impliques dans le phenotype cognitif.

International audience; Objective: Uniparental disomy (UPD) testing is currently recommended during pregnancy in fetuses carrying a balanced Robertsonian translocation (ROB) involving chromosome 14 or 15, both chromosomes containing imprinted genes. The overall risk that such a fetus presents a UPD has been previously estimated to be around ~0.6‐0.8%. However, because UPD are rare events and this estimate has been calculated from a number of studies of limited size, we have reevaluated the risk of UPD in fetuses for whom one of the parents was known to carry a nonhomologous ROB (NHROB).Method: We focused our multicentric study on NHROB involving chromosome 14 and/or 15. A total of 1747 UPD testing were performed in fetuses during pregnancy for the presence of UPD(14) and/or UPD(15).Result: All fetuses were negative except one with a UPD(14) associated with a maternally inherited rob(13;14).Conclusion: Considering these data, the risk of UPD following prenatal diagnosis of an inherited ROB involving chromosome 14 and/or 15 could be estimated to be around 0.06%, far less than the previous estimation. Importantly, the risk of miscarriage following an invasive prenatal sampling is higher than the risk of UPD. Therefore, we do not recommend prenatal testing for UPD for these pregnancies and parents should be reassured.

Background Microdeletions encompassing chromosome bands 2q14.1q14.3 are rare. To date, eight reports of relatively large deletions of this region (∼20 Mb) but only two small deletions (

Background Transposition of great arteries (TGA) defined as the combination of concordant atrioventricular and discordant ventriculo-arterial connections is one of the most common congenital heart defects. Prenatal diagnosis of TGA remains difficult. To determine the impact of antenatal diagnosis we evaluated the sensitivity of antenatal detection and the neonatal mortality of TGA considering two study periods and two major types of TGA. Methods A cross-sectional study was performed. Data were collected from a French population-based birth defect registry. From 1988 to 2012, 94 fetuses with TGA were registered. The study period was subdivided into the 1988 to 1999 period and the 2000 to 2012 period. Two types of TGA were considered: isolated TGA (n = 66) and associated TGA (n = 28). A stratified analysis was performed considering the study periods and the types of TGA. RESULTS Considering the study periods, the sensitivity of prenatal detection of TGA increased significantly (9.8% vs. 51.5%, p = 0.0001). The same trend was found for associated TGA (4.8% vs. 33.3%, p = 0.002) and isolated TGA (21.1% vs. 100%, p

International audience; In the interphase cell nucleus, chromosomes adopt a conserved and non-random arrangement in subnuclear domains called chromosome territories (CTs). Whereas chromosome translocation can affect CT organization in tumor cell nuclei, little is known about how aneuploidies can impact CT organization. Here, we performed 3D-FISH on control and trisomic 21 nuclei to track the patterning of chromosome territories, focusing on the radial distribution of trisomic HSA21 as well as 11 disomic chromosomes. We have established an experimental design based on cultured chorionic villus cells which keep their original mesenchymal features including a characteristic ellipsoid nuclear morphology and a radial CT distribution that correlates with chromosome size. Our study suggests that in trisomy 21 nuclei, the extra HSA21 induces a shift of HSA1 and HSA3 CTs out toward a more peripheral position in nuclear space and a higher compaction of HSA1 and HSA17 CTs. We posit that the presence of a supernumerary chromosome 21 alters chromosome compaction and results in displacement of other chromosome territories from their usual nuclear position.

