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1. Osteosarcoma without prior retinoblastoma related to RB1 low‐penetrance germline pathogenic variants: A novel type of RB1‐related hereditary predisposition syndrome?

Author

Marion Imbert‐Bouteille, Marion Gauthier‐Villars, Dominique Leroux, Isabelle Meunier, Isabelle Aerts, Livia Lumbroso‐Le Rouic, Sophie Lejeune, Capucine Delnatte, Caroline Abadie, Pascal Pujol, Claude Houdayer, and Carole Corsini

Subjects
cancer screening, low penetrance, Osteosarcoma, RB1, Sarcoma, whole‐body MRI, Genetics, QH426-470
Abstract

Abstract Background Retinoblastoma (Rb) is a rare intraocular malignant tumor in children with high overall survival. Predisposition to Rb is linked to RB1 germline mutations with high penetrance, but rare RB1 low‐penetrance variants are also known. Rb survivors are at risk of second primary malignancies (SPMs), mostly osteosarcoma and soft‐tissue sarcoma. Nevertheless, the risk of primary osteosarcoma developing without prior Rb has not been reported in RB1 germline mutation carriers. Methods We report a patient in whom osteosarcoma developed at age 17 as a first primary malignancy within a family context of sarcoma. Results Unexpectedly, genetic testing identified a low‐penetrance germline mutation in RB1 [NM_000321.2: c.45_76dup; p.(Pro26Leufs*50)]. In eight additional similar cases from published and unpublished reports of families, first primary osteosarcomas and sarcomas mostly developed in RB1 low‐penetrance mutation carriers without prior Rb. Conclusion We propose that first primary sarcoma and osteosarcoma could be a novel clinical presentation of a RB1‐related hereditary predisposition syndrome linked to RB1 low‐penetrance germline mutations. In these families, careful screening of primary non‐Rb cancer and SPMs is required by maintaining enhanced clinical vigilance. Implementing lifelong periodic whole‐body MRI screening might be a complementary strategy for unaffected carrier relatives in these families.

Published
2019
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2. No Association of Early-Onset Breast or Ovarian Cancer with Early-Onset Cancer in Relatives in BRCA1 or BRCA2 Mutation Families

Author

Marion Imbert-Bouteille, Carole Corsini, Marie-Christine Picot, Lucas Mizrahy, Sandrine Akouete, Helena Huguet, Frédéric Thomas, David Geneviève, Patrice Taourel, Marc Ychou, Virginie Galibert, Chloé Rideau, Karen Baudry, Tatiana Kogut Kubiak, Isabelle Coupier, Rémy Hobeika, Yvette Macary, Alain Toledano, Jérôme Solassol, Antoine Maalouf, Jean-Pierre Daures, and Pascal Pujol

Subjects
breast cancer, ovarian cancer, BRCA1, BRCA2, early-onset, Genetics, QH426-470
Abstract

According to clinical guidelines, the occurrence of very early-onset breast cancer (VEO-BC) (diagnosed ≤ age 30 years) or VEO ovarian cancer (VEO-OC) (diagnosed ≤ age 40 years) in families with BRCA1 or BRCA2 mutation (BRCAm) prompts advancing the age of risk-reducing strategies in relatives. This study aimed to assess the relation between the occurrence of VEO-BC or VEO-OC in families with BRCAm and age at BC or OC diagnosis in relatives. We conducted a retrospective multicenter study of 448 consecutive families with BRCAm from 2003 to 2018. Mean age and 5-year–span distribution of age at BC or OC in relatives were compared in families with or without VEO-BC or VEO-OC. Conditional probability calculation and Cochran–Mantel–Haenszel chi-square tests were used to investigate early-onset cancer occurrence in relatives of VEO-BC and VEO-OC cases. Overall, 15% (19/245) of families with BRCA1m and 9% (19/203) with BRCA2m featured at least one case of VEO-BC; 8% (37/245) and 2% (2/203) featured at least one case of VEO-OC, respectively. The cumulative prevalence of VEO-BC was 5.1% (95% CI 3.6–6.6) and 2.5% (95% CI 1.4–3.6) for families with BRCA1m and BRCA2m, respectively. The distribution of age and mean age at BC diagnosis in relatives did not differ by occurrence of VEO-BC for families with BRCA1m or BRCA2m. Conditional probability calculations did not show an increase of early-onset BC in VEO-BC families with BRCA1m or BRCA2m. Conversely, the probability of VEO-BC was not increased in families with early-onset BC. VEO-BC or VEO-OC occurrence may not be related to young age at BC or OC onset in relatives in families with BRCAm. This finding—together with a relatively high VEO-BC risk for women with BRCAm—advocates for MRI breast screening from age 25 regardless of family history.

