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1. Impact of SARS-CoV-2 Infection on Unvaccinated Pregnant Women: Non-Reassuring Fetal Heart Rate Tracing Because of Placentitis

Author

Alexandra Claudet, Daniele De Luca, Elie Mosnino, Jérémie Mattern, Olivier Picone, Jeanne Sibiude, Estelle Wafo, Vassilis Tsatsaris, Emilie Giral, Irène Grefenstette, Julie Carrara, Dominique A. Badr, Marie-Hélène Saint-Frison, Sophie Prevot, Alexandra Benachi, and Alexandre J. Vivanti

Subjects
COVID-19, infection, coagulopathy, pregnancy, fetus, acidosis, Microbiology, QR1-502
Abstract

In 2020, a new coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. SARS-CoV-2 infection has been shown to be highly morbid in pregnant women, being a risk factor for several obstetric conditions leading to increased maternal and neonatal mortality. A few studies since 2020 have shown SARS-CoV-2 maternal–fetal transmission and noted placental abnormalities grouped under the term placentitis. We hypothesized that these placental lesions could be responsible for abnormalities in placental exchange and therefore abnormalities in cardiotocographic monitoring, leading to premature fetal extraction. The objective is to identify the clinical, biochemical, and histological determinants associated with the occurrence of non-reassuring fetal heart rate (NRFHR) outside labor in fetuses of SARS-CoV-2-infected mothers. We conducted a retrospective multicenter case series of the natural history of maternal SARS-CoV-2 infections resulting in fetal delivery outside labor due to NRFHR. Collaboration was sought with the maternity hospitals in the CEGORIF, the APHP and Brussels hospitals. The investigators were contacted by e-mail on three successive occasions over a period of one year. Data from 17 mothers and 17 fetuses were analyzed. Most women had a mild SARS-CoV-2 infection; only two women presented severe infection. No woman was vaccinated. We found a substantial proportion of maternal coagulopathy at birth: elevation of APTT ratio (62%), thrombocytopenia (41%) and liver cytolysis (58.3%). Iatrogenic prematurity was noted in 15 of 17 fetuses, and 100% were born by cesarean delivery due to emergency criteria. One male neonate died on the day of birth due to peripartum asphyxia. Three cases of maternal–fetal transmission were recorded following WHO criteria. Placental analysis in 15 cases revealed eight cases of SARS-CoV-2 placentitis, causing placental insufficiency. In total, 100% of the placentas analyzed showed at least one lesion suggestive of placentitis. SARS-CoV-2 maternal infection during pregnancy is likely to generate neonatal morbidity in relation to placental damage resulting in placental insufficiency. This morbidity may be the consequence of induced prematurity as well as acidosis in the most severe situations. Placental damage occurred in unvaccinated women and in women with no identified risk factor, in contrast to severe maternal clinical forms.

Published
2023
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3. Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenital

Author

Ivo Gut, Sarah Grotto, Céline Bellesme, Arnold Munnich, Cyril Gitiaux, Jeanne Amiel, Chloé Quélin, Annie Laquerrière, Suonavy Khung, Hanitra Ranjatoelina-Randrianaivo, Luc Rigonnot, Christine Francannet, Loic Quevarec, Jérôme Bouligand, Fabienne Prieur, Alexandra Benachi, Valérie Cormier-Daire, Laurence Perrin, Judith Melki, Pierre-Simon Jouk, Flora Nolent, Tania Attié-Bitach, Delphine Héron, Marie-Line Jacquemont, Claire Beneteau, Fabien Guimiot, Laetitia Lambert, Sandra Mercier, Valérie Biancalana, Fanny Laffargue, Elise Boucher, Jean-Louis Bessereau, P. Landrieu, Annick Toutain, Alain Verloes, Alice Goldenberg, Philippe Latour, Dominique Martin-Coignard, Anne Guiochon-Mantel, Dan Mejlachowicz, Damien Sternberg, Haluk Topaloglu, Bruno Eymard, Géraldine Viot, Catherine Fallet-Bianco, Julien Saada, Isabelle Desguerre, Marie-Hélène Saint-Frison, Catherine Vincent-Delorme, Sophie Blesson, Radka Stoeva, Alexandre J. Vivanti, Martine Bucourt, Pascaline Letard, Jérome Maluenda, Laurence Loeuillet, Lionel Van Maldergem, Didier Lacombe, Marcel Tawk, Michèle Granier, Stanislas Lyonnet, Anne-Lise Delezoide, Andrée Delahaye-Duriez, André Mégarbané, Marie Gonzales, Florence Petit, Juliette Piard, Laurence Faivre, Helene Verhelst, Bettina Bessières, Sabine Sigaudy, Sandra Whalen, Valérie Layet, Yline Capri, Fanny Pelluard, Emanuela Abiusi, Klaus Dieterich, Marie Vincent, Marine Legendre, Dana Jaber, Romulus Grigorescu, Florent Marguet, Eric Bieth, Helge Amthor, Christine Barnerias, Estelle Colin, Laetitia Trestard, Mathilde Nizon, Jelena Martinovic, Daniel Amram, and Nicoletta Resta

Subjects
musculoskeletal diseases, Artrogriposi múltiple congènita, Settore BIO/18 - GENETICA, human genetics, neuromuscular diseases, Genomics, Biology, CONTRACTURES, CLASSIFICATION, diseases, symbols.namesake, Diagnòstic, Gene mapping, arthrogryposis multiplex congenita, Exome Sequencing, OF-FUNCTION MUTATIONS, Genetics, Medicine and Health Sciences, genomics, Humans, Genetics (clinical), Exome sequencing, Arthrogryposis, Sanger sequencing, Arthrogryposis multiplex congenita, Genetic heterogeneity, SPINAL MUSCULAR-ATROPHY, Proteins, nervous system malformations, DYSTROPHY, Disease gene identification, GENE, Human genetics, Pedigree, ETIOLOGY, Phenotype, symbols, neuromuscular, Genètica, Transcription Factors
Abstract

BackgroundArthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.MethodsSeveral genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.ResultsWe achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).ConclusionNew genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

Published
2022

4. 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

5. Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

Author

Bertrand Isidor, Christelle Arrondel, Camille Humbert, Flora Silbermann, Marie-Hélène Said-Menthon, Cécile Jeanpierre, Christelle Cabrol, Audrey Desgrange, Frédéric Tores, Laurence Heidet, Lara De Tomasi, Ishwar C. Verma, Marie-Pierre Cordier, Ratna Dua Puri, Laurent Gavard, Jelena Martinovic, Christine Pietrement, Juliette Piard, Olivier Niel, Marie Gonzales, Patrick Nitschke, Robert Novo, Stéphane Fouquet, Joelle Roume, Philippe Khau Van Kien, Jacqueline Aziza, Pierre David, Sophie Saunier, Marie-Hélène Saint-Frison, Hubert Journel, Christine Bole-Feysot, The molecular basis of kidney diseases: cystinosis and hereditary nephrotic syndrome (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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 (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Coordination des Cellules et Morphogenèse / Heart Morphogenesis (Imagine - Institut Pasteur U1163), Institut Pasteur [Paris] (IP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Hôpital Robert Debré Paris, Hôpital Robert Debré, CHI Poissy-Saint-Germain, Centre Hospitalier Universitaire de Reims (CHU Reims), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Lille, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), and Sir Ganga Ram Hospital [New Delhi, India]

Subjects
0301 basic medicine, Male, nephrogenesis, 030105 genetics & heredity, Kidney, Mice, Missense mutation, Exome, Child, Urinary Tract, Genetics (clinical), Exome sequencing, kidney development, Mice, Knockout, kidney agenesis, heart defect, tubulogenesis, Hypoplasia, Neoplasm Proteins, medicine.anatomical_structure, Phenotype, Agenesis, Female, Kidney Diseases, medicine.medical_specialty, Heterozygote, Urinary system, mouse model, Biology, Congenital Abnormalities, 03 medical and health sciences, Fetus, Internal medicine, Report, Genetics, medicine, Animals, Humans, Renal agenesis, CAKUT, Membrane Proteins, Proteins, genital tract, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, medicine.disease, 3DISCO, GREB1L, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Urogenital Abnormalities, Mutation, Kidney disease
Abstract

International audience; Congenital anomalies of the kidney and urinary tract (CAKUT) constitute a major cause of chronic kidney disease in children and 20% of prenatally detected anomalies. CAKUT encompass a spectrum of developmental kidney defects, including renal agenesis, hypoplasia, and cystic and non-cystic dysplasia. More than 50 genes have been reported as mutated in CAKUT-affected case subjects. However, the pathophysiological mechanisms leading to bilateral kidney agenesis (BKA) remain largely elusive. Whole-exome or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L (growth regulation by estrogen in breast cancer 1-like), a gene reported as a target of retinoic acid signaling. Four loss-of-function and 12 damaging missense variants, 14 being absent from GnomAD, were identified. Twelve of them were present in familial or simplex BKA-affected case subjects. Female BKA-affected fetuses also displayed uterus agenesis. We demonstrated a significant association between GREB1L variants and BKA. By in situ hybridization, we showed expression of Greb1l in the nephrogenic zone in developing mouse kidney. We generated a Greb1l knock-out mouse model by CRISPR-Cas9. Analysis at E13.5 revealed lack of kidneys and genital tract anomalies in male and female Greb1l-/- embryos and a slight decrease in ureteric bud branching in Greb1l+/- embryos. We showed that Greb1l invalidation in mIMCD3 cells affected tubulomorphogenesis in 3D-collagen culture, a phenotype rescued by expression of the wild-type human protein. This demonstrates that GREB1L plays a major role in early metanephros and genital development in mice and humans.

Published
2017

6. Kif7 Mutations Cause Fetal Hydrolethalus And Acrocallosal Syndromes

Author

Marie Hélène Saint Frison, Sophie Patrier, Elif Uz, Gülen Eda Utine, Valérie Cormier-Daire, Nicolas Goudin, Nadia Elkhartoufi, Gönöl Ogur, Nurten A. Akarsu, Stanislas Lyonnet, Daniela Buzas, Koray Boduroğlu, Mark Winey, Tania Attié-Bitach, L. Fertitta, Karlien L.M. Coene, Sophie Thomas, Christine Bole-Feysot, Christopher L. Bennett, Raoul C.M. Hennekam, Arnold Munnich, Philip L. Beales, Nicholas Katsanis, Marie Gonzales, Luc Rigonnot, Patrick Nitschke, Estelle Colin, Christel Thauvin-Robinet, Yasemin Alanay, Alain Schmitt, Michel Vekemans, Solenn Pruvost, Férechté Encha-Razavi, Jean Pierre Siffroi, Nicolas Cagnard, Erica E. Davis, Céline Gomes, N. Joye, Audrey Putoux, Çocuk Sağlığı ve Hastalıkları, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatrics, and OMÜ

Subjects
Heart Defects, Congenital, Male, medicine.medical_specialty, animal structures, Adolescent, Acrocallosal Syndrome, Hydrolethalus syndrome, Kinesins, Biology, medicine.disease_cause, Ciliopathies, Article, Cerebral Ventricles, Consanguinity, Internal medicine, GLI3, Genetics, medicine, Humans, Hedgehog Proteins, Cilia, Child, Genetics & Heredity, Mutation, Cilium, Infant, Acrocallosal syndrome, medicine.disease, Magnetic Resonance Imaging, Hedgehog signaling pathway, Pedigree, Ciliopathy, Endocrinology, Child, Preschool, Female, Hand Deformities, Congenital, Hydrocephalus
Abstract

Coene, Karlien/0000-0001-9873-1458; Alanay, Yasemin/0000-0003-0683-9731; THOMAS, Sophie/0000-0002-8569-3277; Lyonnet, Stanislas/0000-0001-5426-9417; Akarsu, Nurten/0000-0001-5432-0032; ATTIE-BITACH, Tania/0000-0002-1155-3626; Davis, Erica/0000-0002-2412-8397; Boduroglu, Koray/0000-0001-6260-1942; Cagnard, Nicolas/0000-0002-9051-1896; cormier-daire, valerie/0000-0002-2839-9856; Katsanis, Nicholas/0000-0002-2480-0171; PUTOUX, Audrey/0000-0001-5496-4604 WOS: 000291017000021 PubMed: 21552264 KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies. ANRFrench National Research Agency (ANR) [07-MRAR-010-02, BLAN-1122-01]; E-RARE [07-ERare-001-01]; Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [108S420]; US National Institutes of Health from the National Institute of Child Health and Development [R01HD04260]; National Institute of Diabetes, Digestive and Kidney DisordersUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK072301]; Academie de Medecine; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NS039818-07]; Huygens Scholarship Programme; Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [NWO Toptalent-021.001.014]; March of Dimes FoundationMarch of Dimes [1-FY07-422]; Medical Research CouncilMedical Research Council UK (MRC) [G0801843] We are grateful to families and to the French Society of Fetal Pathology (SOFFOET) for participating in the study, to C. Dubourg, P. Wieacker, B. Leroy, N. Laurent, V. Fermeaux, S. Odent for fetuses' referral and to A. Schinzel and A. David for ACLS samples. We thank M. Zarhrate, A. Aguilar, N. Spasky and L. Besse for technical help. We thank N. Boddaert for helpful discussion. This work was supported by grants from ANR (FETALCILIOPATHIES number 07-MRAR-010-02 and FOETOCILPATH number BLAN-1122-01), E-RARE (Cranirare number 07-ERare-001-01) the Scientific and Technological Research Council of Turkey (TUBITAK, grant number 108S420 to N. A. A.), the US National Institutes of Health grant R01HD04260 from the National Institute of Child Health and Development (N. K.), R01DK072301 from the National Institute of Diabetes, Digestive and Kidney Disorders (N. K.) and the European Union (EU-SYSCILIA; E. E. D., N. K. and P. L. B.). A. P. was granted a fellowship from the Academie de Medecine. S. T. is supported by NIH 'Hereditary Basis of Neural Tube Defects' No NS039818-07 to M. Speer. K. L. M. C. is supported by the Huygens Scholarship Programme and the Netherlands Organization for Scientific Research (NWO Toptalent-021.001.014). M. W. was a fellow of the Guggenheim Foundation and was supported by the March of Dimes Foundation (1-FY07-422). P. L. B. is a Wellcome Trust Senior Research Fellow. N. K. is a Distinguished George W. Brumley Professor.

Published
2011

7. Diaphanospondylodysostosis (DSD): confirmation of a recessive disorder with abnormal vertebral ossification and nephroblastomatosis

Author

N. Joye, Marie Gonzales, Marie-Hélène Saint Frison, Alain Verloes, Férechté Encha-Razavi, Jean-Louis Taillemite, Roland Walbaum, Rudolf Pfeiffer, Odile Bourdet, Chantal Perrotez, and Pierre Maroteaux

Subjects
Male, Axial skeleton, Appendicular skeleton, Abnormal vertebral ossification, Genes, Recessive, Wilms Tumor, Spinal Osteophytosis, Fatal Outcome, Terminology as Topic, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), Cystic kidney, Family Health, Rib cage, Bone Diseases, Developmental, business.industry, Ossification, Infant, Newborn, Anatomy, Sacrum, Kidney Neoplasms, Vertebra, Pedigree, Radiography, medicine.anatomical_structure, Female, medicine.symptom, business
Abstract

We report on four patients from three families, with similar radiological findings: absent (or severely delayed) ossification of vertebral bodies and associated anomalies. The babies were stillborn or died soon after birth of respiratory insufficiency. Two patients are sibs (female and male) born to first cousin Malian parents. The two others were non-consanguineous. This perinatally lethal entity comprises short neck, short wide thorax, and normally shaped limbs. Associated, inconstant anomalies are myelomeningocele, cystic kidneys with nephrogenic rests (in the sibs), and cleft palate. Radiologically, the hallmarks are absence of ossification of the vertebral bodies and sacrum, abnormal position of the vertebral pedicles, which are lamellar and angulated, ribbon-like ribs reduced in number, narrow pelvis, upward widening of the iliac wings, and unusual tilt of the ischiopubic rami, contrasting with the normal appendicular skeleton. Maroteaux briefly described one of the patients in the 2002 edition of "Maladies osseuses de l'enfant" and three sibs with similar renal and radiological findings were reported in 2003 in this Journal. Combined with the latter cases, these four new patients allow delineation of a specific lethal AR syndrome with ossification defect of the axial skeleton and renal dysplasia. We propose to name this entity diaphanospondylodysostosis.

Published
2005

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