Nous presentons le cas de Camille, petit garcon, ne a terme a 41 + 6 SA par cesarienne pour stagnation du travail. Une hypotonie axiale et peripherique est apparue a la naissance dans un contexte d’anaoxo-ischemie neonatale (APGAR a 0-6-9). La grossesse s’est deroulee sans particularite. Le depistage combine au premier trimestre pour la trisomie 21 a ete calcule a 1/315 (clarte nucale a 0,7 mm). Le depistage sur ADN fœtal libre circulant etait negatif. Devant l’hypotonie majeure de Camille, sans point d’appel particulier, une Analyse sur Puce a ADN (ACPA) a ete prescrite. L’ACPA (Agilent®, puce Oligo 60 K, hg19) a montre des profils de fluorescence complexes au niveau des gonosomes. La realisation d’un caryotype et de FISH a permis de mettre en evidence dans toutes les cellules analysees 47 chromosomes avec presence de deux isodicentriques du bras court du chromosome Y (chromosome X a priori normal), a l’origine d’une tetrasomie de la region du chromosome Y depuis l’extremite du bras court jusqu’a la region Yq11.222 et d’une deletion terminale Yq11.222qter, de novo. Seul un petit nombre d’isodicentrique du bras court du chromosome Y a ete decrit dans la litterature. Les isodicentriques sont des remaniements de structure tres instable liee a la presence des deux centromeres. Ils sont frequemment observes en mosaique associes soit a un contingent 46,XY soit a un clone 45,X. Le tableau phenotypique associe a ces isodicentriques depend donc de la presence ou non d’une mosaique et de la proportion des differents clones mais egalement de la taille des segments concernes. Ici les deux isodicentriques semblent etre retrouves de maniere homogene suggerant une certaine stabilite et laisse envisager des retentissements phenotypiques pour cet enfant assez similaires a ceux dus a la presence d’une polysomie du chromosome Y (susceptibilite accrue au deficit intellectuel, retard des apprentissages, dysmorphie faciale, malformations squelettiques, perturbation de la spermatogenese) [1] , [2] .

Background The prognosis and early neonatal management of the VACTERL association depend mainly on the severity of malformations ascertained prenatally. Methods Here we reviewed the spectrum of clinical features observed in cases of VACTERL association ascertained prenatally through ultrasound examination but examined at birth and compared them with cases ascertained postnatally. Results From 1995 to 2011, a total of 19 cases of VACTERL association were observed in our center; 10 were ascertained prenatally and confirmed after birth whereas 9 were ascertained only after birth. The types and frequencies of malformations observed prenatally were as follows: renal malformations (45%), tracheoesophageal fistula (44%), cardiac malformations (20%), vertebral (13%), and limb (11%) defects. Anal atresia was never detected using routine prenatal ultrasound examination. Conclusion Further studies of fetuses with the VACTERL association are necessary to better delineate the malformations spectrum observed prenatally to improve the early recognition of the VACTERL association. Birth Defects Research (Part A) 103:880–886, 2015. © 2015 Wiley Periodicals, Inc.

Research question Is sperm fluorescence in-situ hybridization (FISH) useful to evaluate the risk of chromosomally unbalanced gametes in interchromosomal reciprocal insertion (IRI) carriers? How do these imbalances lead to recurrent miscarriages? Design This study reports a clinical and molecular study of a rare familial balanced IRI resulting in recurrent spontaneous miscarriage. Sperm FISH was performed to estimate the number of unbalanced gametes. Results A 31-year-old healthy male (proband) and his 28-year-old female partner were referred to the Genetics Department for three spontaneous miscarriages occurring during the first trimester of pregnancy. FISH analysis of the proband with the LSI TRA/D (14q11.2) and DiGeorge N25 (22q11.2) break-apart probes showed the presence of a balanced IRI between 14q11.2 and 22q11.2 chromosomal regions. This IRI was also identified in the proband's father. Sperm FISH with the same probes showed that more than 40% of gametes of the proband were unbalanced for either 14q11.2 or 22q11.2, despite normal sperm parameters. FISH analysis of a product of conception indicated that unbalanced gametes result in a non-viable fetus. Conclusions This study shows the value of sperm FISH analysis in improving genetic reproductive advice for IRI carriers. Disruption of critical genes through this rearrangement and their consequent functional impairment could result in recurrent miscarriages. In this case, several genes located in the 14q11.2 region, particularly RNase 3, would be good candidates to explain the lethality of the imbalances.

Microdeletions of 17q12 encompassing TCF2 are associated with maturity-onset of diabetes of the young type 5, cystic renal disease, pancreatic atrophy, Mullerian aplasia in females and variable cognitive impairment. We report on a patient with a de novo 17q12 microdeletion, 1.8 Mb in size, associated with congenital diaphragmatic hernia (CDH). The 5-year-old male patient presented multicystic renal dysplasia kidneys, minor facial dysmorphic features and skeletal anomalies, but neither developmental delay nor behavioral abnormalities. CDH has been previously associated with the 17q12 microdeletion syndrome only in one prenatal case. The present study reinforces the hypothesis that CDH is part of the phenotype for 17q12 microdeletion and that 17q12 encompasses candidate(s) gene(s) involved in diaphragm development. We suggest that PIGW, a gene involved in an early step of GPI biosynthesis, could be a strong candidate gene for CDH. © 2014 Wiley Periodicals, Inc.

High proportion of disease-associated copy number variant maps to chromosome 17. Genomic studies have provided an insight into its complex genomic structure such as relative abundance of segmental duplication and intercepted repetitive elements. 17q21.31, 17q11.2 and 17q12 loci are well known on this chromosome and are associated with microdeletion and microduplication syndrome. No syndrome associated with 17q21.33 locus have been described. We report clinical, cytogenetic and molecular investigations of a 13 years-old girl admitted for evaluation of microcephaly, scoliosis, skeletal defects and learning difficulties. We carried out detailed analysis of the clinical phenotype of this patient and investigated the genetic basis using Agilent 180K Array Comparative Genomic Hybridization. We identified a ∼0.9 Mb de novo microduplication on chromosome 17q21.33. Four genes, COL1A1, SGCA, PPP1R9B and CHAD located within the duplicated region are possible candidates for clinical features present in our patients. Gene expression studies by real-time RT-PCR assay only showed an overexpression of SGCA (P < 0.01), a component of the dystrophin glycoprotein complex. Defect of SGCA was previously shown to lead to severe childhood autosomal recessive muscular dystrophy (LGMD2D) which result in progressive muscle weakness and can also be associated with hyperlordosis or scoliosis. Further cases with similar duplications are expected to be diagnosed. This will contribute to the delineation of this potential new microduplication syndrome and to improve genetic counseling.

Background Interstitial 2q36 deletion is a rare event. Only two previously published cases of 2q36 deletions were characterized using array-CGH. This is the first case diagnosed prenatally. Methods We report on the prenatal diagnosis of a 2q36.1q36.3 interstitial deletion in a fetus with facial dysmorphism, spina bifida, and cleft palate. Results Array-CGH analysis revealed a 5.6 Mb interstitial deletion of the long arm of chromosome 2q36.1q36.3, including the PAX3 and EPHA4 genes. Conclusion The present study reinforces the hypothesis that PAX3 haploinsufficiency may be associated with neural tube defects in humans and suggests that the EPHA4 gene might be implicated during palate development. This report also illustrates the added value of array-CGH to detect cryptic chromosomal imbalances in malformed fetuses and to improve genetic counseling prenatally. Birth Defects Research (Part A) 100:507–511, 2014. © 2014 Wiley Periodicals, Inc.

Le role de la longueur des telomeres a ete largement etudie en cancerologie et dans plusieurs pathologies regroupees sous le terme de « telomeropathies » mais reste meconnu dans le developpement embryonnaire et la survenue de malformations congenitales. Plusieurs etudes ont montre un raccourcissement des telomeres dans les villosites choriales en cas de retard de croissance intra-uterin mais a ce jour, une seule etude a decrit l’association de telomeres courts avec des malformations congenitales [1] . Dans notre etude nous avons mesure la longueur des telomeres par PCR quantitative (Light cycler 480, technique SYBR Green I), a partir d’ADN extrait en direct sur des prelevements de liquide amniotique (n = 55) et de villosites choriales (n = 32) de fœtus « sains », hypotrophes ( [2] mais contrairement a ce qui avait ete decrit dans trois autres etudes [3] , [4] , [5] .

BACKGROUND Wolf-Hirschhorn syndrome (WHS) is associated with facial dysmorphism including high forehead, high nasal bridge, hypertelorism and severe mental retardation. WHS results from a 4p16.3 deletion. Only a small number of reports have been made on the prenatal ultrasound findings observed in WHS. CASES Here we report our experience on 10 cases of WHS ascertained prenatally between 1983 and 2009 through the CEMC-Auvergne registry of congenital malformations. CONCLUSION The assumption that a “Greek warrior helmet” facies is pathognomonic of WHS could lead to misdiagnosis. Other clinical findings such as severe and early onset intrauterine growth retardation, facial dysmorphism (high forehead, high nasal bridge, low-set ears, micrognathia, hypertelorism), atrial or ventricular septal defect, and renal dysplasia should help obstetricians to suspect the diagnosis of WHS prenatally. Birth Defects Research (Part A), 97:806–811, 2013. © 2013 Wiley Periodicals, Inc.

Microdeletions of 8q21.3–8q22.1 have been identified in all patients with Nablus mask-like facial syndrome (NMLFS). A recent report of a patient without this specific phenotype presented a 1.6 Mb deletion in this region that partially overlapped with previously reported 8q21.3 microdeletions, thus restricting critical region for this syndrome. We report on another case of an 8q21.3 deletion revealed by array comparative genome hybridization (aCGH) in a 4-year-old child with global developmental delay, autism, microcephaly, but without Nablus phenotype. The size of the interstitial deletion was estimated to span 5.2 Mb. By combining the data from previous reports on 8q21.3–8q22.1 deletions and our case, we were able to narrow the critical region of Nablus syndrome to 0.5 Mb. The deleted region includes FAM92A1, which seems to be a potential candidate gene in NMLFS. © 2012 Wiley Periodicals, Inc.

Microduplications 22q11.2 have been recently characterized as a new genomic duplication syndrome showing an extremely variable phenotype ranging from normal or mild learning disability to multiple congenital defects and sharing some overlapping features with DiGeorge/velocardiofacial syndrome (DGS/VCFS), including heart defects, urogenital abnormalities and velopharyngeal insufficiency. We present an atypical and inherited 0.8-Mb duplication at 22q11.2, in the distal segment of the DGS/VCFS syndrome typically deleted region (TDR), in a 3-year-old boy with motor delay, language disorders and mild facial phenotype. This 22q11.2 microduplication was identified by MLPA, designed to detect recurrent microdeletions and microduplications of chromosomal regions frequently involved in mental retardation syndromes and was further characterized by aCGH. The duplicated region encompasses 14 genes, excluding TBX1 but including CRKL, ZNF74, PIK4CA, SNAP29 and PCQAP known to contribute to several aspects of the DGS/VCFS phenotype. To the best of our knowledge, only one case of an isolated duplication in the distal segment of the TDR between chromosome 22-specific low-copy repeats B (LCR22-B) and D (LCR22-D) has been published, but the present report is the first one with a detailed description of physical and developmental features in a patient carrying this kind of atypical 22q11.2 duplication. This case illustrates the importance of reporting unusual 22q11.2 duplications to further evaluate the incidence of these rearrangements in the general population and to improve genotype-phenotype correlations and genetic counseling.

Introduction/Objectifs Les insertions reciproques interchromosomiques sont des rearrangements tres rares. Ils consistent en un echange de segment interstitiel entre deux chromosomes et necessitent donc la presence de quatre points de cassure. Seul 12 cas ont ete publies [1] , [2] , [3] , [4] . Materiels/Patients et methodes Nous rapportons le cas d’un homme de 28 ans adresse dans le service de genetique medicale suite a la survenue de 3 fausses couches spontanees (FCS) chez sa compagne. L’histoire familiale retrouve egalement la notion de 6 FCS chez sa mere. Le caryotype du patient (bandes GTG, RHG ; resolution : 400–550) met en evidence la presence d’un chromosome 14 atypique avec une bande sombre dans la region 14q11 en bandes R. Resultats La FISH de peinture du chromosome 14 montre une absence de marquage sous le centromere d’un des deux chromosome 14 ainsi que la presence de deux signaux sous les centromeres des chromosomes 22 correspondant a l’hybridation croisee des sequences alpha-satellites pericentromeriques. Une FISH LSI DiGeorge N25 (22q11) et LSI TRA/D ba (14q11.2) a confirme la presence d’une insertion reciproque interchromosomique entre les regions chromosomiques 14q11.2 et 22q11.2. L’etude par Sperm FISH montre 40 % des gametes desequilibres malgre des parametres normaux au spermogramme, ainsi qu’un possible effet interchromosomique (EIC). Cette inversion est heritee du pere du patient. Conclusions Les desequilibres de la region 22q11.2 ne semblent pas etre a l’origine des FCS. Les microdeletions de la region 14q11.2 emportant les genes SUPT16H et CDH8 sont rares et associes un retard du developpement, une deficience intellectuelle, des troubles autistiques et une macrocephalie [5] . L’haploinsuffisance des genes APEX1 et PARP2, impliques dans la reparation de l’ADN, et de plusieurs genes de la famille des RNase A pourrait etre impliquee dans la survenue des FCS. La description de cas supplementaire est necessaire pour preciser l’implication d’un desequilibre de la region 14q11.2 dans la survenue de FCS.

Objectif Le cancer du sein triple negatif (TNBC), environ 15 % des cancers du sein, se caracterise par un fort potentiel invasif. Lors de l’invasion tumorale, les cellules epitheliales realisent une transition epithelio-mesenchymateuse (TEM) pour acquerir leur mobilite et disseminer. L’incidence du cancer du sein etant moindre chez les trisomiques 21 [1] , [2] notre objectif etait de determiner si une matrice extracellulaire (MEC) de type trisomie 21 (T21) peut alterer in vitro la TEM de cellules TNBC. Materiel et methode Des cellules d’adenocarcinome mammaire TNBC (MDA-MB468) ont ete cultivees sur une MEC secretee par des fibroblastes T21 (F-T21) ou euploides (F-Eup), ou sur plastique (P), « sans » ou « avec » stimulation de la TEM par du TGFα. L’expression de genes codant des marqueurs epitheliaux (CDH1, OCLN1, CLDN1) et mesenchymateux (VIM, FN1) a ete evaluee a 24 h (j1), 48 h (j2), 72 h (j3) et 96 h (j4) apres stimulation par qRT-PCR en temps reel. Resultats Genes epitheliaux : diminution de leur expression a j4 (tous supports), « sans » et « avec » stimulation. Genes mesenchymateux : faible expression de FN1 rendant difficile l’interpretation des variations d’expression observees. Pour VIM, « sans » stimulation, augmentation progressive de l’expression de j1 a j4 (tous supports) mais plus forte expression sur MEC F-Eup que sur MEC F-T21 a j4. « Avec » stimulation, augmentation de l’expression de j2 a j4 sur MEC F-Eup et a partir de j3 sur MEC-T-21 mais plus forte expression sur MEC F-T21 que sur MEC F-Eup a j3. Conclusion Ces resultats sont en faveur d’un processus « TEM-like » a j4 « sans » et « avec » stimulation. Les differences d’expression observees sur MEC F-Eup et MEC F-T21 suggerent qu’une MEC-T21 pourrait interferer in vitro au niveau transcriptionnel sur la TEM de cellules TNBC.

Le TGNI T21 est realise a partir de l’ADN libre circulant (ADN-LC) present dans le sang. Durant la grossesse, une partie (jusqu’a 20 %) de cet ADN-LC provient des cellules trophoblastiques. Il peut donc etre utilise pour depister une T21 fœtale en faisant appel a du sequencage haut debit. Apres extraction de l’ADN-LC et preparation des librairies, un sequencage parallele massif « tout genome » ou « cible » est realise et, apres alignement sur un genome de reference euploidie, une surrepresentation des sequences du chromosome 21 est statistiquement recherchee. Ce test est indique lorsqu’il existe un risque accru de T21. Le test utilise dans cette etude (Clarigo® – Multiplicom) est une approche ciblee sur 4000 amplicons presents sur les chromosomes 13, 18, 21 et X. Chaque amplicon contient des SNP afin de calculer la fraction fœtale (FF) d’ADN-LC. Le traitement bioinformatique des donnees est assure par un logiciel (Clarigo™ Reporter) accessible sur un cloud prive et securise qui calcule la FF et conclut : – negatif (NEG) ; – positif (POS) ; – FF basse (LFF) ; – non automatiquement calcule (NAC) ; – correlation de l’echantillon basse (ECHEC). A ce jour, pres de 650 gestantes ont beneficie du test. Le test s’est avere POS dans 2 cas, NEG dans pres de 97 % des cas et non-interpretable (LFF et/ou NAC ; ECHEC) dans environ 3 % des cas. Le test, simple d’utilisation, determine la FF d’ADN-LC et permet le TGNI T21 en routine. Le taux d’echec est faible (≈ 3 %). Son utilisation en cas de grossesse gemellaire monochoriale ne pose pas de probleme particulier, contrairement aux bichoriales pour lesquelles la mesure de la FF peut etre prise en defaut. Le surpoids (IMC > 30) s’accompagne d’un taux d’echec superieur. L’incrementation du test dans le Service a permis de diminuer de plus de 55 % le nombre de prelevements invasifs.

Background We report on a fetus with radiographic features of Larsen Syndrome (LS) and unbalanced 3;5 translocation. Recently LS was shown to be caused by mutations in FLNB gene which maps on 3p14.3. Methods Comparative genomic hybridization (CGH) was performed to search for genomic imbalances. Fluorescence in situ analysis (FISH) was done with BAC clone RP11-754F19 probe from the FLNB gene region (3p14.3). Results CGH showed a large loss of the chromosome 5 short arm and a gain of half of the short arm of chromosome 3 resulting from a derivative chromosome 5. FISH analysis with FLNB probe demonstrated that it was not triplicated. Thus, we excluded the role of a gene dosage effect of FLNB in abnormal craniofacial development in this fetus. Conclusions To our knowledge, this is the first report of Larsen-like phenotype associated with unbalanced translocation resulting in partial trisomy 3p and monosomy 5p. Copyright © 2008 John Wiley & Sons, Ltd.

We report on a 3-year-old boy with moderate developmental delay, abnormal craniofacial features and ventricular septal defect resulting from trisomy of the long arm of chromosome 20. The cytogenetic defect consists of a de novo isolated interstitial duplication in distal 20q [dup(20)(q13.2q13.2)]. The duplication was detected by comparative genomic hybridization (CGH) and confirmed by array CGH. Other cases of comparable trisomies are reviewed. This new case further delineates the recognizable phenotype of trisomy 20q13 --> 20qter and highlights the relevance of CGH for the detection of such rearrangements.

Fetuses with increased nuchal translucency thickness (NT) are at increased risk for chromosomal abnormalities. In case of a normal karyotype, a minority of them may present with structural abnormalities or genetic syndromes, which may be related to submicroscopic chromosomal imbalances. The objective of this study was to evaluate whether MLPA screening of 21 syndromic and subtelomeric regions could improve the detection rate of small chromosomal aberrations in fetuses with increased NT and a normal karyotype. A total of 106 prenatal samples from fetuses with NT ≥99th centile and normal R- and G-banding were analyzed by MLPA for subtelomeric imbalances (SALSA P036 and P070) and 21 syndromic regions (SALSA P245). One sample showed a benign CNV (dup(8)pter, FBXO25 gene), and 1 patient was found to have a loss of 18qter and a gain of 5pter as a result of an unbalanced translocation. The incidence of cryptic pathogenic variants was

International audience

Heterochromatin confined to pericentromeric and secondary constriction regions plays a major role in morphological variation of chromosome 9, because of its size and affinity for pericentric inversion. We report on a 6-year-old boy with growth and language delay, minor facial anomalies and unusual chromosome 9 variant with an extra-band in the centromeric region on the conventional karyotype. Subsequent analysis by FISH and CGH identified this variant as a dicentric chromosome 9 with a duplication of the 9p12-q21 region. An identical chromosome 9 variant was found in the mild language retarded brother and in the phenotypically normal father and grandfather. The presumed mechanism accounting for the phenotypic discordance observed in this family and the usefulness of CGH in characterization of such variants are discussed. To our knowledge, this is the first investigation of an unusual chromosome 9 variant by CGH.

Nous presentons le cas d’un enfant porteur d’une hernie diaphragmatique gauche de decouverte antenatale associee a des reins hyperechogenes multikystiques. Devant les malformations renales une recherche de mutation du gene HNF1B/TCF2 avait ete realisee en prenatal et avait permis d’identifier une deletion heterozygote de l’ensemble des exons de TCF2 survenue de novo. A 5 ans et 8 mois l’enfant presente une hyperreactivite bronchique secondaire a de nombreuses infections respiratoires, un astigmatisme, une dysmorphie faciale moderee et des anomalies squelettiques. Il est scolarise normalement et ne presente pas de retard psychomoteur. Une ACPA (Agilent 180K) a permis de mettre en evidence une microdeletion 17q12 de 1,8 Mb emportant 19 genes codants dont TCF2, LHX1 et PIGW. L’enquete familiale a confirme son caractere de novo. La microdeletion 17q12 est associee a la presence de reins dysplasiques multikystiques, d’un diabete MODY5 et d’anomalies pancreatiques, hepatiques et genitales. Un retard mental modere et des troubles neuropsychiatriques ont ete rapportes mais il semble exister une penetrance incomplete pour ces troubles neurocognitifs [1] , [2] . L’haploinsuffisance du gene TCF2 est responsable des anomalies renales et du diabete et le gene LHX1 pourrait etre implique dans les troubles neurologiques. Le gene PIGW, codant pour une proteine du systeme d’ancrage lipidique de certaines proteines, pourrait etre un candidat pour la hernie diaphragmatique congenitale (HDC). A ce jour, l’association microdeletion 17q12 et HDC n’a ete decrite qu’une seule fois [3] . Deux cas de microduplications de cette region ont egalement ete decrits chez des fœtus presentant une HDC [4] . Il semble donc que cette region chromosomique renferme un/des gene(s) implique(s) dans le developpement du diaphragme. L’utilisation de plus en plus repandue de l’ACPA en prenatal devrait permettre de mieux estimer la prevalence de la HDC dans la microdeletion 17q12, probablement sous-evaluee en post-natal en raison de la forte mortalite de cette malformation.

Introduction Depuis de nombreuses annees, il etait propose que les genes du chromosome 21, presents en trois exemplaires, etaient responsables de la deficience intellectuelle et des autres traits du syndrome de Down. Mais depuis peu, une deregulation de genes localises sur d’autres chromosomes dans les cellules trisomiques a ete observee et pourrait concourir aux traits phenotypiques « inconstants » du syndrome [1] , [2] . Or, a ce jour, les mecanismes conduisant a cette deregulation secondaire pangenomique ainsi que les mecanismes physiopathologiques qui sous-tendent les divers aspects du syndrome de Down, sont totalement meconnus. Objectif Voir si la presence d’un chromosome 21 surnumeraire provoque une alteration de l’organisation spatiale des territoires chromosomiques (TC) dans le noyau interphasique. Materiel/Methodes Un protocole de FISH-3D a ete applique a deux populations de cellules issues de villosites choriales « T21 » (n = 3) et de villosite choriale « controles » (n = 3). Le volume des noyaux et de 12 TC ont ete etudies ainsi que la position radiale de ces TC. Resultats/Conclusion Les premiers resultats obtenus pour les TC 18, 19 et 21 de deux villosites choriales T21 et de deux villosites choriales controles ont permis l’etude de 1079 noyaux. Il ne semble pas y avoir de variation du volume nucleaire entre la population T21 et la population temoin. Cependant, il semble que l’organisation intranucleaire soit modifiee dans les noyaux T21 pour ces trois TC qui semblent plus petits dans les noyaux trisomiques 21. Les TC 19 et 21 semblent egalement localises plus pres du centre du noyau.

The prognosis and early neonatal management of the VACTERL association depend mainly on the severity of malformations ascertained prenatally.Here we reviewed the spectrum of clinical features observed in cases of VACTERL association ascertained prenatally through ultrasound examination but examined at birth and compared them with cases ascertained postnatally.From 1995 to 2011, a total of 19 cases of VACTERL association were observed in our center; 10 were ascertained prenatally and confirmed after birth whereas 9 were ascertained only after birth. The types and frequencies of malformations observed prenatally were as follows: renal malformations (45%), tracheoesophageal fistula (44%), cardiac malformations (20%), vertebral (13%), and limb (11%) defects. Anal atresia was never detected using routine prenatal ultrasound examination.Further studies of fetuses with the VACTERL association are necessary to better delineate the malformations spectrum observed prenatally to improve the early recognition of the VACTERL association.

International audience; Interstitial duplication within the long arm of chromosome 20 is an uncommon chromosome structural abnormality. We report here the clinical and molecular characterization associated with pure 20q13.2 duplication in three unrelated patients. The most frequent clinical features were developmental delay, facial dysmorphism, cardiac malformation and skeletal anomalies. All DNA gains occurred de novo, ranging from 1.1 Mb to 11.5 Mb. Compared with previously reported conventional cytogenetic analyses, oligonucleotides array CGH allowed us to refine breakpoints and determine the genes of interest in the region. Involvement of SALL4 in cardiac malformations and NFATC2 gene disruption in both cardiac and skeletal anomalies are discussed.

Low MCL-1 mRNA expression correlates with prolonged survival in B-cell chronic lymphocytic leukemia

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Interstitial 2q36 deletion is a rare event. Only two previously published cases of 2q36 deletions were characterized using array-CGH. This is the first case diagnosed prenatally.We report on the prenatal diagnosis of a 2q36.1q36.3 interstitial deletion in a fetus with facial dysmorphism, spina bifida, and cleft palate.Array-CGH analysis revealed a 5.6 Mb interstitial deletion of the long arm of chromosome 2q36.1q36.3, including the PAX3 and EPHA4 genes.The present study reinforces the hypothesis that PAX3 haploinsufficiency may be associated with neural tube defects in humans and suggests that the EPHA4 gene might be implicated during palate development. This report also illustrates the added value of array-CGH to detect cryptic chromosomal imbalances in malformed fetuses and to improve genetic counseling prenatally.

Wolf-Hirschhorn syndrome (WHS) is associated with facial dysmorphism including high forehead, high nasal bridge, hypertelorism and severe mental retardation. WHS results from a 4p16.3 deletion. Only a small number of reports have been made on the prenatal ultrasound findings observed in WHS.Here we report our experience on 10 cases of WHS ascertained prenatally between 1983 and 2009 through the CEMC-Auvergne registry of congenital malformations.The assumption that a "Greek warrior helmet" facies is pathognomonic of WHS could lead to misdiagnosis. Other clinical findings such as severe and early onset intrauterine growth retardation, facial dysmorphism (high forehead, high nasal bridge, low-set ears, micrognathia, hypertelorism), atrial or ventricular septal defect, and renal dysplasia should help obstetricians to suspect the diagnosis of WHS prenatally.

Objet Clarigo® (Multiplicom) est un nouveau test de DPNI des T13, T18 et T21. Il s’agit d’une approche ciblee reposant sur le sequencage massif parallele de sequences specifiques de ces chromosomes. Nous rapportons les resultats de nos premiers essais pour la validation du test dans notre service. Materiel et methode 36 echantillons (4 T21, 1 T18 et 31 temoins negatifs) ont ete analyses. L’ADN circulant a ete extrait (Blood DNA circulating, Qiagen). Vingt microlitres ont ete utilises pour la PCR multiplexe. Les produits amplifies ont ete purifies pour servir de matrice a la PCR universelle (ajout de MID specifiques a chaque echantillon). Apres purification et controle de la qualite de la PCR, les echantillons ont ete doses et melanges de facon equimolaire. Le pool a ensuite ete sequence (V3 MiSeq, Illumina). Les donnees ont ete traitees avec le logiciel Clarigo Reporter® (Multiplicom). Resultats Pour 3 des 4 echantillons T21, la trisomie 21 a ete detectee ; pour le 4e, le logiciel a conclu a « non automatiquement classe » (NAC). Parmi les 32 autres echantillons (1T18 et 31 temoins), 3 (dont le T18) presentaient une fraction fœtale trop faible pour donner un resultat fiable. Pour les 29 autres, l’analyse s’est revelee negative pour la T21 et « NAC » une fois pour la T18 et trois fois pour la T13. Conclusions Les premiers resultats sont satisfaisants avec une bonne sensibilite pour la trisomie 21 et une tres bonne specificite. Pour les echantillons classes « NAC », l’analyse des graphes a permis de suspecter la trisomie 21 sur le 4e echantillon T21 et d’ecarter une telle T21 pour les 4 temoins. Sur les 3 echantillons a faible fraction fœtale, 2 provenaient de femmes enceintes presentant un indice de masse corporelle ≥ 35, confirmant ce facteur comme limitant a la realisation du test.