Published
2021
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3. Correction: The genomic and clinical landscape of fetal akinesia

Author

Peter Nürnberg, Katharina Schoner, Haluk Topaloglu, Goknur Haliloglu, Janine Altmüller, Mert Karakaya, Harald Ehrhardt, Hülya-Sevcan Daimagüler, Susanne Motameny, Sebahattin Cirak, Anne Koy, Eva Maria Christina Schwaibold, Mona Kreutzer, Kerstin Becker, Cho-Ming Chao, Marion Imbert-Bouteille, Haicui Wang, Matthias Pergande, Amit Kawalia, Jens H. Westhoff, Jens Reimann, Slavica Ostojic, Harald von Pein, Nursel Elcioglu, Özkan Özdemir, Mireille Cossée, Andreas Hahn, Özgür Duman, Holger Thiele, Raoul Heller, and Anne Schänzer

Subjects
Fetal akinesia, business.industry, Published Erratum, Hardware_INTEGRATEDCIRCUITS, MEDLINE, Medicine, ComputingMilieux_LEGALASPECTSOFCOMPUTING, ComputerApplications_COMPUTERSINOTHERSYSTEMS, Hardware_PERFORMANCEANDRELIABILITY, Bioinformatics, business, GeneralLiterature_MISCELLANEOUS, Genetics (clinical)
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

4. Clinical practice guidelines for BRCA1 and BRCA2 genetic testing

Author

Marion Vandromme, Jean Philippe Spano, Olivier Cussenot, Chloé Rideau, Carole Corsini, Isabelle Treilleux, Michèle Vintraud, Ignace Vergote, Yves-Jean Bignon, Kevin S. Hughes, Bernard Baertschi, Eitan Friedman, Daniel Zarca, Marie Duboys de Labarre, Pascal Pujol, Jean Marc Rey, Joseph Gligorov, Ettore D. Capoluongo, Clarisse Duriez, Marion Imbert-Bouteille, Yann Neuzillet, Jean-Louis Mandel, Isabelle Ray-Coquard, Laurence Gladieff, Jose E. Alés Martínez, Frédérique Penault-Llorca, Karim Fizazi, Pierre Jean Lamy, Julie A. Vendrell, Pascal Hammel, Thibault De La Motte Rouge, Jesus Garcia Foncillas, Diether Lambrechts, Tatiana Kogut-Kubiak, Karen Baudry, William Jacot, William D. Foulkes, Frédéric Thomas, Sophie Nambot, Massimo Barberis, Michèle Anahory, Matti Aapro, Xavier Rebillard, Josep M. Piulats, Florence Duchamp, Steven A. Narod, Sylviane Olschwang, Banu Arun, Marc Bollet, Philp Beer, Clare Turnbull, Helen Hanson, Nicola Normanno, Virginie Galibert, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, 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), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), Institut Universitaire de Cancérologie [Sorbonne Université] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Gustave Roussy (IGR), Oncologie génito-urinaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cancer de Montpellier (ICM), Institut médical d'anayse génomique (IMAGENOME), Labosud, 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 Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre de Recherches Ecologiques et Evolutives sur le Cancer (MIVEGEC-CREEC), Processus Écologiques et Évolutifs au sein des Communautés (PEEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Centre Léon Bérard [Lyon], Harvard Medical School [Boston] (HMS), Hospital Nuestra Señora de Sonsoles, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Clinique Hartmann [Neuilly-sur-Seine], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncologie gynécologique, Institut Claudius Regaud, AP-HP Hôpital Tenon [Paris], Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP]-Université de Paris (UP), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Massachusetts General Hospital [Boston], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), 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), Pujol, P., Barberis, M., Beer, P., Friedman, E., Piulats, J. M., Capoluongo, E. D., Garcia Foncillas, J., Ray-Coquard, I., Penault-Llorca, F., Foulkes, W. D., Turnbull, C., Hanson, H., Narod, S., Arun, B. K., Aapro, M. S., Mandel, J. -L., Normanno, N., Lambrechts, D., Vergote, I., Anahory, M., Baertschi, B., Baudry, K., Bignon, Y. -J., Bollet, M., Corsini, C., Cussenot, O., De la Motte Rouge, T., Duboys de Labarre, M., Duchamp, F., Duriez, C., Fizazi, K., Galibert, V., Gladieff, L., Gligorov, J., Hammel, P., Imbert-Bouteille, M., Jacot, W., Kogut-Kubiak, T., Lamy, P. -J., Nambot, S., Neuzillet, Y., Olschwang, S., Rebillard, X., Rey, J. -M., Rideau, C., Spano, J. -P., Thomas, F., Treilleux, I., Vandromme, M., Vendrell, J., Vintraud, M., Zarca, D., Hughes, K. S., Ales Martinez, J. E., Institut Universitaire de Cancérologie [Paris] (IUC), Service d'urologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Service d'Oncologie médicale [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, endocrine system diseases, Genetic counseling, Advanced breast, [SDV]Life Sciences [q-bio], BRCA1 and BRCA2 testing, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Guideline, Guidelines, BRCA-related cancer, Càncer de mama, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Humans, Genetic Testing, Intensive care medicine, skin and connective tissue diseases, PARP inhibitors, Germ-Line Mutation, Genetic testing, BRCA2 Protein, Ovarian Neoplasms, Adjuvant treatment of cancer, medicine.diagnostic_test, business.industry, BRCA1 Protein, Cancer, medicine.disease, Metastatic breast cancer, 3. Good health, Clinical Practice, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, PARP inhibitor, Practice Guidelines as Topic, Female, Risk assessment, business, Tractament adjuvant del càncer
Abstract

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices. ispartof: EUROPEAN JOURNAL OF CANCER vol:146 pages:30-47 ispartof: location:England status: published

Published
2021

5. Single Circulating Fetal Trophoblastic Cells Eligible for Non Invasive Prenatal Diagnosis: the Exception Rather than the Rule

Author

Cyril Goizet, Patrick Calvas, Marie-Claire Vincent, Claire Guissart, Virginie Dorian, Nicolas Molinari, Caroline Rooryck-Thambo, Cathy Liautard-Haag, Annabelle Chaussenot, Romain Favre, Catherine Alix-Panabières, Sandra Pierredon, Laetitia Monteil, Philippe Khau Van Kien, Mélanie Fradin, Amandine Boureau-Wirth, Marion Imbert-Bouteille, Emmanuelle Haquet, Elsa Le Boette, Yuliya Petrov, Jacques Puechberty, Cécile Zordan, Céline Moutou, Laure Cayrefourcq, Cécile Rouzier, Marjolaine Willems, Claire Miry, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Strasbourg, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital de la Colombière, CHU de Bordeaux Pellegrin [Bordeaux], Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Les Hôptaux universitaires de Strasbourg (HUS), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre hospitalier Saint-Brieuc, and Salvy-Córdoba, Nathalie

Subjects
0301 basic medicine, MESH: Trophoblasts, Molecular biology, lcsh:Medicine, Diseases, Disease, Cell Separation, 0302 clinical medicine, Trinucleotide Repeats, Prenatal Diagnosis, lcsh:Science, MESH: High-Throughput Nucleotide Sequencing, Genetics, Whole Genome Amplification, 030219 obstetrics & reproductive medicine, Multidisciplinary, Molecular medicine, High-Throughput Nucleotide Sequencing, Trophoblasts, Huntington Disease, Microsatellite, Single-Cell Analysis, Biotechnology, MESH: Trinucleotide Repeats, Cell biology, Prenatal diagnosis, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Cell Separation, Article, 03 medical and health sciences, Medical research, Fetus, Multiplex polymerase chain reaction, Humans, Allele, MESH: Prenatal Diagnosis, Genotyping, MESH: Humans, Point mutation, lcsh:R, Health care, MESH: Fetus, MESH: Huntington Disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Feasibility Studies, lcsh:Q, MESH: Feasibility Studies, MESH: Single-Cell Analysis
Abstract

Non-Invasive Prenatal Diagnosis (NIPD), based on the analysis of circulating cell-free fetal DNA (cff-DNA), is successfully implemented for an increasing number of monogenic diseases. However, technical issues related to cff-DNA characteristics remain, and not all mutations can be screened with this method, particularly triplet expansion mutations that frequently concern prenatal diagnosis requests. The objective of this study was to develop an approach to isolate and analyze Circulating Trophoblastic Fetal Cells (CFTCs) for NIPD of monogenic diseases caused by triplet repeat expansion or point mutations. We developed a method for CFTC isolation based on DEPArray sorting and used Huntington’s disease as the clinical model for CFTC-based NIPD. Then, we investigated whether CFTC isolation and Whole Genome Amplification (WGA) could be used for NIPD in couples at risk of transmitting different monogenic diseases. Our data show that the allele drop-out rate was 3-fold higher in CFTCs than in maternal cells processed in the same way. Moreover, we give new insights into CFTCs by compiling data obtained by extensive molecular testing by microsatellite multiplex PCR genotyping and by WGA followed by mini-exome sequencing. CFTCs appear to be often characterized by a random state of genomic degradation.

Published
2020

6. The genomic and clinical landscape of fetal akinesia

Author

Eva Maria Christina Schwaibold, Katharina Schoner, Harald von Pein, Haluk Topaloglu, Harald Ehrhardt, Goknur Haliloglu, Raoul Heller, Haicui Wang, Mona Kreutzer, Mireille Cossée, Andreas Hahn, Slavica Ostojic, Anne Schänzer, Cho-Ming Chao, Mert Karakaya, Özgür Duman, Janine Altmüller, Nursel Elcioglu, Susanne Motameny, Hülya-Sevcan Daimagüler, Holger Thiele, Anne Koy, Özkan Özdemir, Sebahattin Cirak, Marion Imbert-Bouteille, Kerstin Becker, Amit Kawalia, Jens Reimann, Peter Nürnberg, Matthias Pergande, Jens H. Westhoff, Center for Molecular Medicine [Cologne] (CMMC), University of Cologne, Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine, University of Cologne, Cologne Center for Genomics [Cologne] (CCG), University Hospital of Cologne [Cologne], Institute of Human Genetics [Cologne], Universitätsklinikum Köln (Uniklinik Köln)-University of Cologne, Justus-Liebig-Universität Gießen (JLU), Marmara University [Kadıköy - İstanbul], Eastern Mediterranean University (EMU), Mother and Child Health Care Institute of Serbia [Belgrade, Serbia] (MCHCI), Akdeniz University, Rheinische Friedrich-Wilhelms-Universität Bonn, Philipps University of Marburg, Department of Neurology, Justus-Liebig-University, University Children's Hospital of Heidelberg [Heidelberg, Germany], Institute of Human Genetics [Heidelberg, Germany], Universität Heidelberg [Heidelberg], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, University Medical Center of the Johannes Gutenberg-University Mainz, Hacettepe University Children's Hospital, Genetic Health Service New Zealand, Faculty of Medicine [Cologne], University Hospital of Cologne [Cologne]-University of Cologne, Pergande, Matthias, Motameny, Susanne, Oezdemir, Oezkan, Kreutzer, Mona, Wang, Haicui, Daimagueler, Huelya-Sevcan, Becker, Kerstin, Karakaya, Mert, Ehrhardt, Harald, Elcioglu, Nursel, Ostojic, Slavica, Chao, Cho-Ming, Kawalia, Amit, Duman, Ozgur, Koy, Anne, Hahn, Andreas, Reimann, Jens, Schoner, Katharina, Schaenzer, Anne, Westhoff, Jens H., Schwaibold, Eva Maria Christina, Cossee, Mireille, Imbert-Bouteille, Marion, von Pein, Harald, Haliloglu, Goknur, Topaloglu, Haluk, Altmueller, Janine, Nuernberg, Peter, Thiele, Holger, Heller, Raoul, and Cirak, Sebahattin

Subjects
Male, Candidate gene, Myopathy, VARIANTS, Fetal akinesia, MESH: Ryanodine Receptor Calcium Release Channel, 0302 clinical medicine, MESH: Child, Guanine Nucleotide Exchange Factors, MESH: Guanine Nucleotide Exchange Factors, Exome, Copy-number variation, Child, MESH: High-Throughput Nucleotide Sequencing, Genetics (clinical), Genetics, Arthrogryposis, 0303 health sciences, MESH: Infant, Newborn, MESH: Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, RNA-Binding Proteins, MESH: Infant, 3. Good health, Fetal Diseases, MESH: Fetal Diseases, MESH: Young Adult, Child, Preschool, ASAH1, Female, MESH: DNA Copy Number Variations, medicine.symptom, Adult, GENETICS, Adolescent, DNA Copy Number Variations, MESH: Trans-Activators, MESH: Arthrogryposis, Biology, ASPM, Young Adult, 03 medical and health sciences, Muscular Diseases, medicine, Humans, Genetic Predisposition to Disease, Gene, 030304 developmental biology, MESH: Adolescent, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Humans, MUTATIONS, MESH: Child, Preschool, Infant, Newborn, MESH: Muscular Diseases, Infant, NEMALINE MYOPATHY, Ryanodine Receptor Calcium Release Channel, MESH: Adult, medicine.disease, Congenital myopathy, MESH: Male, MESH: RNA-Binding Proteins, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DISTAL ARTHROGRYPOSIS, Trans-Activators, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood.Methods: In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA).Results: We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3, EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1, SCN5A, SCN8A, and ZEB2. Furthermore, a sibling pair harbored a homozygous copy-number variant in TNNT1, an ultrarare congenital myopathy gene that has been linked to arthrogryposis via Gene Ontology analysis.Conclusion: Our analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1, IQSEC3 and RYR3. Of those, IQSEC3, and RYR3 had been proposed as neuromuscular disease-associated genes recently, and our findings endorse them as FA candidate genes. By combining NGS with deep clinical phenotyping, we achieved a 73% success rate of solved cases.

Published
2020

7. Osteosarcoma without prior retinoblastoma related to RB1 low‐penetrance germline pathogenic variants: A novel type of RB1‐related hereditary predisposition syndrome?

Author

Sophie Lejeune, Pascal Pujol, Livia Lumbroso-Le Rouic, Dominique Leroux, Claude Houdayer, Carole Corsini, Isabelle Meunier, Caroline Abadie, Marion Imbert-Bouteille, Capucine Delnatte, Isabelle Aerts, Marion Gauthier-Villars, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Curie [Paris], Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CRLCC René Gauducheau, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, Adolescent, lcsh:QH426-470, Ubiquitin-Protein Ligases, Bone Neoplasms, Penetrance, 030105 genetics & heredity, Germline, 03 medical and health sciences, Germline mutation, Genetics, Humans, Medicine, Genetic Predisposition to Disease, Orthopedic Procedures, Molecular Biology, Germ-Line Mutation, Genetics (clinical), Genetic testing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Osteosarcoma, medicine.diagnostic_test, business.industry, Retinoblastoma, whole‐body MRI, Cancer, Sarcoma, Induction Chemotherapy, Original Articles, medicine.disease, eye diseases, Pedigree, 3. Good health, Retinoblastoma Binding Proteins, lcsh:Genetics, 030104 developmental biology, