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1. Ultrasound Presentation of a Disseminated Fetal and Neonatal Rhabdoid Tumor

Author

Yolaine Joueidi, Aline Rousselin, Céline Rozel, Philippe Loget, Dominique Ranchere Vince, Sylvie Odent, Franck Bourdeaut, Vincent Lavoue, and Maela Le Lous

Subjects
Gynecology and obstetrics, RG1-991
Abstract

This is a case report of a disseminated fetal rhabdoid tumor discovered at 32 weeks of gestation in a 29-year-old woman on immunosuppressive therapy. The mother consulted for a decrease in fetal movement. Fetal ultrasound showed signs of a disseminated tumor affecting the left armpit, liver, spleen, and limbs. A caesarian section was performed because of signs of fetal distress. Immunohistochemical analysis of a fetal biopsy showed deletion of the SMARCB1 gene. Pathological analysis of the placenta showed a rhabdoid tumor invading both fetal and maternal compartments. The mother underwent a whole-body MRI, and no metastasis was found. To the best of our knowledge, this is the first report of a disseminated rhabdoid tumor invading both fetal and maternal compartments.

Published
2018
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2. Chorioamnionitis following preterm premature rupture of membranes and fetal heart rate variability.

Author

Laurent Vandenbroucke, Matthieu Doyen, Maëla Le Lous, Alain Beuchée, Philippe Loget, Guy Carrault, and Patrick Pladys

Subjects
Medicine, Science
Abstract

The objective of this study was to identify prenatal markers of histological chorioamnionitis (HC) during pPROM using fetal computerized cardiotocography (cCTG).Retrospective review of medical records from pregnant women referred for pPROM between 26 and 34 weeks, in whom placental histology was available, in a tertiary level obstetric service over a 5-year period. Fetal heart rate variability was assessed using cCTG. Patients were included if they were monitored at least six times in the 72 hours preceding delivery. Clinical and biological cCTG parameters during the pPROM latency period were compared between cases with or without HC.In total, 222 pPROM cases were observed, but cCTG data was available in only 23 of these cases (10 with and 13 without HC) after exclusion of co-morbidities which may potentially perturb fetal heart rate variability measures. Groups were comparable for maternal age, parity, gestational age at pPROM, pPROM duration and neonatal characteristics (p>0.1). Baseline fetal heart rate was higher in the HC group [median 147.3 bpm IQR (144.2-149.2) vs. 141.3 bpm (137.1-145.4) in no HC group; p = 0.02]. The number of low variation episodes [6.4, (3.5-15.3) vs. 2.3 (1-5.2); p = 0.04] was also higher in the HC group, whereas short term variations were lower in the HC group [7.1 ms (6-7.4) vs. 8.1 ms (7.4-9); p = 0.01] within 72 hours before delivery. Differences were especially discriminant within 24 hours before delivery, with less short-term variation [5 ms (3.7-5.9) vs. 7.8 ms (5.4-8.7); p = 0.007] and high variation episodes [3.9 (4.9-3.2) vs. 0.8 (1.5-0.2); p < 0.001] in the HC group.These results show differences in fetal heart rate variability, suggesting that cCTG could be used clinically to diagnoses chorioamnionitis during the pPROM latency period.

Published
2017
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3. New insight on FGFR3-related chondrodysplasias molecular physiopathology revealed by human chondrocyte gene expression profiling.

Author

Laurent Schibler, Linda Gibbs, Catherine Benoist-Lasselin, Charles Decraene, Jelena Martinovic, Philippe Loget, Anne-Lise Delezoide, Marie Gonzales, Arnold Munnich, Jean-Philippe Jais, and Laurence Legeai-Mallet

Subjects
Medicine, Science
Abstract

Endochondral ossification is the process by which the appendicular skeleton, facial bones, vertebrae and medial clavicles are formed and relies on the tight control of chondrocyte maturation. Fibroblast growth factor receptor (FGFR)3 plays a role in bone development and maintenance and belongs to a family of proteins which differ in their ligand affinities and tissue distribution. Activating mutations of the FGFR3 gene lead to craniosynostosis and multiple types of skeletal dysplasia with varying degrees of severity: thanatophoric dysplasia (TD), achondroplasia and hypochondroplasia. Despite progress in the characterization of FGFR3-mediated regulation of cartilage development, many aspects remain unclear. The aim and the novelty of our study was to examine whole gene expression differences occurring in primary human chondrocytes isolated from normal cartilage or pathological cartilage from TD-affected fetuses, using Affymetrix technology. The phenotype of the primary cells was confirmed by the high expression of chondrocytic markers. Altered expression of genes associated with many cellular processes was observed, including cell growth and proliferation, cell cycle, cell adhesion, cell motility, metabolic pathways, signal transduction, cell cycle process and cell signaling. Most of the cell cycle process genes were down-regulated and consisted of genes involved in cell cycle progression, DNA biosynthesis, spindle dynamics and cytokinesis. About eight percent of all modulated genes were found to impact extracellular matrix (ECM) structure and turnover, especially glycosaminoglycan (GAG) and proteoglycan biosynthesis and sulfation. Altogether, the gene expression analyses provide new insight into the consequences of FGFR3 mutations in cell cycle regulation, onset of pre-hypertrophic differentiation and concomitant metabolism changes. Moreover, impaired motility and ECM properties may also provide clues about growth plate disorganization. These results also suggest that many signaling pathways may be directly or indirectly altered by FGFR3 and confirm the crucial role of FGFR3 in the control of growth plate development.

Published
2009
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4. Functional Assessment of a New PBX1 Variant in a 46,XY Fetus with Severe Syndromic Difference of Sexual Development through CRISPR-Cas9 Gene Editing

Author

Laura Mary, Delphine Leclerc, Audrey Labalme, Pascale Bellaud, Séverine Mazaud-Guittot, Stéphane Dréano, Bertrand Evrard, Antoine Bigand, Aurélie Cauchoix, Philippe Loget, Anna Lokchine, Laurence Cluzeau, David Gilot, Marc-Antoine Belaud-Rotureau, Sylvie Jaillard, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Hospices Civils de Lyon (HCL), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), This study received financial support from AVIESAN Plan Cancer, Région Bretagne, Agence Nationale de Recherche, University of Rennes 1 and Ministère de la Recherche et de l’Enseignement Supérieur (MESRI, PhD Scholarship)., and Jonchère, Laurent

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, sexual development, Genetics, DSD, genome editing, [SDV.GEN] Life Sciences [q-bio]/Genetics, RNA-seq, CRISPR-Cas9, Genetics (clinical)
Abstract

International audience; Sexual development is a complex process relying on numerous genes. Disruptions in some of these genes are known to cause differences of sexual development (DSDs). Advances in genome sequencing allowed the discovery of new genes implicated in sexual development, such as PBX1. We present here a fetus with a new PBX1 NM_002585.3: c.320G>A,p.(Arg107Gln) variant, presenting with severe DSD along with renal and lung malformations. Using CRISPR-Cas9 gene editing on HEK293T cells, we generated a KD cell line for PBX1. The KD cell line showed reduced proliferation and adhesion properties compared with HEK293T cells. HEK293T and KD cells were then transfected plasmids coding either PBX1 WT or PBX1-320G>A (mutant). WT or mutant PBX1 overexpression rescued cell proliferation in both cell lines. RNA-seq analyses showed less than 30 differentially expressed genes, in ectopic mutant-PBX1-expressing cells compared with WT-PBX1. Among them, U2AF1, encoding a splicing factor subunit, is an interesting candidate. Overall, mutant PBX1 seems to have modest effects compared with WT PBX1 in our model. However, the recurrence of PBX1 Arg107 substitution in patients with closely related phenotypes calls for its impact in human diseases. Further functional studies are needed to explore its effects on cellular metabolism.

Published
2023
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5. Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder

Author

Nuno Maia, Sven Potelle, Hamide Yildirim, Sandrine Duvet, Shyam K. Akula, Celine Schulz, Elsa Wiame, Alexander Gheldof, Katherine O’Kane, Abbe Lai, Karen Sermon, Maïa Proisy, Philippe Loget, Tania Attié-Bitach, Chloé Quelin, Ana Maria Fortuna, Ana Rita Soares, Arjan P.M. de Brouwer, Emile Van Schaftingen, Marie-Cécile Nassogne, Christopher A. Walsh, Katrien Stouffs, Paula Jorge, Anna C. Jansen, François Foulquier, Public Health Sciences, Faculty of Medicine and Pharmacy, Neurogenetics, Clinical sciences, Medical Genetics, Basic (bio-) Medical Sciences, Reproduction and Genetics, Centre for Medical Genetics, Mental Health and Wellbeing research group, Neuroprotection & Neuromodulation, Universidade do Minho = University of Minho [Braga], Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lille, CNRS, and Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Subjects
Male, Adolescent, Child, preschool, glycosylation, [SDV]Life Sciences [q-bio], Hamartoma, Hypothalamus, Oligosaccharides, Hamartoma/genetics, Brain Stem/metabolism, Congenital Disorders of Glycosylation, All institutes and research themes of the Radboud University Medical Center, Tongue, alpha-Mannosidase, Intellectual Disability, Cell Line, Tumor, Leukocytes, Genetics, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase, Humans, Central Nervous System Cysts/genetics, Central Nervous System Cysts, Child, Genetics (clinical), Alleles, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase/deficiency, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Oligosaccharides/metabolism, Congenital Disorders of Glycosylation/genetics, Hypothalamus/metabolism, alpha-Mannosidase/deficiency, Cerebellar Vermis/metabolism, Intellectual Disability/genetics, Mannose/metabolism, fetus, Polymicrogyria/genetics, Polymicrogyria, Leukocytes/metabolism, Female, Tongue/metabolism, Mannose, Brain Stem, Cerebellar Vermis
Abstract

International audience; Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is knownabout fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss offunction of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has beenlinked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves a1,2-, a1,3-, and a1,6-mannose residues. In this study,we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants inMAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomaliessuch as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemisphericcysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experimentswith isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstratethat MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize theinvolvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.

Published
2022

6. Role of Chromosomal Imbalances in the Pathogenesis of DSD: A Retrospective Analysis of 4657 Prenatal Samples

Author

Laura Mary, Melanie Fradin, Laurent Pasquier, Chloé Quelin, Philippe Loget, Maëla Le Lous, Gwénaëlle Le Bouar, Sylvie Nivot-Adamiak, Anna Lokchine, Christèle Dubourg, Vincent Jauffret, Bénédicte Nouyou, Catherine Henry, Erika Launay, Sylvie Odent, Sylvie Jaillard, and Marc-Antoine Belaud-Rotureau

Subjects
History, Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering
Published
2022

8. Bardet‐Biedl syndrome: Antenatal presentation of forty‐five fetuses with biallelic pathogenic variants in known Bardet‐Biedl syndrome genes

Author

Kirsley Chennen, Philippe Loget, Alix Clemenson, Elise Schaefer, Marie-Josée Perez, Elsa Nourisson, Laura Mary, Corinne Stoetzel, Bernard Gasser, Jean Muller, Annie Buenerd, Lucile Pinson, Louise Devisme, Florence Petit, Olivier Poch, Anne Sophie Leuvrey, Fabien Guimiot, Patrice Bouvagnet, Caroline Rooryck-Thambo, Brigitte Leroy, Manuela Antin, Tania Attié-Bitach, Jelena Martinovic, Fanny Pelluard, Raymonde Bouvier, Hélène Dollfus, Brigitte Gilbert-Dussardier, Elisabeth Alanio-Detton, Maria Cristina Antal, and Philippe Khau Van Kien

Subjects
0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, Genotype, Biopsy, Autopsy, Disease, 030105 genetics & heredity, 03 medical and health sciences, Bardet–Biedl syndrome, Prenatal Diagnosis, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Bardet-Biedl Syndrome, Alleles, Genetic Association Studies, Genetics (clinical), Cystic kidney, Fetus, Polydactyly, business.industry, medicine.disease, Ciliopathy, Phenotype, 030104 developmental biology, Amino Acid Substitution, Mutation, business
Abstract

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.

Published
2019

9. Le facteur de transcription PBX1 est responsable d’anomalies du développement sexuel associé à une atteinte rénale

Author

Chloé Quélin, Marc-Antoine Belaud-Rotureau, Audrey Labalme, Philippe Loget, Erika Launay, Gaetan Lesca, Frédérique Dijoud, Laura Mary, Caroline Schluth-Bolard, Antoine Bigand, Laurence Cluzeau, Sylvie Jaillard, and Aurélie Cauchoix

Subjects
Anatomy
Abstract

Introduction Les anomalies du developpement sexuel (DSD) sont des malformations congenitales complexes resultant en une discordance entre sexe chromosomique, gonadique et anatomique. A ce jour, dans les DSD, de nombreux patients restent encore sans diagnostic. Les resultats du sequencage d’exome d’un fœtus atteint de DSD syndromique a permis de mettre en evidence l’implication d’un nouveau gene, PBX1, dans le developpement sexuel. Patient et methodes Un fœtus mort-ne a ete adresse pour examen fœtopathologique pour syndrome polymalformatif (retard de croissance intra-uterin, DSD, rein droit pelvien). Le developpement gonadique a ete etudie par immunohistochimie (OCT4, CD117, SF1, FOXL2, inhibine). Les etudes genetiques ont inclus caryotype, FISH, ACPA et sequencage d’exome. Une etude par immunofluorescence ciblant PBX1 sur tissu congele a ete realisee. Resultats Le fœtus presentait une hypotrophie renale bilaterale avec rein droit pelvien, une hypoplasie pulmonaire et une dysgenesie gonadique (gonade de type testiculaire a droite, streak gonad a gauche) associee a la presence de derives wolffiens et mulleriens, un tubercule genital proeminent, un hypospadias, des bourrelets genitaux non fusionnes. L’ACPA etait normale. Caryotype et FISH ont montre un resultat 46,XY. L’exome retrouvait un variant heterozygote de novo dans le gene PBX1 : p.(Arg107Gln). L’etude en immunofluorescence montrait une localisation nucleaire (normale) de PBX1, comparable aux temoins. PBX1 code pour un facteur de transcription fonctionnant en complexe proteique avec certaines proteines dont HOX [1] . Les dysfonctions de cette proteine ont ete impliquees dans les anomalies renales et urinaires syndromiques (CAKUT) [2] . Cinq cas ont ete associes a des DSD, principalement chez des patients 46,XY, dont deux cas presentant une substitution touchant l’arginine 107 [PBX1 : p.(Arg107Trp)] [3] , [4] , [5] . D’autres etudes fonctionnelles sont en cours. Conclusion PBX1, facteur de transcription implique dans les CAKUT syndromiques, joue un role majeur dans la differenciation gonadique et la masculinisation des individus 46,XY.

Published
2021

10. Multicolor-FISH Characterization of a Prenatal Mosaicism for a Chromosomal Rearrangement Undetected by Molecular Cytogenetics

Author

Gwenaelle Le Bouar, Laura Mary, Dominique Aussel, Marc-Antoine Belaud-Rotureau, Sylvie Jaillard, Catherine Henry, Sylvie Odent, Erika Launay, Philippe Loget, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Clinique mutualiste La Sagesse, Chard-Hutchinson, Xavier, and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Monosomy, [SDV]Life Sciences [q-bio], Population, Prenatal diagnosis, Chromosomal rearrangement, Biology, Molecular cytogenetics, 03 medical and health sciences, aCGH, Genetics, medicine, Multiplex ligation-dependent probe amplification, Multicolor-FISH, education, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Chromosome rearrangement, Mosaicism, 030305 genetics & heredity, Karyotype, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Chromosome 17 (human)
Abstract

International audience; Fetal mosaicism for chromosomal rearrangements remains a challenge to diagnose, even in the era of whole-genome sequencing. We present here a case of fetal mosaicism for a chromosomal rearrangement explored in amniocytes and fetal muscle, consisting of a major cell population (95%) with partial monosomy 4q and a minor population (5%) with additional material replacing the 4qter deleted segment. Molecular techniques (MLPA, array-CGH) failed to assess the origin of this material. Only multicolor-FISH identified the additional segment on chromosome 4 as derived from chromosome 17. Due to the poor prognosis, the couple chose to terminate the pregnancy. Because of low-level mosaicism, chromosomal microarray analysis (CMA), now considered as first-tier prenatal genetic analysis, did not allow the identification of the minor cell line. In case of large CNVs (>5 Mb) detected by CMA, karyotyping may be considered to elucidate the mechanism of the underlying rearrangement and eliminate mosaicism.

Published
2021

11. Elucidating in utero fetal demise time to reassemble the pieces of the puzzle?

Author

Philippe Loget, Gwenaelle Le Bouar, Patrick Jego, Florence Rouget, Alain Lescoat, Leïla Caillault, Alice Ballerie, Nicolas Belhomme, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Chard-Hutchinson, Xavier, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)

Subjects
030203 arthritis & rheumatology, 030219 obstetrics & reproductive medicine, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Obstetrics and Gynecology, 03 medical and health sciences, 0302 clinical medicine, In utero, Pediatrics, Perinatology and Child Health, Medicine, Fetal Demise, business, Neuroscience, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2020

12. Prenatal phenotype of 22q11 micro-duplications: A systematic review and report on 12 new cases

Author

Laura Mary, Alinoë Lavillaureix, Adélie Perrot, Philippe Loget, Erika Launay, Anne-Sophie Leborgne, Florence Demurger, Mélanie Fradin, Gwenaelle Le Bouar, Chloé Quélin, Christèle Dubourg, Laurent Pasquier, Sylvie Odent, Marc-Antoine Belaud-Rotureau, Sylvie Jaillard, Chard-Hutchinson, Xavier, École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pontchaillou [Rennes], Clinique mutualiste La Sagesse, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Centre Hospitalier Universitaire [Rennes], and This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Subjects
Male, [SDV.GEN]Life Sciences [q-bio]/Genetics, Chromosomes, Human, Pair 22, [SDV]Life Sciences [q-bio], Infant, Newborn, [SDV.GEN] Life Sciences [q-bio]/Genetics, General Medicine, Genotype-phenotype, Phosphoproteins, 22q11, [SDV] Life Sciences [q-bio], Fetus, Phenotype, aCGH, Chromosome Duplication, DiGeorge Syndrome, Genetics, Humans, Prenatal, Abnormalities, Multiple, Female, Foetal, Genetics (clinical), Adaptor Proteins, Signal Transducing
Abstract

International audience; The 22q11 region is prone to generating recurring Copy Number Variations (CNVs) as a result of the large numbers of Low Copy Repeats (LCRs). Typical duplications encompass the LCR-A-to-D region but atypical duplications of various sizes have also been reported. These duplications are responsible for highly variable phenotypes with incomplete penetrance and expressivity, which is challenging for adequate genetic counselling, especially in the prenatal period. To better delineate prenatal phenotypes associated with these CNVs, we report here a clinical and molecular description of twelve cases (9 foetuses and 3 deceased new-borns babies) carrying recurrent 22q11 duplications (diagnosed via aCGH), along with a review of the existing literature. 22q11 duplications were inherited from an apparently healthy parent in almost 60% of the cases. Other CNVs were diagnosed for 8% of the cases. Increased nuchal translucency and cardiac anomalies (CHD) were the most prominent phenotypes observed, along with mild renal and skeletal anomalies. Duplications encompassing the LCR-C-to-D region (and the CRKL gene) seemed more likely to generate CHDs and renal malformations. Cleft lip/palate were observed in foetuses with duplications encompassing the LCR-A-to-B region or the SPECC1L gene, as previously suggested. However, genotype-phenotype correlations remain difficult to ascertain. Second-hit point variants, epigenetic or environmental variations could play a role in the phenotypic variability of 22q11 duplications, but remain a challenge for assessment in the short period of pregnancy.

Published
2022

13. Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations

Author

Tania Attié-Bitach, Philippe Jonveaux, Alice Goldenberg, Antonio Vitobello, Nicole Laurent, Marjolaine Willems, Valérie Kremer, Dominique Gaillard, Chloé Quélin, Sebastien Moutton, Marion Aubert-Lenoir, Yannis Duffourd, Anne-Sophie Lebre, Anne-Claire Brehin, James Lespinasse, Yline Capri, Nolwenn Jean-Marçais, Maria Cristina Antal, Frédéric Tran Mau-Them, Nathalie Marle, Daphné Lehalle, Nicolas Bourgon, Sophie Blesson, Bernard Foliguet, Laetita Lambert, Nicole Bigi, Mélanie Fradin, Emilie Tisserant, Christel Thauvin-Robinet, Ange-Line Bruel, Elisabeth Alanio, Marie-Hélène Saint-Frison, Christine Francannet, Anne-Marie Guerrot, Paul Kuentz, Elise Schaefer, Anne-Marie Beaufrere, Sylvie Odent, Francine Arbez-Gindre, Laurence Faivre, Christophe Philippe, Julien Thevenon, Sophie Patrier-Sallebert, Nada Houcinat, Celine Poirisier, Sophie Nambot, Mathilde Lefebvre, Mirna Assoum, Françoise Girard-Lemaitre, Sophie Collardeau-Frachon, Marie-José Perez, Jean-Louis Mandel, Jean-Pierre Mazutti, Renaud Touraine, Philippe Loget, Salima El Chehadeh, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, CHU Strasbourg, Hôpital de Hautepierre [Strasbourg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), European Organization for Nuclear Research (CERN), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Anatomie pathologique [CHRU Besançon], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pontchaillou [Rennes], Hôpital Lapeyronie [Montpellier] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Biomécanique Humaine Georges Charpak (IBHGC), Université Sorbonne Paris Nord-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Clermont-Ferrand, CHU Rouen, Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Métropole Savoie [Chambéry], CHU Saint-Etienne, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Robert Debré, Plateau technique de Biologie [CHU de Dijon], Centre Hospitalier Universitaire [Grenoble] (CHU), CarMeN, laboratoire, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 14-013 FOETEX, Interregional French PHRC, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
Candidate gene, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], Biology, Congenital Abnormalities, Cohort Studies, complex traits, 03 medical and health sciences, Fetus, Molecular genetics, medicine, Humans, Abnormalities, Multiple, Exome, Clinical significance, genetics, Gene, Genetic Association Studies, Genetics (clinical), Exome sequencing, 030304 developmental biology, Genetics, 0303 health sciences, 030305 genetics & heredity, Sequence Analysis, DNA, Phenotype, [SDV] Life Sciences [q-bio], molecular genetics, reproductive medicine
Abstract

PurposeMolecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.MethodsWe performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.ResultssES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).ConclusionsThis method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.

Published
2020

14. Loss of function IFT27 variants associated with an unclassified lethal fetal ciliopathy with renal agenesis

Author

Mélanie Fradin, Sophie Thomas, Florence Demurger, Nadia Elkhartoufi, Tania Attié-Bitach, Sylvie Odent, J. Milon, Chloé Quélin, Laurent Pasquier, Philippe Loget, and Lucile Boutaud

Subjects
Male, 0301 basic medicine, Biology, Kidney, Compound heterozygosity, Ciliopathies, Congenital Abnormalities, 03 medical and health sciences, Fatal Outcome, Intraflagellar transport, Genetics, medicine, Humans, Renal agenesis, Genetics (clinical), Polydactyly, medicine.disease, Phenotype, Pedigree, Bilateral Renal Agenesis, Fetal Diseases, Ciliopathy, 030104 developmental biology, rab GTP-Binding Proteins, Mutation, Female, Kidney Diseases, sense organs
Abstract

Ciliopathies comprise a group of clinically heterogeneous and overlapping disorders with a wide spectrum of phenotypes ranging from prenatal lethality to adult-onset disorders. Pathogenic variants in more than 100 ciliary protein-encoding genes have been described, most notably those involved in intraflagellar transport (IFT) which comprises two protein complexes, responsible for retrograde (IFT-A) and anterograde transport (IFT-B). Here we describe a fetus with an unclassified severe ciliopathy phenotype including short ribs, polydactyly, bilateral renal agenesis, and imperforate anus, with compound heterozygosity for c.118_125del, p.(Thr40Glyfs*11) and a c.352 +1G > T in IFT27, which encodes a small GTPase component of the IFT-B complex. We conclude that bilateral renal agenesis is a rare feature of this severe ciliopathy and this report highlights the phenotypic overlap of Pallister-Hall syndrome and ciliopathies. The phenotype in patients with IFT27 gene variants is wide ranging from Bardet-Biedl syndrome to a lethal phenotype.

Published
2018

15. Fraser syndrome: features suggestive of prenatal diagnosis in a review of 38 cases

Author

Philippe Loget, Fanny Pelluard, Valérie Goua, Annie Laquerrière, Alain Verloes, Laurence Faivre, P. Dechelotte, Nicole Laurent, Thierry Frebourg, Martine Bucourt, Sophie Blesson, Fabien Guimiot, Martine Maréchaud, Aude Tessier, Charlotte Mechler, J.C. Sabourin, Corinne Jeanne-Pasquier, Marie-Josée Perez, Anne-Marie Guerrot, Sophie Patrier, Alice Goldenberg, Gwenaëlle André, Mélie Sarreau, and Mathilde Lefebvre

Subjects
0301 basic medicine, Pregnancy, Pathology, medicine.medical_specialty, Omphalocele, Obstetrics, business.industry, Obstetrics and Gynecology, Oligohydramnios, Prenatal diagnosis, 030105 genetics & heredity, medicine.disease, 03 medical and health sciences, 030104 developmental biology, Dysplasia, Agenesis, medicine, Syndactyly, business, Fraser syndrome, Genetics (clinical)
Abstract

Objective Fraser syndrome (FS) is a rare malformation recessive disorder. Major criteria are cryptophtalmos, syndactyly, respiratory, genital and urinary tract anomalies. Few prenatal presentations have been reported. Method We analyzed the prenatal and postnatal fetal phenotype in 38 cases of FS, including 25 pregnancy termination cases, 8 intra-uterine death cases and 4 cases that died after birth. Results Including both prenatal and postnatal fetal phenotypic evaluation, all cases presented dysmorphic features with nose and ear dysplasia. Renal anomalies and syndactyly were present in 37/38 cases, cryptophtalmos in 36/38, airways anomalies in 30/37 and genital anomalies in 30/35 cases. Anomalies of the abdominal wall such as low set umbilicus and omphalocele were found in 31 cases. Among the 26 cases for which ultrasound data were available, detectable anomalies included oligohydramnios (22), ascites/hydrops (9), renal anomalies (20), evidence for high airways obstruction (11), ophthalmologic anomalies (4), ear dysplasia (2) and syndactyly (2). Conclusion This study shows that the postnatal phenotype of FS is very specific, whereas oligohydramnios hampers the prenatal recognition of the cardinal FS diagnosis criteria. Association of oligohydramnios, kidney agenesis and CHAOS should lead to consider this diagnosis. © 2016 John Wiley & Sons, Ltd.

Published
2016

16. Microduplications 22q11.2 typiques et atypiques en fœtopathologie

Author

Chloé Quélin, Gwenaelle Le Bouar, Sylvie Odent, Mélanie Fradin, Marion Beaumont, Laurent Pasquier, Sylvie Jaillard, Adélie Perrot, Paul Rollier, Florence Demurger, Erika Launay, Philippe Loget, and Marc-Antoine Belaud-Rotureau

Subjects
030222 orthopedics, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, 030301 anatomy & morphology, Anatomy
Abstract

Il existe au niveau de la region proximale du bras long du chromosome 22 huit low copy repeat (LCR22) favorisant les recombinaisons et la survenue de remaniements chromosomiques. La microduplication typique 22q11.2 montre une expressivite tres variable et une penetrance incomplete, ayant rendu sa decouverte tardive et son etude complexe. Des duplications atypiques, consequence d’anomalies de recombinaison dans des LCR alternatifs, surviennent de facon plus rare, avec de ce fait des consequences phenotypiques moins bien identifiees. Nous presenterons 6 cas de duplications 22q11.2 atypiques, identifiees par analyse chromosomique sur puce a ADN, apres examen fœtopathologique. Elles correspondent a deux duplications d’1.3 Mb LCR22-F/LCR22-H (agenesie thymique dans un cas, hygroma colli et cardiopathie dans l’autre cas), une duplication d’1.2 Mb LCR22-D/LCR22-E survenue de novo (hypertrophie renale bilaterale et anomalies digitales), une duplication d’1,8 Mb LCR22-E/LCR22-H heritee du pere (dysmorphie faciale, cardiopathie et agenesie renale), une duplication de 745 kb LCR-B/LCR-D heritee du pere (tableau polymalformatif) et une duplication de 400 kb LCR-C/LCR-D (clarte nucale augmentee en echographie). Par ailleurs, 6 cas de duplication 22q11.2 typiques ont ete identifies chez des fœtus presentant un phenotype variable avec souvent une cardiopathie congenitale. Notre etude permet de preciser la description du phenotype fœtal associe aux microduplications 22q11.2, typiques et atypiques. L’implication de ces duplications 22q11.2 mais aussi de facteurs moleculaires additionnels permettant d’expliquer le phenotype est discutee. Par ailleurs, grâce a l’apport des techniques de sequencage massif en parallele (MPS), des variants geniques pathogeniques ont recemment ete identifies chez des patients presentant une duplication 22q11.21 et une presentation clinique atypique ou tres severe, demontrant l’utilite de rechercher un deuxieme evenement moleculaire dans ces cas [1] . Cette approche complementaire par MPS est conseillee pour les variations du nombre de copies d’ADN a penetrance incomplete, afin d’aider a la realisation d’un conseil genetique plus precis.

Published
2019

17. Elucidating

Author

Nicolas, Belhomme, Alain, Lescoat, Alice, Ballerie, Florence, Rouget, Gwenaelle, Le Bouar, Philippe, Loget, Leïla, Caillault, and Patrick, Jego

Subjects
Humans, Fetal Death
Published
2019

18. Author response for 'Bardet-Biedl syndrome - antenatal presentation of 45 fetuses with biallelic pathogenic variants in known BBS genes'

Author

Louise Devisme, E. Alanio-Detton, Anne Sophie Leuvrey, Kirsley Chennen, Raymonde Bouvier, Hélène Dollfus, Olivier Poch, Elsa Nourisson, Brigitte Gilbert-Dussardier, Fabien Guimiot, Maria Cristina Antal, Patrice Bouvagnet, Laura Mary, Lucile Pinson, Bernard Gasser, Jean Muller, Jelena Martinovic, Manuela Antin, Annie Buenerd, Tania Attié-Bitach, Corinne Stoetzel, Alix Clemenson, C. Rooryck, Philippe Loget, Fanny Pelluard, Elise Schaefer, P. Khau Van Kien, Brigitte Leroy, Florence Petit, and Marie-Josée Perez

Subjects
Fetus, Bardet–Biedl syndrome, business.industry, Medicine, Presentation (obstetrics), business, Bioinformatics, medicine.disease, Gene
Published
2018

19. A series of 38 novel germline and somatic mutations ofNIPBLin Cornelia de Lange syndrome

Author

Hervé Testard, Martine Doco-Fenzy, Alice Goldenberg, Fabienne Prieur, Caroline Michot, Marcia Henry, Sandrine Marlin, Sophie Blesson, Clarisse Baumann, Valérie Cormier-Daire, Philippe Loget, Sylvie Odent, Marlène Rio, Anne-Lise Delezoide, Andrée Delahaye-Duriez, Jean-Paul Bonnefont, Anne Dieux-Coeslier, Audrey Putoux, Marie-Pierre Cordier-Alex, Ghislaine Plessis, Valérie Layet, Albert David, Mathilde Nizon, Bettina Bessières, Jelena Martinovic, Laurent Pasquier, Anne Bazin, and Laurence Faivre

Subjects
0301 basic medicine, Genetics, Sanger sequencing, Mutation, Microcephaly, Cornelia de Lange Syndrome, Genetic counseling, Buccal swab, NIPBL, Biology, medicine.disease_cause, medicine.disease, Germline, 3. Good health, 03 medical and health sciences, symbols.namesake, 030104 developmental biology, medicine, symbols, Genetics (clinical)
Abstract

Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to an heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: 1) intrauterine growth retardation and postnatal short stature, 2) feeding difficulties and/or gastro-oesophageal reflux, 3) microcephaly, 4) intellectual disability and 5) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and three in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for twenty cases which does not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counseling

Published
2016

20. Microremaniements 16p11.2 BP4-BP5 en diagnostic prénatal : expérience du service de cytogénétique du CHU de Rennes

Author

Anne-Sophie Neyroud, Chloé Quélin, Catherine Henry, Erika Launay, Paul Rollier, Laurent Pasquier, Gwenaelle Le Bouar, Sylvie Odent, Marion Beaumont, Sylvie Jaillard, Marc Antoine Belaud-Rotureau, Adélie Perrot, and Philippe Loget

Subjects
Gynecology, medicine.medical_specialty, Prenatal experience, medicine, Anatomy, Hygroma colli
Abstract

Les microremaniements recurrents 16p11.2 situes entre BP4 et BP5 (550–600 kb) sont associes aux troubles du spectre autistique, neuro-developpementaux et a la schizophrenie [1] . Neanmoins, une forte variabilite d’expression est decrite, surtout en cas de microduplication [2] . Les signes d’appel echographiques (SAE) et la conduite a tenir en cas d’identification d’un tel microremaniement en periode prenatale sont peu documentes. Entre 2009 et 2018, le service de cytogenetique du CHU de Rennes a realise environ 1200 analyses chromosomiques sur puce a ADN en prenatal chez des fœtus a caryotype normal, ce qui a permis l’identification de cinq microremaniements 16p11.2 (5/1200 soit 0,4 %). Quatre microduplications 16p11.2 ont ete observees chez des fœtus presentant respectivement un arc aortique droit (1), un hydramnios (2), un RCIU associe a un rhombencephalosynapsis (3), des femurs et humerus courts associes a des anomalies des organes genitaux externes (4). Chez les fœtus 1 et 2, un autre diagnostic genetique pouvait expliquer les SAE observes : microdeletion 22q11.21 impliquant TBX1 chez le fœtus 1 et syndrome de Steinert congenital chez le fœtus 2. Le microremaniement etait herite d’un parent en bonne sante chez les fœtus 1 et 3, de novo chez le fœtus 2 et l’enquete familiale n’a pas ete realisee pour le fœtus 4. Par ailleurs, une microdeletion 16p11.2 heritee de la mere a ete identifiee chez un fœtus presentant un hygroma colli (5). Un cas d’hyperclarte nucale isolee a precedemment ete rapporte dans une serie de 12 fœtus porteurs de cette microdeletion 16p11.2 [3] . A notre connaissance, aucune etude ne s’est interessee specifiquement aux microduplications. Le manque de donnees cliniques associe a la grande variabilite d’expression rend le conseil genetique difficile. Une etude sur une plus large cohorte de fœtus est necessaire pour mieux apprehender l’impact de ces microremaniements 16p11.2.

Published
2019

21. Fetal cerebral hemorrhage due to X-linked GATA1 gene mutation

Author

Philippe Loget, Lydie Da Costa, Sophie Collardeau-Frachon, Chloé Quélin, Lorraine Maheut, Julie Galimand, Jelena Martinovic, Marie-Victoire Senat, Hanane Bouchghoul, and Férechté Encha-Razavi

Subjects
0301 basic medicine, Adult, Pathology, medicine.medical_specialty, GATA1 Gene Mutation, 03 medical and health sciences, Exon, Genes, X-Linked, Pregnancy, medicine, Humans, GATA1 Transcription Factor, Allele, Genetics (clinical), Hemochromatosis, Cerebral Hemorrhage, Fetus, Fetal cerebral hemorrhage, business.industry, Obstetrics and Gynecology, medicine.disease, Phenotype, Fetal Diseases, 030104 developmental biology, Mutation, Gestation, Female, business
Abstract

We report a multiplex family with a GATA1 gene mutation responsible for a massive fetal cerebral hemorrhage occurring at 36 weeks. Two other stillbirth cousins presented with fetal hydrops and congenital hemochromatosis' phenotype at 37 and 12 weeks of gestation. Molecular screening revealed the presence of a c.613G>A pathogenic allelic variation in exon 4 of GATA1 gene in the 3 male siblings and their carrier mothers. The diagnosis of a GATA1 gene mutation may be suspected in cases of male fetuses with intracerebral bleeding, particularly if a history of prior fetal loss(es) and mild maternal thrombocytopenia are also present.

Published
2018

22. Ultrasound Presentation of a Disseminated Fetal and Neonatal Rhabdoid Tumor

Author

Maela Le Lous, Dominique Ranchere Vince, Céline Rozel, Yolaine Joueidi, Philippe Loget, Aline Rousselin, Franck Bourdeaut, Vincent Lavoué, and Sylvie Odent

Subjects
Fetus, Pathology, medicine.medical_specialty, 030219 obstetrics & reproductive medicine, medicine.diagnostic_test, business.industry, Obstetrics and Gynecology, Case Report, medicine.disease, lcsh:Gynecology and obstetrics, Metastasis, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Placenta, Fetal movement, Biopsy, embryonic structures, medicine, Fetal distress, Gestation, business, Pathological, lcsh:RG1-991
Abstract

This is a case report of a disseminated fetal rhabdoid tumor discovered at 32 weeks of gestation in a 29-year-old woman on immunosuppressive therapy. The mother consulted for a decrease in fetal movement. Fetal ultrasound showed signs of a disseminated tumor affecting the left armpit, liver, spleen, and limbs. A caesarian section was performed because of signs of fetal distress. Immunohistochemical analysis of a fetal biopsy showed deletion of the SMARCB1 gene. Pathological analysis of the placenta showed a rhabdoid tumor invading both fetal and maternal compartments. The mother underwent a whole-body MRI, and no metastasis was found. To the best of our knowledge, this is the first report of a disseminated rhabdoid tumor invading both fetal and maternal compartments.

Published
2018

23. Fetal phenotypes in otopalatodigital spectrum disorders

Author

Philippe Loget, Didier Lacombe, Marie-Pierre Cordier, Sébastien Moutton, Cyril Goizet, C. Abel, Cédric Hubert, Sophie Patrier, Julie Pilliod, G. Viot, Benoit Arveiler, Bettina Bessières, Alice Goldenberg, Julie Deforges, Isabelle Coupry, Caroline Rooryck, G. Sole, Anne-Lise Delezoide, Sophie Blesson, Patricia Fergelot, Elodie Guerineau, Alain Verloes, Judith Melki, F. Le Breton, S. Deves, Sophie Collardeau-Frachon, Sylvie Odent, and Sophie Naudion

Subjects
0301 basic medicine, Genetics, Mutation, Mutation rate, Omphalocele, Craniofacial abnormality, Genetic counseling, 030105 genetics & heredity, Biology, medicine.disease_cause, Bioinformatics, medicine.disease, 3. Good health, 03 medical and health sciences, Dysplasia, medicine, FLNA, Obstructive uropathy, Genetics (clinical)
Abstract

Otopalatodigital spectrum disorders (OPDSD) include OPD syndromes types 1 and type 2 (OPD1, OPD2), Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra-skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families.

Published
2015

24. Non-specific post-mortem modifications on whole-body post-mortem computed tomography in sudden unexpected death in infancy

Author

Catherine Tréguier, Philippe Loget, P. Darnault, M. Roussey, Renaud Bouvet, Maïa Proisy, Fabienne Pelé, Céline Rozel, and Bertrand Bruneau

Subjects
medicine.medical_specialty, Ligamentum arteriosum, business.industry, medicine.medical_treatment, Umbilical artery, Hemopericardium, medicine.disease, Unexpected death, Ground-glass opacity, Pathology and Forensic Medicine, medicine.artery, medicine.ligament, medicine, Radiology, Nuclear Medicine and imaging, Radiology, Cardiopulmonary resuscitation, medicine.symptom, business, Cause of death, Calcification
Abstract

Objectives To provide an overview of non-specific modifications on whole-body post-mortem computed tomography (PMCT) images of infants and children. Materials and methods 69 infants and children underwent a whole-body PMCT scan at our institution following sudden unexpected death. Two paediatric radiologists reviewed the PMCT images, specifically focusing on non-specific postmortem modifications unrelated to the presumed cause of death. Results Iatrogenic post-mortem modifications included focal infiltration of the legs ( n =15) and hemopericardium ( n =2). Vascular postmortem modifications included hypostasis (density in the posterior sagittal sinus was correlated with density in the dependent portion of the heart ( p n =56, 75.3%), hyperattenuating aortic wall and reduced abdominal aortic diameter ( n =69, 100%). Intravascular gas was detected in 40 subjects (57.9%). Ligamentum arteriosum calcification was seen in 42 children and was not correlated with age ( p =0.68). Umbilical artery calcification was found in 30 children and was correlated with age ( p n =45, 65.2%) and bowels ( n =44, 63.7%) was a frequent finding. Mean liver density was 49.6±7.5HU and mean spleen density was 43.2±5.9HU. Ground-glass opacity was observed in 63 cases (91.3%) and mild bilateral consolidation in 16 cases (23.1%). Conclusion Non-specific post-mortem signs are rare and new to clinical paediatric radiologists. They should be aware of these signs when interpreting whole-body PMCT images in cases of sudden unexpected death in infancy or childhood in order to avoid pitfalls that may have a critical impact.

Published
2015

25. Investigating in utero fetal death: outcome of internal medicine consultation

Author

Thomas Le Gallou, Nicolas Belhomme, Patrick Jego, Florence Rouget, Philippe Loget, Marine de Carlan, A. Lescoat, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
placental pathology, Placenta Diseases, Epidemiology, Placenta, 030204 cardiovascular system & hematology, Hospitals, University, Drug treatment, 0302 clinical medicine, Pregnancy, Risk Factors, Prevalence, Referral and Consultation, 030219 obstetrics & reproductive medicine, Fetal death, Obstetrics, Clinical aspects, Gestational age, Stillbirth, Antiphospholipid Syndrome, Thrombosis, Pathophysiology, 3. Good health, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, In utero, Infarction, Antibodies, Antiphospholipid, Female, France, Adult, medicine.medical_specialty, placental vascular disorders, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 03 medical and health sciences, Young Adult, Rheumatology, Internal medicine, medicine, Internal Medicine, Humans, Pathological, Fetal Death, Retrospective Studies, business.industry, antiphospholipid antibodies syndrome, medicine.disease, Etiology, in utero fetal death, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Biomarkers
Abstract

International audience; Aim: The objectives were to determine the frequency of in utero fetal death (IUFD) related to placental disorders and to assess the frequency of antiphospholipid antibodies syndrome (APS) among women referred to the internal medicine department.Methodology: A retrospective clinical study conducted in Rennes University Hospital, France. From January 2007 to December 2014, 53 women who presented an IUFD at 14 weeks or more of gestational age were included. The main cause for each IUFD was determined by expert agreement. Primary outcome was to analyze the final etiologies diagnosed and the prevalence of IUFD related to placental disorders. Secondary outcomes included the frequency of APS among patients with IUFD of placental origin and the pathological and clinical features associated with APS.Results: IUFD resulted from placental disorders in 36/53 (68%) patients, and remained unexplained in 11 cases (20.8%). Among the 36 patients with placental disorders, APS was diagnosed in five (13.9%) cases, and four (11.1%) patients were considered as having 'non-criteria' APS. History of thrombosis (P = 0.001) and placental infarcts (P = 0.047) were significantly associated with APS.Conclusion: Placental disorders were the major cause for IUFD in patients who were referred to internal medicine specialists. Importantly, APS was seldom found in patients with placental disorders. Venous thromboembolism history and placental infarcts were both significantly associated with APS. Further studies are needed in order to deepen our understanding of the physiopathology of placental disorders and its underlying causes among non-APS women, and to determine the best treatment regimen for future pregnancies.

Published
2017

26. Fetal costello syndrome with neuromuscular spindle excess and p.Gly12Val HRAS mutation

Author

Laurent Pasquier, Florence Demurger, Pascale Marcorelles, Mélanie Fradin, Céline Rozel, Chloé Quélin, Dominique D'Hervé, Philippe Loget, Hélène Cavé, Sylvie Odent, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie Pathologique, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de génétique clinique, hôpital Sud, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Pathology, Mutation, Missense, Neuromuscular disorder, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 030105 genetics & heredity, Biology, HRAS gene, Fetal, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Germline mutation, Costello syndrome, Pregnancy, Internal medicine, Prenatal Diagnosis, Genetics, medicine, Humans, HRAS, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Arthrogryposis, Muscle biopsy, medicine.diagnostic_test, Costello, Coarse facial features, Costello Syndrome, General Medicine, medicine.disease, Congenital myopathy, 3. Good health, Fetal Diseases, 030104 developmental biology, Endocrinology, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, Congenital disorder
Abstract

Costello syndrome (CS) is a rare multiple congenital disorder caused by activating germline mutations in HRAS gene and is characterized by coarse facial features, severe feeding difficulties, failure to thrive, mild to severe intellectual disability, severe postnatal growth retardation, cardiac abnormalities or cancer predisposition. Phenotypic spectrum associated with HRAS mutations is broad, ranging from attenuated CS phenotype to neonatal and lethal forms with limited genotype-phenotype correlations. Congenital myopathy with neuromuscular spindle excess has been rarely described in the literature. We report a new severe fetal case of CS with distal arthrogryposis due to neuromuscular spindle excess, confirmed by the detection of the p.Gly12Val mutation in HRAS gene. This case emphasizes the fact that HRAS is the only gene responsible for neuromuscular spindle excess, underlines a correlation between p.Gly12Val mutation and severe CS phenotype and points out the importance of a muscle biopsy performed according to the suitable procedure in neuromuscular disorders for any fetal arthrogryposis.

Published
2017

27. Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes

Author

Nadège Gigot, Anne Dieux, Yannis Duffourd, Bernard Aral, Lydie Burglen, Bérénice Doray, Olivier Rosnet, Alice Goldenberg, Martijn A. Huynen, Oliver E. Blacque, Brunella Franco, André Mégarbané, Diane Doummar, Ernie M.H.F. Bongers, Anne Fargeot-Espaliat, Clarisse Baumann, Judith St-Onge, Daniel Birnbaum, Sophie Saunier, Thibaut Eguether, Jean-François Deleuze, Estelle Lopez, Dominique Gaillard, Geneviève Pierquin, Shubha R. Phadke, Michel R. Leroux, Rachel H. Giles, Tania Attié-Bitach, Jaclyn S. Goldstein, Isabelle Desguerres, Elisabeth Steichen-Gersdorf, Brigitte Gilbert-Dussardier, Manuela Morleo, Jesús Argente, Jean Baptiste Rivière, Gregory J. Pazour, Christel Thauvin-Robinet, Julien Thevenon, Albert David, Maxence V. Nachury, Laurence Faivre, Philippe Loget, Véronique Chevrier, Bruno Reversade, Laurence Jego, Ange Line Bruel, Vicente Herranz-Pérez, Laurent Pasquier, Colin A. Johnson, John B. Wallingford, Valérie Cormier-Daire, Inusha Panigrahi, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut d'Astrophysique et de Géophysique [Liège], Université de Liège, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service: neuropédiatrie pathologie du développement, Université Pierre et Marie Curie - Paris 6 (UPMC), University Medical Center [Utrecht], University of Leeds, Radboud University [Nijmegen], Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Génétique Humaine, Université de Liège-CHU Liège, Service de Génétique, Hôpital de Hautepierre [Strasbourg], Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Laboratory of Human Embryology and Genetics, Institute of Medical Biology, Singapore, Department of Pediatrics, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Département de Génétique Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Advanced Pediatric Center (PGIMER), Pediatry center, Pédiatrie Neonatalogie, Centre Hospitalier Général, Brive-la-Gaillarde, Brive-la-Gaillarde, France, Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Dauphine Recherches en Management - MLAB (DRM - MLAB), Dauphine Recherches en Management (DRM), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Department of human genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Centre de génétique et Centre de référence maladies rares et anomalies du développement et syndromes malformatifs du Centre Est, Département de Génétique et Procréation UF-Hôpital Couple Enfant de Grenoble-CHU Grenoble, Hospital Universitario La Paz, Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], FHU TRANSLAD, Département de Génétique, Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie intégrative de la molécule à l'organisme, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique médicale, Université Saint-Joseph de Beyrouth (USJ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands, Section of Ophthalmology and Neurosciences, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK, Radboud university [Nijmegen], Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de neuropédiatrie et pathologie du développement, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service de neurométabolisme, Hôpital Necker-Enfants Malades, CHU, Paris, France, CHU de Poitiers-Centre de Référence Anomalies du Développement Ouest, Innsbruck Medical University [Austria] ( IMU ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Advanced Pediatric Center ( PGIMER ), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Dauphine Recherches en Management - MLAB ( DRM - MLAB ), Dauphine Recherches en Management ( DRM ), Université Paris-Dauphine-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Dauphine-Centre National de la Recherche Scientifique ( CNRS ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Saint-Joseph de Beyrouth ( USJ ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Innsbruck Medical University [Austria] (IMU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Bruel, Ange Line, Franco, Brunella, Duffourd, Yanni, Thevenon, Julien, Jego, Laurence, Lopez, Estelle, Deleuze, Jean Françoi, Doummar, Diane, Giles, Rachel H, Johnson, Colin A, Huynen, Martijn A, Chevrier, Véronique, Burglen, Lydie, Morleo, Manuela, Desguerres, Isabelle, Pierquin, Geneviève, Doray, Bérénice, Gilbert Dussardier, Brigitte, Reversade, Bruno, Steichen Gersdorf, Elisabeth, Baumann, Clarisse, Panigrahi, Inusha, Fargeot Espaliat, Anne, Dieux, Anne, David, Albert, Goldenberg, Alice, Bongers, Ernie, Gaillard, Dominique, Argente, Jesú, Aral, Bernard, Gigot, Nadège, St Onge, Judith, Birnbaum, Daniel, Phadke, Shubha R, Cormier Daire, Valérie, Eguether, Thibaut, Pazour, Gregory J, Herranz Pérez, Vicente, Goldstein, Jaclyn S, Pasquier, Laurent, Loget, Philippe, Saunier, Sophie, Mégarbané, André, Rosnet, Olivier, Leroux, Michel R, Wallingford, John B, Blacque, Oliver E, Nachury, Maxence V, Attie Bitach, Tania, Rivière, Jean Baptiste, Faivre, Laurence, Thauvin Robinet, Christel, Bruel, Al, Franco, B, Duffourd, Y, Thevenon, J, Jego, L, Lopez, E, Deleuze, Jf, Doummar, D, Giles, Rh, Johnson, Ca, Huynen, Ma, Chevrier, V, Burglen, L, Morleo, M, Desguerres, I, Pierquin, G, Doray, B, Gilbert-Dussardier, B, Reversade, B, Steichen-Gersdorf, E, Baumann, C, Panigrahi, I, Fargeot-Espaliat, A, Dieux, A, David, A, Goldenberg, A, Bongers, E, Gaillard, D, Argente, J, Aral, B, Gigot, N, St-Onge, J, Birnbaum, D, Phadke, Sr, Cormier-Daire, V, Eguether, T, Pazour, Gj, Herranz-Perez, V, Goldstein, J, Pasquier, L, Loget, P, Saunier, S, Megarbane, A, Rosnet, O, Leroux, Mr, Wallingford, Jb, Blacque, Oe, Nachury, Mv, Attie-Bitach, T, Riviere, Jb, Faivre, L, and Thauvin-Robinet, C

Subjects
Male, 0301 basic medicine, Heterozygote, ciliopathie, Oral facial digital, [SDV]Life Sciences [q-bio], [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, Ciliopathies, Centriole elongation, 03 medical and health sciences, Intraflagellar transport, Genotype, Genetics, Polycystic kidney disease, medicine, Humans, Abnormalities, Multiple, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Functional studies, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, oral-facial-digital syndromes, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Encephalocele, Polycystic Kidney Diseases, [ SDV ] Life Sciences [q-bio], ciliopathies, Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Orofaciodigital Syndromes, medicine.disease, 030104 developmental biology, Face, Mutation, Female, Retinitis Pigmentosa, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Ciliary Motility Disorders
Abstract

Oral–facial–digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in theOFD1gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3,TMEM107,INTU,KIAA0753andIFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42,TMEM138,TMEM231andWDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype.

Published
2017

28. TCF2/HNF-1beta mutations: 3 cases of fetal severe pancreatic agenesis or hypoplasia and multicystic renal dysplasia

Author

Bernard Le Fiblec, Laurence Heidet, Margaret Redpath, Alice Fiévet, Anne-Sophie Cabaret-Dufour, Corinne Antignac, Dominique D'Hervé, Sophie Taque, Delphine Body-Bechou, Philippe Loget, Caroline Labarthe, Odent Sylvie, Hélène Le Guern, Poulain Patrice, and Anne-Gaelle Grebille

Subjects
Pathology, medicine.medical_specialty, Fetus, Mutation, business.industry, Multicystic dysplastic kidney, Obstetrics and Gynecology, Oligohydramnios, Heterozygote advantage, Anatomy, medicine.disease, medicine.disease_cause, Hypoplasia, 3. Good health, medicine.anatomical_structure, medicine, Hepatocyte Nuclear Factor 1-Beta, business, Pancreas, Genetics (clinical)
Abstract

Objective The aim of this study was to document the association between pancreatic agenesis or hypoplasia and multicystic renal dysplasia related to transcription factor 2 (TCF2) or hepatocyte nuclear factor 1 beta mutations. Methodology We describe the phenotype of the pancreas and the kidneys from three fetuses heterozygous for a mutation of TCF2. Cases Case 1 had bilateral hyperechogenic, multicystic kidneys, bilateral clubfoot and pancreatic agenesis. Case 2 had two enlarged polycystic kidneys, anamnios and pancreatic agenesis. Case 3 had multicystic renal dysplasia, oligohydramnios and hypoplasia of the tail of the pancreas. Conclusion TCF2 mutations are frequently discovered in fetuses presenting with bilateral hyperechogenic kidneys. The association between pancreatic agenesis and a TCF2 mutation has not previously been reported. TCF2 deficiency in mice leads to pancreatic agenesis, suggesting that the gene is essential for pancreatic development. Our observations indicate the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered. © 2013 John Wiley & Sons, Ltd.

Published
2014

29. Rôle du gène SOX3 dans le développement : à propos d’un fœtus 46,XX présentant une duplication Xq27.1

Author

Laurent Pasquier, Sylvie Jaillard, Célia Ravel, Sylvie Odent, Philippe Loget, Marion Beaumont, Marc-Antoine Belaud-Rotureau, Nathalie Dejucq-Rainsford, Nathalie Rioux-Leclercq, and Erika Launay

Subjects
Anatomy
Abstract

Nous rapportons la description d’un fœtus ayant presente, lors de l’echographie obstetricale du premier trimestre, une clarte nucale augmentee, un retard de croissance intra-uterin, des membres courts et un oligoamnios. Le caryotype fœtal realise a partir d’une biopsie de trophoblaste a montre une formule chromosomique 46,XX. Une interruption medicale de grossesse a ete realisee a 13 SA. L’examen fœtopathologique a montre un fœtus de phenotype feminin avec des ovaires normaux, des anomalies des membres (agenesie des jambes, pieds bots, main bote droite), une dysmorphie faciale (hypertelorisme, agenesie nasale, fente labiopalatine, retrognathisme, glossoptose), une asplenie, une hypertrophie pancreatique, des calcifications hepatiques, un mesentere commun, des anomalies de la lobulation pulmonaire, une artere ombilicale unique, une veine cave superieure gauche persistante, 11 paires de cotes et un colobome retinien. L’analyse chromosomique par puce a ADN a mis en evidence une duplication d’environ 800 kb en Xq27.1, impliquant notamment le gene SOX3. Ce gene semble avoir un role dans le developpement des gonades. Des duplications du locus Xq27.1 impliquant SOX3, a l’origine d’un gain de fonction du gene, ont ete associees a une reversion sexuelle avec un phenotype masculin chez des patientes 46,XX-SRY negatif et a un hypopituitarisme lie a l’X chez des patients 46,XY. SOX3 interviendrait donc dans le developpement cerebral mais egalement, selon les donnees de la litterature, dans le developpement craniofacial, principalement dans le developpement de la deuxieme paire d’arcs branchiaux. Le fœtus decrit dans notre cas presente un developpement sexuel normal de type feminin (examen histologique des ovaires normal). Les anomalies squelettiques et craniofaciales peuvent, pour certaines d’entre elles, faire evoquer une dysplasie campomelique. Ces donnees suggerent un lien entre SOX3 et SOX9 avec la possibilite qu’une surexpression de SOX3 agisse comme une deletion de SOX9.

Published
2017

30. Split hand/foot malformation with long-bone deficiency andBHLHA9duplication: report of 13 new families

Author

C Le Caignec, Pierre-Simon Jouk, Fabienne Escande, Nicole Porchet, Anne-Sophie Jourdain, Joris Andrieux, Philippe Loget, Sylvie Manouvrier-Hanu, Brigitte Gilbert-Dussardier, Muriel Holder-Espinasse, Laurence Faivre, Claire Beneteau, Florence Petit, Geneviève Baujat, Albert David, Clarisse Baumann, Dominique Gaillard, and Laurent Pasquier

Subjects
Ectrodactyly, business.industry, Foot malformation, Long bone, Anatomy, medicine.disease, Split-Hand/Foot Malformation, medicine.anatomical_structure, Gene duplication, Genetics, medicine, Tibia, business, Genetics (clinical)
Abstract

Split hand/foot malformation (SHFM) with long-bone deficiency (SHFLD, MIM#119100) is a rare condition characterized by SHFM associated with long-bone malformation usually involving the tibia. Previous published data reported several unrelated patients with 17p13.3 duplication and SHFLD. Recently, the minimal critical region had been reduced, suggesting that BHLHA9 copy number gains are associated with this limb defect. Here, we report on 13 new families presenting with ectrodactyly and harboring a BHLHA9 duplication.

Published
2013

31. Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases

Author

Frédérique Jossic, Férecheté Razavi, Dominique Gaillard, Louise Devisme, Anne-Lise Delezoide, Carla Fernandez, Madeleine Joubert, Jelena Martinovic, Blandine Fabre, Nathalie Drouot, Homa Adle-Biassette, Marie Gonzales, Mario Tosi, Martine Bucourt, Dominique Carles, Nicole Laurent, Bettina Bessières, Martine Sinico, Annie Laquerrière, Daniel Satge, Thierry Frebourg, Sophie Blesson, Jacques Benichou, Philippe Loget, Marie-José Perez, Catherine Fallet-Bianco, Anne-Marie Beaufrère, Anne Bazin, Pierre Gressens, Pascale Saugier-Veber, Laurence Loeuillet, Frédérique Dijoud, Brigitte Leroy, and Pascale Marcorelles

Subjects
Pathology, medicine.medical_specialty, Neural Cell Adhesion Molecule L1, Biology, Corpus callosum, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Pregnancy, medicine, Humans, Abnormalities, Multiple, L1 syndrome, 030304 developmental biology, Phenocopy, 0303 health sciences, Corpus Callosum Agenesis, Cerebral Aqueduct, Infant, Newborn, Genetic Diseases, X-Linked, medicine.disease, Hypoplasia, Pedigree, 3. Good health, Hydrocephalus, Phenotype, Agenesis, Mutation, Female, Neurology (clinical), Nervous System Diseases, Differential diagnosis, 030217 neurology & neurosurgery
Abstract

L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the L1CAM gene were retrospectively reviewed. Fifty-seven cases had deleterious L1CAM mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had L1CAM mutations of unknown significance. Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations.

Published
2013

32. Severe Prenatal Renal Anomalies Associated with Mutations in HNF1B or PAX2 Genes

Author

Tania Attié-Bitach, Rémi Salomon, Pierre Dechelotte, Jelena Martinovic, Bruno Turlin, Vincent Morinière, Michèle Mathieu, Corinne Antignac, Uffe Birk Jensen, Nathalie Leporrier, Cécile Jeanpierre, Philippe Loget, Marie-Claire Gubler, Christel Thauvin-Robinet, Dominique Gaillard, Laurence Heidet, Raymonde Bouvier, and Leire Madariaga

Subjects
Male, Pathology, medicine.medical_specialty, Pediatrics, Heredity, Epidemiology, Genetic counseling, Urinary system, medicine.medical_treatment, DNA Mutational Analysis, Autopsy, Critical Care and Intensive Care Medicine, Severity of Illness Index, Ultrasonography, Prenatal, Predictive Value of Tests, Pregnancy, Prenatal Diagnosis, Humans, Medicine, Genetic Predisposition to Disease, Renal replacement therapy, Family history, Abortion, Therapeutic, Hepatocyte Nuclear Factor 1-beta, Retrospective Studies, Vesico-Ureteral Reflux, Transplantation, Kidney, business.industry, PAX2 Transcription Factor, Original Articles, medicine.disease, HNF1B, Pedigree, Phenotype, medicine.anatomical_structure, Nephrology, Urogenital Abnormalities, Mutation, Female, business
Abstract

Summary Background and objectives Congenital anomalies of the kidney and urinary tract (CAKUT) are a frequent cause of renal failure in children, and their detection in utero is now common with fetal screening ultrasonography. The clinical course of CAKUT detected before birth is very heterogeneous and depends on the level of nephron reduction. The most severe forms cause life-threatening renal failure, leading to perinatal death or the need for very early renal replacement therapy. Design, setting, participants, & measurements This study reports the screening of two genes (HNF1B and PAX2) involved in monogenic syndromic CAKUT in a cohort of 103 fetuses from 91 families with very severe CAKUT that appeared isolated by fetal ultrasound examination and led to termination of pregnancy. Results This study identified a disease-causing mutation in HNF1B in 12 cases from 11 families and a mutation in PAX2 in 4 unrelated cases. Various renal phenotypes were observed, but no case of bilateral agenesis was associated with HNF1B or PAX2 mutations. Autopsy identified extrarenal abnormalities not detected by ultrasonography in eight cases but confirmed the absence of extrarenal defects in eight other cases. A positive family history of renal disease was not significantly more frequent in cases with an identified mutation. Moreover, in cases with an inherited mutation, there was a great phenotypic variability regarding the severity of the renal disease within a single family. Conclusions Our results suggest that mutations in genes involved in syndromic CAKUT with Mendelian inheritance are not rare in fetal cases with severe CAKUT appearing isolated at prenatal ultrasound, a finding of clinical importance because of genetic counseling.

Published
2013

33. Fraser syndrome: features suggestive of prenatal diagnosis in a review of 38 cases

Author

Aude, Tessier, Mélie, Sarreau, Fanny, Pelluard, Gwenaelle, André, Sophie, Blesson, Martine, Bucourt, Pierre, Dechelotte, Laurence, Faivre, Thierry, Frébourg, Alice, Goldenberg, Valérie, Goua, Corinne, Jeanne-Pasquier, Fabien, Guimiot, Annie, Laquerriere, Nicole, Laurent, Mathilde, Lefebvre, Philippe, Loget, Martine, Maréchaud, Charlotte, Mechler, Marie-Josée, Perez, Jean Christophe, Sabourin, Alain, Verloes, Sophie, Patrier, and Anne-Marie, Guerrot

Subjects
Hydrops Fetalis, Infant, Newborn, Ear, Gestational Age, Kidney, Oligohydramnios, Ultrasonography, Prenatal, Congenital Abnormalities, Airway Obstruction, Craniofacial Abnormalities, Phenotype, Pregnancy, Prenatal Diagnosis, Urogenital Abnormalities, Humans, Abnormalities, Multiple, Female, Eye Abnormalities, Syndactyly, Fraser Syndrome
Abstract

Fraser syndrome (FS) is a rare malformation recessive disorder. Major criteria are cryptophtalmos, syndactyly, respiratory, genital and urinary tract anomalies. Few prenatal presentations have been reported.We analyzed the prenatal and postnatal fetal phenotype in 38 cases of FS, including 25 pregnancy termination cases, 8 intra-uterine death cases and 4 cases that died after birth.Including both prenatal and postnatal fetal phenotypic evaluation, all cases presented dysmorphic features with nose and ear dysplasia. Renal anomalies and syndactyly were present in 37/38 cases, cryptophtalmos in 36/38, airways anomalies in 30/37 and genital anomalies in 30/35 cases. Anomalies of the abdominal wall such as low set umbilicus and omphalocele were found in 31 cases. Among the 26 cases for which ultrasound data were available, detectable anomalies included oligohydramnios (22), ascites/hydrops (9), renal anomalies (20), evidence for high airways obstruction (11), ophthalmologic anomalies (4), ear dysplasia (2) and syndactyly (2).This study shows that the postnatal phenotype of FS is very specific, whereas oligohydramnios hampers the prenatal recognition of the cardinal FS diagnosis criteria. Association of oligohydramnios, kidney agenesis and CHAOS should lead to consider this diagnosis. © 2016 John WileySons, Ltd.

Published
2016

34. OTX2mutations contribute to the otocephaly-dysgnathia complex

Author

Patrick Calvas, Susanna Sorrentino, Ahmet Yesilyurt, Consolato Sergi, Dominique Carles, Hülya Kayserili, Ona Faye-Petersen, Dominique Martin-Coignard, Anthony J. Iacovelli, Adeline Vigouroux, Surasak Puvabanditsin, Nicolas Chassaing, Nicholas Katsanis, Philippe Loget, Ethylin Wang Jabs, William A. Paznekas, Férechté Encha-Razavi, Erica E. Davis, Simeon A. Boyadjiev, Catherine Mercer, Bryn D. Webb, Leopoldine Lequeux, Heather C. Etchevers, and Chih Ping Chen

Subjects
Otocephaly, Embryo, Nonmammalian, Molecular Sequence Data, Locus (genetics), Microphthalmia, Jaw Abnormalities, Holoprosencephaly, Genetics, medicine, Animals, Humans, Zebrafish, Genetics (clinical), Loss function, Otx Transcription Factors, Anophthalmia, Base Sequence, biology, Genetic heterogeneity, Sequence Analysis, DNA, medicine.disease, Dysgnathia, biology.organism_classification, Pedigree, Disease Models, Animal, Female
Abstract

Background Otocephaly or dysgnathia complex is characterised by mandibular hypoplasia/agenesis, ear anomalies, microstomia, and microglossia; the molecular basis of this developmental defect is largely unknown in humans. Methods and results This study reports a large family in which two cousins with micro/anophthalmia each gave birth to at least one child with otocephaly, suggesting a genetic relationship between anophthalmia and otocephaly. OTX2 , a known microphthalmia locus, was screened in this family and a frameshifting mutation was found. The study subsequently identified in one unrelated otocephalic patient a sporadic OTX2 mutation. Because OTX2 mutations may not be sufficient to cause otocephaly, the study assayed the potential of otx2 to modify craniofacial phenotypes in the context of known otocephaly gene suppression in vivo. It was found that otx2 can interact genetically with pgap1 , prrx1 , and msx1 to exacerbate mandibular and midline defects during zebrafish development. However, sequencing of these loci in the OTX2-positive families did not unearth likely pathogenic lesions, suggesting further genetic heterogeneity and complexity. Conclusion Identification of OTX2 involvement in otocephaly/dysgnathia in humans, even if loss of function mutations at this locus does not sufficiently explain the complex anatomical defects of these patients, suggests the requirement for a second genetic hit. Consistent with this notion, trans suppression of otx2 and other developmentally related genes recapitulate aspects of the otocephaly phenotype in zebrafish. This study highlights the combined utility of genetics and functional approaches to dissect both the regulatory pathways that govern craniofacial development and the genetics of this disease group.

Published
2012

35. Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies

Author

Annie Laquerrière, Dominique Bonneau, Fabien Guimiot, Françoise Menez, Bettina Bessières, Nicole Bigi, Agnès Liprandi, C. Bouchet, Dominique Figarella-Branger, Tania Attié-Bitach, Elisabeth Alanio, Dominique Gaillard, Stéphane Triau, Catherine Fallet-Bianco, Anne-Lise Delezoide, Madeleine Joubert, Martine Bucourt, Marie-José Perez, Pascale Marcorelles, Sophie Delahaye, Patricia Blanchet, Fanny Pelluard, Bernard Gasser, Maryse Bonnières, Louise Devisme, Sophie Patrier, Nicole Laurent, Marie Gonzales, Dominique Carles, Anne Bazin, Philippe Loget, B. Clarisse, Jelena Martinovic, Férechté Encha-Razavi, Sandrine Vuillaumier-Barrot, Caroline Rouleau, and Nathalie Seta

Subjects
Male, Pathology, medicine.medical_specialty, Cobblestone Lissencephaly, Lissencephaly, Biology, N-Acetylglucosaminyltransferases, Mannosyltransferases, Fetus, Bone plate, medicine, OMIM : Online Mendelian Inheritance in Man, Humans, Pentosyltransferases, Muscular dystrophy, Dystroglycans, Walker–Warburg syndrome, Infant, Newborn, Brain, Membrane Proteins, Proteins, Cortical dysplasia, medicine.disease, Dysplasia, Female, Neurology (clinical)
Abstract

Cobblestone lissencephaly represents a peculiar brain malformation with characteristic radiological anomalies, defined as cortical dysplasia combined with dysmyelination, dysplastic cerebellum with cysts and brainstem hypoplasia. Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or ‘cobblestone’ brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker–Warburg syndrome, muscle–eye–brain and Fukuyama muscular dystrophy. Mutations in POMT1 , POMT2 , POMGNT1 , LARGE , FKTN and FKRP genes attributed these diseases to α-dystroglycanopathies. However, studies have not been able to identify causal mutations in the majority of patients and to establish a clear phenotype/genotype correlation. Therefore, we decided to perform a detailed neuropathological survey and molecular screenings in 65 foetal cases selected on the basis of histopathological criteria . After sequencing the six genes of α-dystroglycanopathies, a causal mutation was observed in 66% of cases. On the basis of a ratio of severity, three subtypes clearly emerged. The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 ( 8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%). An intermediary type, cobblestone lissencephaly B, was linked to LARGE mutations (4.5%) identified for the first time in foetuses. We conclude that cobblestone lissencephaly encompasses three distinct subtypes of cortical malformations with different degrees of neuroglial ectopia into the arachnoid space and cortical plate disorganization regardless of gestational age. In the cerebellum, histopathological changes support the novel hypothesis that abnormal lamination arises from a deficiency in granule cells. Our studies demonstrate the positive impact of histoneuropathology on the identification of α-dystroglycanopathies found in 66% of cases, while with neuroimaging criteria and biological values, mutations are found in 32–50% of patients. Interestingly, our morphological classification was central in the orientation of genetic screening of POMT1 , POMT2 , POMGNT1 , LARGE and FKRP . Despite intensive research, one-third of our cases remained unexplained; suggesting that other genes and/or pathways may be involved. This material offers a rich resource for studies on the affected neurodevelopmental processes of cobblestone lissencephaly and on the identification of other responsible gene(s)/pathway(s). * Abbreviations : MDDGA : muscular congenital α-dystroglycanopathy with brain and eye anomalies OMIM : Online Mendelian Inheritance in Man

Published
2012

36. Diagnosis of fetal urinary tract malformations: prenatal management and postnatal outcome

Author

Florence Rouget, Dominique D'Hervé, Patrice Poulain, Josette Lucas, G. Le Bouar, A. Ryckewaert-D'Halluin, Philippe Loget, Sylvie Odent, J. Milon, Sophie Taque, and E. Le Gall

Subjects
Gynecology, medicine.medical_specialty, Pregnancy, Fetus, Univariate analysis, 030219 obstetrics & reproductive medicine, business.industry, Obstetrics, Urinary system, 030232 urology & nephrology, Obstetrics and Gynecology, Retrospective cohort study, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine, Severity Criteria, business, Pathological, Genetics (clinical), URINARY TRACT MALFORMATION
Abstract

Objective To evaluate prenatal management and to define the criteria of gravity for accurate assessment of the renal and overall prognosis of fetuses presenting malformations of the urinary tract. Methods We carried out a retrospective study of 127 cases of urinary tract malformation. We carried out descriptive statistical and univariate analyses as a function of severity criteria and the outcome of pregnancy. Results One-third of fetuses presented associated extrarenal malformations and 10% of the karyotypes were abnormal. There were more abortions in case of decrease in amniotic fluid volume (p < 0.001), extent of renal damage (p < 0.05), presence of associated extrarenal malformations (p < 0.05), early diagnosis of the malformation (p < 0.001) and presence of chromosomal syndrome (p = 0.01). In our study, there was an excellent correlation between prenatal data and pathological findings for the fetus following abortions for medical reasons or obtained during the surveillance of live-born children. Fetal biochemistry made very little contribution. Conclusion In cases of urinary tract malformation, this work confirms the need for regular and frequent ultrasound scans, checking for the echographic factors indicative of gravity and for adapted karyotyping. It also demonstrates that pluridisciplinary management is necessary for the prenatal evaluation of renal and overall fetal prognosis. Copyright © 2011 John Wiley & Sons, Ltd.

Published
2011

37. Critical stenosis of a right ventricle to coronary artery fistula seen at dual-source CT in a newborn with pulmonary atresia and intact ventricular septum

Author

Jean-Dominique Piot, Pierre-Emmanuel Séguéla, Philippe Loget, Jean-François Paul, and Lucile Houyel

Subjects
Heart Defects, Congenital, Male, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Fistula, Heart Ventricles, Iohexol, Dual source ct, Contrast Media, Autopsy, Constriction, Pathologic, Coronary Artery Disease, Ventricular Septum, Coronary Angiography, Coronary circulation, Fatal Outcome, Coronary Circulation, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Blalock-Taussig Procedure, Neuroradiology, business.industry, Infant, Newborn, medicine.disease, Radiographic Image Enhancement, Stenosis, medicine.anatomical_structure, Pulmonary Atresia, Ventricle, Pediatrics, Perinatology and Child Health, Cardiology, Radiology, Tomography, X-Ray Computed, Pulmonary atresia, business, Artery
Abstract

We report the case of a newborn with pulmonary atresia with intact ventricular septum and right ventricle-dependent coronary circulation. He died several weeks after a Blalock-Taussig procedure because of a progressive stenosis of the main coronary artery. We present echocardiographic and dual-source CT images of the stenosis, with autopsy correlation. To our knowledge, CT images of this quality have never been reported in a newborn. This case illustrates the extreme difficulty in prognosticating the outcome for these patients and underlines the need for a detailed neonatal coronary mapping to assess right ventricle-dependent coronary circulation.

Published
2011

38. Osteopathia striata with cranial sclerosis: when a fetal malformation syndrome reveals maternal pathology

Author

Chloé Quélin, Maria Garcia Hoyos, Delphine Body-Bechou, Catherine Tréguier, Sylvie Odent, Philippe Loget, Mélanie Fradin, J. Milon, Mathilde Ferry, and Dominique D'Hervé

Subjects
Pathology, medicine.medical_specialty, Cranial sclerosis, business.industry, Obstetrics and Gynecology, Medicine, business, medicine.disease, Fetal malformation, Genetics (clinical), Osteopathia striata
Published
2014

39. Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies

Author

S. Kitsiou Tzeli, Hülya Kayserili, L. Giordano, B. Rodriguez, P. Collignon, V. Sabolic Avramovska, Silvana Briuglia, Christopher A. Walsh, Laila Bastaki, Amy Goldstein, Francesca Faravelli, F. Papadia, A. Permunian, Alessandro Simonati, S. Halldorsson, Gian Marco Ghiggeri, David G. Brooks, Clara Barbot, Kathryn J. Swoboda, Chiara Pantaleoni, O. D'Addato, Jason W. Caldwell, Maria Roberta Cilio, Soumaya Mougou-Zerelli, M. Vascotto, Andreas Zankl, Gaetano Tortorella, Julia Tantau, Elliott H. Sherr, Patrizia Accorsi, Maurizio Genuardi, Carmelo Salpietro, G. Marra, Pierangela Castorina, Petter Strømme, J. Johannsdottir, Bruno Dallapiccola, Kenton R. Holden, Donatella Greco, Maria Spanò, Pasquale Parisi, Roberta Battini, Paola Grammatico, P. Ludvigsson, Dorit Lev, Daria Riva, C. Ae Kim, WB Dobyns, L. Martorell Sampol, Robert P. Cruse, H. Raynes, Sabrina Signorini, A. Seward, Raoul C.M. Hennekam, Elena Andreucci, Manuela Priolo, Banu Anlar, Bernard Stuart, Christopher P. Bennett, S. Comu, Christopher Geoffrey Woods, Vlatka Mejaški-Bošnjak, J. Milisa, Eamonn Sheridan, Melissa Lees, C. Moco, Ender Karaca, Miriam Iannicelli, Annalisa Mazzotta, C. Dacou-Voutetakis, Tania Attié-Bitach, Philippe Loget, D. Petkovic, L. Demerleir, Loredana Boccone, Meriem Tazir, Kalpathy S. Krishnamoorthy, Damir Lončarević, Dominika Swistun, Yves Sznajer, Stefano D'Arrigo, Ginevra Zanni, Angela Barnicoat, Marina Michelson, L. I. Al Gazali, Vincenzo Leuzzi, G. Uziel, A. Adami, B. Gener Querol, V. Udani, M. Di Giacomo, Maryse Bonnière, Enrico Bertini, K. Dias, Edward Blair, Johannes M. Penzien, M. Cazzagon, Susana Quijano-Roy, Trine Prescott, Barbara Scelsa, Giuseppina Vitiello, Francesco Brancati, Gilda Stringini, Trudy McKanna, Roser Pons, Renato Borgatti, M. Gentile, Dean Sarco, C. Von Der Lippe, Eugen Boltshauser, Luigina Spaccini, A. Pessagno, Alex Magee, Marilena Briguglio, Margherita Silengo, Lena Starck, M. L. Di Sabato, Roshan Koul, Nicole I. Wolf, A. M. Laverda, Elizabeth Flori, Clotilde Lagier-Tourenne, A. Matuleviciene, Matloob Azam, Kathrin Ludwig, Ghada M H Abdel-Salam, Atıl Yüksel, Johannes R. Lemke, Stefania Bigoni, Elizabeth Said, Anna Rajab, Mary Kay Koenig, Andreas R. Janecke, Asma A. Al-Tawari, Agnese Suppiej, Henry Sanchez, Wendy K. Chung, P. Guanciali, Heike Philippi, Silvia Majore, E. DeMarco, J. Hahn, Gianluca Caridi, Marc D'Hooghe, M. M. De Jong, M. Akcakus, Franco Stanzial, Silvia Battaglia, Gian Luigi Ardissino, Giangennaro Coppola, Jane A. Hurst, Terry D. Sanger, Alessandra Renieri, Nadia Elkhartoufi, Rita Fischetto, Alex E. Clark, S. Strozzi, S. Romano, Alain Verloes, Marzia Pollazzon, Elisa Fazzi, L. Yates, Faustina Lalatta, Sabine Sigaudy, Alessandra D'Amico, Brigitte Leroy, Joel Victor Fluss, David Viskochil, Alice Abdel-Aleem, Darryl C. De Vivo, Padraic Grattan-Smith, Corrado Romano, D. Nicholl, Regine Schubert, A. Moreira, Claudia Izzi, Barbara Gentilin, Gustavo Maegawa, Céline Gomes, László Sztriha, C. Donahue, Luciana Rigoli, Jean Messer, Sophie Thomas, E. Del Giudice, R. Van Coster, André Mégarbané, Ignacio Pascual-Castroviejo, Alessandra Ferlini, Topcu, R. Touraine, Ginevra Guanti, Lorena Travaglini, L. Ali Pacha, R. De Vescovi, Enza Maria Valente, Filippo Bernardi, L. Carr, Shubha R. Phadke, S. Bernes, Maria Teresa Divizia, C. Daugherty, M. Akgul, C. Macaluso, Maha S. Zaki, E. Finsecke, Itxaso Marti, Lorenzo Pinelli, F. McKay, Maria Amorini, Joseph G. Gleeson, F. Benedicenti, Bruria Ben-Zeev, Carla Uggetti, R. Romoli, Richard J. Leventer, Francesco Emma, T. E. Gallager, P. De Lonlay, Marco Seri, Bernard L. Maria, M.A. Donati, Bosanka Jocic-Jakubi, IANNICELLI M, BRANCATI F, MOUGOU-ZERELLI S, MAZZOTTA A, THOMAS S, ELKHARTOUFI N, TRAVAGLINI L, GOMES C, ARDISSINO GL, BERTINI E, BOLTSHAUSER E, CASTORINA P, D'ARRIGO S, FISCHETTO R, LEROY B, LOGET P, BONNIÈRE M, STARCK L, TANTAU J, GENTILIN B, MAJORE S, SWISTUN D, FLORI E, LALATTA F, PANTALEONI C, PENZIEN J, GRAMMATICO P, INTERNATIONAL JSRD STUDY GROUP, DALLAPICCOLA B, GLEESON JG, ATTIE-BITACH T, VALENTE EM. COLLABORATORS: ALI PACHA L, TAZIR M, ZANKL A, LEVENTER R, GRATTAN-SMITH P, JANECKE A, D'HOOGHE M, SZNAJER Y, VAN COSTER R, DEMERLEIR L, DIAS K, MOCO C, MOREIRA A, AE KIM C, MAEGAWA G, LONCAREVIC D, MEJASKI-BOSNJAK V, PETKOVIC D, ABDEL-SALAM GM, ABDEL-ALEEM A, ZAKI MS, MARTI I, QUIJANO-ROY S, SIGAUDY S, DE LONLAY P, ROMANO S, VERLOES A, TOURAINE R, KOENIG M, LAGIER-TOURENNE C, MESSER J, COLLIGNON P, WOLF N, PHILIPPI H, LEMKE J, DACOU-VOUTETAKIS C, KITSIOU TZELI S, PONS R, SZTRIHA L, HALLDORSSON S, JOHANNSDOTTIR J, LUDVIGSSON P, PHADKE SR, UDANI V, STUART B, MAGEE A, LEV D, MICHELSON M, BEN-ZEEV B, DI GIACOMO M, GENTILE M, GUANTI G, D'ADDATO O, PAPADIA F, SPANO M, BERNARDI F, SERI M, BENEDICENTI F, STANZIAL F, BORGATTI R, ACCORSI P, BATTAGLIA S, FAZZI E, GIORDANO L, IZZI C, PINELLI L, BOCCONE L, GUANCIALI P, ROMOLI R, BIGONI S, FERLINI A, ANDREUCCI E, DONATI MA, GENUARDI M, CARIDI G, DIVIZIA MT, FARAVELLI F, GHIGGERI G, PESSAGNO, AMORINI M, BRIGUGLIO M, BRIUGLIA S, RIGOLI L, SALPIETRO C, TORTORELLA G, ADAMI A, MARRA G, RIVA D, SCELSA B, SPACCINI L, UZIEL G, COPPOLA G, DEL GIUDICE E, VITIELLO G, LAVERDA AM, LUDWIG K, PERMUNIAN A, SUPPIEJ A, MACALUSO C, SIGNORINI S, UGGETTI C, BATTINI R, PRIOLO M, CILIO MR, D'AMICO A, DI SABATO ML, EMMA F, LEUZZI V, PARISI P, STRINGINI G, ZANNI G, POLLAZZON M, RENIERI A, VASCOTTO M, SILENGO M, DE VESCOVI R, GRECO D, ROMANO C, CAZZAGON M, SIMONATI A, AL-TAWARI AA, BASTAKI L, MÉGARBANÉ A, MATULEVICIENE A, SABOLIC AVRAMOVSKA V, SAID E, DE JONG MM, PRESCOTT T, STROMME P, VON DER LIPPE C, KOUL R, RAJAB A, AZAM M, BARBOT C, JOCIC-JAKUBI B, GENER QUEROL B, MARTORELL SAMPOL L, RODRIGUEZ B, PASCUAL-CASTROVIEJO I, STROZZI S, FLUSS J, TEBER S, TOPCU M, ANLAR B, COMU S, KARACA E, KAYSERILI H, YÜKSEL A, AKGUL M, AKCAKUS M, AL GAZALI L, NICHOLL D, WOODS CG, BENNETT C, HURST J, SHERIDAN E, BARNICOAT A, CARR L, HENNEKAM R, LEES M, MCKAY F, YATES L, BLAIR E, BERNES S, SANCHEZ H, CLARK AE, DEMARCO E, DONAHUE C, SHERR E, HAHN J, SANGER TD, GALLAGER TE, DOBYNS WB, DAUGHERTY C, KRISHNAMOORTHY KS, SARCO D, WALSH CA, MCKANNA T, MILISA J, CJUNG WK, DE VIVO DC, RAYNES H, SCHUBERT R, SEWARD A, BROOKS DG, GOLDSTEIN A, CALDWELL J, FINSECKE E, MARIA BL, HOLDEN K, CRUSE RP, SWOBODA KJ, VISKOCHIL D., Pediatric surgery, NCA - Childhood White Matter Diseases, Iannicelli, M, Brancati, F, Mougou Zerelli, S, Mazzotta, A, Thomas, S, Elkhartoufi, N, Travaglini, L, Gomes, C, Ardissino, Gl, Bertini, E, Boltshauser, E, Castorina, P, D'Arrigo, S, Fischetto, R, Leroy, B, Loget, P, Bonnière, M, Starck, L, Tantau, J, Gentilin, B, Majore, S, Swistun, D, Flori, E, Lalatta, F, Pantaleoni, C, Penzien, J, Grammatico, P, Dallapiccola, B, Gleeson, Jg, Attie Bitach, T, Valente, Em, International JSRD Study, Group, DEL GIUDICE, Ennio, University of Zurich, and Attie-Bitach, T

Subjects
Liver Cirrhosis, 2716 Genetics (clinical), meckelin, Ciliopathies, Joubert syndrome, Genotype, congenital hepatic fibrosis, coach syndrome, mks3, meckel syndrome, joubert syndrome, tmem67, TMEM67, Meckel syndrome, DNA Mutational Analysis, 610 Medicine & health, Biology, medicine.disease_cause, MKS3, COACH syndrome, Article, NO, 1311 Genetics, Nephronophthisis, Pregnancy, Prenatal Diagnosis, Genetics, medicine, COACH syndrome, Congenital hepatic fibrosis, Joubert syndrome, Meckel syndrome, MKS3, TMEM67, Missense mutation, Humans, Abnormalities, Multiple, Genetics (clinical), Mutation, Cilium, Membrane Proteins, Kidney Diseases, Cystic, medicine.disease, Phenotype, 10036 Medical Clinic, Female
Abstract

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

Published
2010

40. Molecular heterogeneity in fetal forms of type II lissencephaly

Author

Pascale Marcorelles, Férechté Encha-Razavi, Bettina Bessieres-Grattagliano, Sandrine Vuillaumier-Barrot, Dominique Carles, F. Pelluard-Nehmé, Jelena Martinovic, Louise Devisme, S. Triau, Sophie Patrier, Fabien Guimiot, Maryse Bonnières, Nicole Laurent, Dominique Bonneau, S. Delahaye, Nathalie Seta, A. Liprandi, Dominique Figarella-Branger, C. Lebizec, Annie Laquerrière, Madeleine Joubert, C. Rouleau-Dubois, C. Bouchet, M.J. Perez, E. Alanio, Marie Gonzales, B. Gasser, Philippe Loget, Catherine Fallet-Bianco, F. Menez, N. Bigi, Anne Bazin, Dominique Gaillard, and Patricia Blanchet

Subjects
Male, Genotype, Gestational Age, Disease, Biology, Mannosyltransferases, Polymorphism, Single Nucleotide, Muscular Dystrophies, Genetics, medicine, Humans, Muscular dystrophy, Allele, Dystroglycans, Walker–Warburg syndrome, Alleles, Genetics (clinical), Models, Genetic, fungi, Type II lissencephaly, Fetal Presentation, medicine.disease, Phenotype, Gene Expression Regulation, Mutation, Female, Microsatellite Repeats
Abstract

Type II lissencephaly (type II LIS) is a group of autosomal recessive congenital muscular dystrophies (CMD) associated with defects in alpha-DG O-glycosylation, which comprises Walker-Warburg syndrome, Fukuyama cerebral and muscular dystrophy, or muscle-eye-brain disease. The most severe forms of these diseases often have a fetal presentation and lead to a pregnancy termination. We report here the first molecular study on fetal type II LIS in a series of 47 fetuses from 41 unrelated families. Sequencing of the different genes known to be involved in alpha-DG O-glycosylation allowed the molecular diagnosis in 22 families: involvement of POMT1 was demonstrated in 32% of cases, whereas POMGNT1 and POMT2 were incriminated in 15% and in 7% of cases, respectively. We found 30 different mutations in these three genes, 25 were described herein for the first time, 15 in POMT1, and five in POMT2 and POMGNT1. Despite sequencing of FKRP, FCMD, and LARGE, no definitive molecular diagnosis could be made for the other half of our cases. Preliminary results concerning genotype-phenotype correlations show that the choice of the first gene sequenced should depend on the clinical severity of the type II LIS; POMT1 and POMT2 for severest clinical picture and POMGNT1 for milder disease. The other genes, FKRP, FCMD, and LARGE, seem not to be implicated in the fetal form of CMD.

Published
2007

41. Diagnostic anténatal d’une sirénomélie

Author

Philippe Loget, Patrice Poulain, H. Ladure, and Dominique D'Hervé

Subjects
medicine.medical_specialty, Pregnancy, Caudal regression syndrome, business.industry, Genetic counseling, Obstetrics and Gynecology, Gestational age, Prenatal diagnosis, General Medicine, medicine.disease, Surgery, Bilateral Renal Agenesis, medicine.anatomical_structure, Reproductive Medicine, Sirenomelia, medicine, Abdomen, Radiology, business
Abstract

Sirenomelia sequence associates a fusion of inferior legs with renal anomalies until bilateral agenesis. It is a rare and lethal polymalformation. The purpose of the ultrasonographic study is to identify the sirenomelia as early as possible during pregnancy and to differentiate it from caudal regression syndrome. A case of sirenomelia diagnosed early is reported together with a review of the literature. The ultrasonographic diagnosis, associated defects, the interest of color Doppler study of abdominal vasculature are discussed. Antenatal ultrasonographic diagnosis should be obtained as early as possible, before 20th gestational week at the latest. Color Doppler is helpful to confirm the diagnosis in case of bilateral renal agenesis. The main differences between sirenomelia and caudal regression syndrome (which requires a very different genetic counselling) are summarized in a table.

Published
2006

42. Antenatal Presentation of Bardet-Biedl Syndrome May Mimic Meckel Syndrome

Author

Géraldine Goudefroye, Marie-Odile Peter, Philippe Loget, Heather C. Etchevers, Dominique Gaillard, Houda Karmous-Benailly, Marie Gonzales, Madeleine Joubert, Ghislaine Plessis, Martine Le Merrer, Férechté Encha-Razavi, Marie-Claire Gubler, Joelle Augé, Chantal Esculpavit, Nora Brahimi, Eric Detrait, Catherine Ozilou, Yoann Sirot, Tania Attié-Bitach, B. Simon-Bouy, Michel Vekemans, Julia Tantau, Hélène Dollfus, Arnold Munnich, Sophie Audollent, Laure Clech, Jelena Martinovic, Corinne Jeanne-Pasquier, and Anne-Lise Delezoide

Subjects
Male, BBS2, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Pathology, BBS1, Heart malformation, DNA Mutational Analysis, BBS5, Kidney, Diagnosis, Differential, Fetus, Bardet–Biedl syndrome, Pregnancy, Prenatal Diagnosis, Internal medicine, medicine, Genetics, Humans, Abnormalities, Multiple, Genetics(clinical), Meckel syndrome, Bardet-Biedl Syndrome, Genetics (clinical), Encephalocele, Cystic kidney, Base Sequence, Polydactyly, business.industry, Infant, Newborn, Articles, Syndrome, medicine.disease, Pedigree, Endocrinology, Liver, Female, business
Abstract

Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (BBS1-BBS8) have been identified to date. A mutation of the BBS1 gene on chromosome 11q13 is observed in 30%-40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder--that is, in some families, three mutations at two BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or "Meckel-like" syndrome. In six cases, we identified a recessive mutation in a BBS gene (three in BBS2, two in BBS4, and one in BBS6). We found a heterozygous BBS6 mutation in three additional cases. No BBS1, BBS3, BBS5, BBS7, or BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome.

Published
2005
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43. Perinatal-lethal Gaucher disease

Author

Joelle Roume, Philippe Loget, Marie T. Vanier, D Le Duff, F Daffos, T. Billette de Villemeur, Josset P, C Fallet Bianco, Bettina Bessières, I Maire, Antoinette Gelot, F Menez, Sylvie Odent, J Costil, P Fargier, Cyril Mignot, and M Voyer

Subjects
Arthrogryposis, congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, business.industry, Ichthyosis, Hepatosplenomegaly, nutritional and metabolic diseases, Disease, medicine.disease, Central nervous system disease, Fetal onset, Hydrops fetalis, Genetics, Lysosomal storage disease, Medicine, medicine.symptom, business, Genetics (clinical)
Abstract

Gaucher disease is a lysosomal storage disease caused by glucocerebrosidase deficiency. Although purely visceral in most cases, some Gaucher disease patients have neurological signs. Signs of Gaucher disease appear after a symptom-free period, except in rare cases with fetal onset. The description of such cases was based mainly on single reports and siblings. We report here a series of perinatal-lethal Gaucher disease cases highlighting the specificity of this phenotype. We retrospectively studied eight original cases of proven Gaucher disease with fetal onset. Non-immune hydrops fetalis was present in all cases but one, and associated with hepatosplenomegaly, ichthyosis, arthrogryposis, and facial dysmorphy. The similarities between our cases and 33 previously described cases allow us to better delineate the perinatal-lethal Gaucher disease phenotype. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurological involvement begins in the first week and leads to death within three months. Hepatosplenomegaly is a major sign, and associated with ichthyosis, arthrogryposis, and facial dysmorphy in some 35-43% of cases. Perinatal-lethal Gaucher disease is a specific entity defined by its particular course and signs that are absent in classical type 2 Gaucher disease. Our study provides clues to the diagnosis of this likely underdiagnosed condition, which must be biochemically confirmed in order to propose appropriate genetic counselling.

Published
2003

44. Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly

Author

Laurence Loeuillet, Karine Poirier, Annie Laquerrière, Nicole Revencu, Fabien Guimiot, Ferechté Razavi, Jamel Chelly, Nathalie Carion, Maryse Marcy-Bonnière, Marie-Claude Addor, Bettina Bessières, Jelena Martinovich, Benoit Lhermitte, Cherif Beldjord, Pascale Marcorelles, Aurélie Toussaint, Philippe Loget, Karine Lascelles, Nadia Bahi-Buisson, Catherine Fallet-Bianco, Frédérique Jossic, Marie Gonzales, Patricia Dias, Département de pathologie et biologie cellulaire, Université de Montréal (UdeM)-Hôpital Sainte-Justine, Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biologie du Développement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Department of Genetics, Hospital de Santa Maria, Service d'Anatomie et de Cytologie Pathologiques, CHI Poissy-Saint-Germain, Children’s Neurosciences Department, Evelina London Children's Hospital, Laboratoire de biochimie et génétique moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Center for Human Genetics, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Cliniques Universitaires Saint-Luc [Bruxelles], Département Génétique Médicale-Maternité, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Service d'Anatomie Pathologique Générale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Pathologie Foetale, Hôpital Antoine-Béclère AP-HP, Services d'Anatomopathologie et de Génétique, CHU de Nantes - Site Saint-Jacques-Hôtel-Dieu et Hôpital de la Mère et de l'enfant, Service d'Anatomie Pathologique, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], This work was supported by funding from INSERM, Fondation pour laRecherche Médicale (FRM, J Chelly—Equipe FRM 2013: DEQ2000326477),Fondation JED-Belgique, Agence National de Recherche (ANR Blanc 1103 01–project R11039KK, ANR E-Rare Program, convention 2011-RARE-012-01–projetE10107KP) and the EU-FP7 project DESIRE, Grant agreement no: 602531., Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bos, Mireille, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Hôpital Sainte-Justine-Université de Montréal, Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement ( Néovasc ), Institute for Research and Innovation in Biomedicine ( IRIB ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'Anatomie et Cytologie Pathologique [Rouen], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 ( UPD5 ), Université Catholique de Louvain ( UCL ) -Cliniques Universitaires Saint-Luc [Bruxelles], Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ), Service de Génétique et d'Embryologie Médicales, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -CHU Trousseau [APHP], Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Université de Rennes 1 ( UR1 ), and Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes]

Subjects
Male, Cerebellum, Microcephaly, DNA Mutational Analysis, Lissencephaly, Biology, medicine.disease_cause, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Fetus, Tubulin, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Polymicrogyria, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Autopsy, Brain/abnormalities, Brain/metabolism, Female, Magnetic Resonance Imaging, Malformations of Cortical Development, Group I/classification, Malformations of Cortical Development, Group I/diagnosis, Mutation/genetics, Tubulin/genetics, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Microlissencephaly, Mutation, Corpus Callosum Agenesis, Research, Brain, Anatomy, Cortical dysplasia, medicine.disease, 3. Good health, medicine.anatomical_structure, Malformations of Cortical Development, Group I, Neurology (clinical), Cerebellar hypoplasia (non-human), Tubulin genes
Abstract

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as “Tubulinopathies”. To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2–3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6). Electronic supplementary material The online version of this article (doi:10.1186/2051-5960-2-69) contains supplementary material, which is available to authorized users.

Published
2014

45. The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation

Author

Laurent Pasquier, Bernard Aral, Jaclyn S Lee, Judith St-Onge, Michel Vekemans, Frédéric Huet, Brunella Franco, Fan Ye, Philippe Loget, Ange-Line Bruel, Arnold Munnich, Nadège Gigot, Carla A.M. Lopes, Sophie Saunier, José Manuel García-Verdugo, Julien Thevenon, Vicente Herranz-Pérez, Susana González-Granero, Laurence Jego, Maxence V. Nachury, André Mégarbané, Jean-Baptiste Rivière, Laurence Faivre, Caroline Alby, Toshinobu Shida, Christel Thauvin-Robinet, Andrew M. Fry, Estelle Lopez, Tania Attié-Bitach, Thauvin Robinet, C, Lee, J, Lopez, E, Herranz Pérez, V, Shida, T, Franco, Brunella, Jego, L, Ye, F, Pasquier, L, Loget, P, Gigot, N, Aral, B, Lopes, Ca, St Onge, J, Bruel, Al, Thevenon, J, González Granero, S, Alby, C, Munnich, A, Vekemans, M, Huet, F, Fry, Am, Saunier, S, Rivière, Jb, Attié Bitach, T, Garcia Verdugo, Jm, Faivre, L, Mégarbané, A, and Nachury, M. V.

Subjects
Male, Microcephaly, Centriole, Microtubule-associated protein, sports, Biology, Ciliopathies, Centriole elongation, Article, Cell Line, Procentriole, Genetics, medicine, Humans, Genetic Predisposition to Disease, Centrioles, Cilium, Proteins, Orofaciodigital Syndromes, medicine.disease, sports.league, HEK293 Cells, Centrosome, Child, Preschool, Microtubule-Associated Proteins
Abstract

Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia(1,2). How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth(3-5), whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation(6,7). Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.

Published
2014

47. TCF2/HNF-1beta mutations: 3 cases of fetal severe pancreatic agenesis or hypoplasia and multicystic renal dysplasia

Author

Delphine, Body-Bechou, Philippe, Loget, Dominique, D'Herve, Bernard, Le Fiblec, Anne-Gaelle, Grebille, Hélène, Le Guern, Caroline, Labarthe, Margaret, Redpath, Anne-Sophie, Cabaret-Dufour, Odent, Sylvie, Alice, Fievet, Corinne, Antignac, Laurence, Heidet, Sophie, Taque, and Poulain, Patrice

Subjects
Adult, Heterozygote, Gestational Age, Oligohydramnios, Ultrasonography, Prenatal, Clubfoot, Phenotype, Pregnancy, Mutation, Humans, Female, Multicystic Dysplastic Kidney, Pancreas, Hepatocyte Nuclear Factor 1-beta
Abstract

The aim of this study was to document the association between pancreatic agenesis or hypoplasia and multicystic renal dysplasia related to transcription factor 2 (TCF2) or hepatocyte nuclear factor 1 beta mutations.We describe the phenotype of the pancreas and the kidneys from three fetuses heterozygous for a mutation of TCF2.Case 1 had bilateral hyperechogenic, multicystic kidneys, bilateral clubfoot and pancreatic agenesis. Case 2 had two enlarged polycystic kidneys, anamnios and pancreatic agenesis. Case 3 had multicystic renal dysplasia, oligohydramnios and hypoplasia of the tail of the pancreas.TCF2 mutations are frequently discovered in fetuses presenting with bilateral hyperechogenic kidneys. The association between pancreatic agenesis and a TCF2 mutation has not previously been reported. TCF2 deficiency in mice leads to pancreatic agenesis, suggesting that the gene is essential for pancreatic development. Our observations indicate the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered.

Published
2013

48. Whole-body post-mortem computed tomography compared with autopsy in the investigation of unexpected death in infants and children

Author

P. Darnault, M. Roussey, Bertrand Bruneau, Maïa Proisy, Antoine Marchand, Céline Rozel, Philippe Loget, Fabienne Pelé, Catherine Tréguier, Renaud Bouvet, Service de radiologie et imagerie médicale [Rennes] = Radiology [Rennes], CHU Pontchaillou [Rennes], Vision, Action et Gestion d'informations en Santé (VisAGeS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Département de médecine de l'enfant et de l'adolescent, hôpital Sud, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Barillot, Christian

Subjects
Child abuse, Male, medicine.medical_specialty, Time Factors, Autopsy, Computed tomography, Sudden death, Unexpected death, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Death, Sudden, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 0302 clinical medicine, MESH: Autopsy Cause of Death Child Child Abuse Child, Preschool Death, Sudden/etiology* Female Head/pathology Humans Infant Male Radiographic Image Interpretation, Computer-Assisted Time Factors Tomography, X-Ray Computed/methods* Whole Body Imaging/methods, Cause of Death, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Whole Body Imaging, 030216 legal & forensic medicine, Child Abuse, Child, Cause of death, Neuroradiology, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, medicine.diagnostic_test, business.industry, Infant, Interventional radiology, General Medicine, 3. Good health, Child, Preschool, Radiographic Image Interpretation, Computer-Assisted, Female, Radiology, business, Tomography, X-Ray Computed, Head
Abstract

International audience; To investigate the contribution of whole-body post-mortem computed tomography (PMCT) in sudden unexpected death in infants and children.METHODS:Forty-seven cases of sudden unexpected death in children investigated with radiographic skeletal survey, whole-body PMCT and autopsy were enrolled. For imaging interpretation, non-specific post-mortem modifications and abnormal findings related to the presumed cause of death were considered separately. All findings were correlated with autopsy findings.RESULTS:There were 31 boys and 16 girls. Of these, 44 children (93.6 %) were younger than 2 years. The cause of death was found at autopsy in 18 cases (38.3 %), with 4 confirmed as child abuse, 12 as infectious diseases, 1 as metabolic disease and 1 as bowel volvulus. PMCT results were in accordance with autopsy in all but three of these 18 cases. Death remains unexplained in 29 cases (61.7 %) and was correlated with no abnormal findings on PMCT in 27 cases. Major discrepancies between PMCT and autopsy findings concerned pulmonary analysis.CONCLUSIONS:Whole-body PMCT may detect relevant findings that can help to explain sudden unexpected death and is essential for detecting non-accidental injuries. We found broad concordance between autopsy and PMCT, except in a few cases of pneumonia. It is a non-invasive technique acceptable to relatives.KEY POINTS:• Whole-body post-mortem computed tomography (PMCT) is an effective non-invasive method. • Whole-body PMCT is essential for detecting child abuse in unexpected death. • There is concordance on cause of death between PMCT and autopsy. • Whole-body PMCT could improve autopsy through dissection and sampling guidance. • PMCT shows findings that may be relevant when parents reject autopsy.

Published
2013

49. Array-CGH Analysis Suggests Genetic Heterogeneity in Rhombencephalosynapsis

Author

Isabelle Gicquel, Leslie Ratié, Christèle Dubourg, Annie Laquerrière, Claude Bendavid, Mylène Beri, Véronique David, Sylvie Jaillard, Valérie Dupé, Sandra Mercier, Philippe Loget, C. Evain, Chloé Quélin, Sylvie Odent, Laurent Pasquier, James Lespinasse, Pascale Marcorelles, Bruno Leheup, Dominique Martin-Coignard, Florence Demurger, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Cytogénétique, CH Chambéry, Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-CHU Rouen

Subjects
Genetics, 0303 health sciences, Candidate gene, [SDV.GEN]Life Sciences [q-bio]/Genetics, Microarray, Genetic heterogeneity, business.industry, Chromosomal translocation, In situ hybridization, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Agenesis, Medicine, Original Article, Copy-number variation, business, Gene, 030217 neurology & neurosurgery, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

Rhombencephalosynapsis is an uncommon, but increasingly recognized, cerebellar malformation defined as vermian agenesis with fusion of the hemispheres. The embryologic and genetic mechanisms involved are still unknown, and to date, no animal models are available. In the present study, we used Agilent oligonucleotide arrays in a large series of 57 affected patients to detect candidate genes. Four different unbalanced rearrangements were detected: a 16p11.2 deletion, a 14q12q21.2 deletion, an unbalanced translocation t(2p;10q), and a 16p13.11 microdeletion containing 2 candidate genes. These genes were further investigated by sequencing and in situ hybridization. This first microarray screening of a rhombencephalosynapsis series suggests that there may be heterogeneous genetic causes.

Published
2013

50. Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly

Author

Louise Devisme, Koryna Socha, Malika Chelbi, Maryse Bonnière, Alix Clemenson, Marie Gonzales, Steven Gazal, Férechté Encha-Razavi, Catherine Fallet-Bianco, Jean-Pierre Bernard, Dominique Carles, Sylvie Odent, Annie Laquerrière, Anne Bazin, Christine Bole-Feysot, Céline Bouchet-Séraphin, Tania Attié-Bitach, Fabien Guimiot, Laurence Loeuillet, Nathalie Seta, Samuel Quentin, Sandrine Vuillaumier-Barrot, Jacqueline Aziza, Bernard Grandchamp, Sophie Monnot, Philippe Loget, Unité UMR_S956, Pôle de Pathologie, Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pathologie et biologie cellulaire, Université de Montréal (UdeM)-Hôpital Sainte-Justine, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de foetopathologie, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], LInguistique et DIdactique des Langues Étrangères et Maternelles (LIDILEM), Université Stendhal - Grenoble 3, Service de Biologie du Développement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'Anatomie et de Cytologie Pathologiques, CHI Poissy-Saint-Germain, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Service de Cytogénétique et Embryologie, Laboratoire de biochimie métabolique et cellulaire, Hôpital Bichat - Claude Bernard, Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'Anatomie et Cytologie Pathologique [Rouen], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement ( Néovasc ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institute for Research and Innovation in Biomedicine ( IRIB ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Sainte-Justine-Université de Montréal, Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), LInguistique et DIdactique des Langues Étrangères et Maternelles ( LIDILEM ), Université Stendhal - Grenoble 3-Université Grenoble Alpes ( UGA ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Service de Génétique et d'Embryologie Médicales, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -CHU Trousseau [APHP], Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université Stendhal - Grenoble 3-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Trousseau [APHP], and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Genotype, Cobblestone Lissencephaly, [SDV]Life Sciences [q-bio], Lissencephaly, Gonadal dysgenesis, Consanguinity, Biology, medicine.disease_cause, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Fetus, Report, Gene Order, medicine, Dystroglycan, Genetics, Humans, Family, Genetics(clinical), Pentosyltransferases, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, Mutation, [ SDV ] Life Sciences [q-bio], Membrane Proteins, Exons, Cortical dysplasia, medicine.disease, Nucleotidyltransferases, Introns, 3. Good health, biology.protein, 030217 neurology & neurosurgery
Abstract

International audience; Cobblestone lissencephaly is a peculiar brain malformation with characteristic radiological anomalies. It is defined as cortical dysplasia that results when neuroglial overmigration into the arachnoid space forms an extracortical layer that produces agyria and/or a "cobblestone" brain surface and ventricular enlargement. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal-recessive diseases characterized by cerebral, ocular, and muscular deficits. These include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN, and FKRP identified these diseases as alpha-dystroglycanopathies. Our exhaustive screening of these six genes, in a cohort of 90 fetal cases, led to the identification of a mutation in only 53% of the families, suggesting that other genes might also be involved. We therefore decided to perform a genome-wide study in two multiplex families. This allowed us to identify two additional genes: TMEM5 and ISPD. Because TMEM has a glycosyltransferase domain and ISPD has an isoprenoid synthase domain characteristic of nucleotide diP-sugar transferases, these two proteins are thought to be involved in the glycosylation of dystroglycan. Further screening of 40 families with cobblestone lissencephaly identified nonsense and frameshift mutations in another four unrelated cases for each gene, increasing the mutational rate to 64% in our cohort. All these cases displayed a severe phenotype of cobblestone lissencephaly A. TMEM5 mutations were frequently associated with gonadal dysgenesis and neural tube defects, and ISPD mutations were frequently associated with brain vascular anomalies.

Published
2012

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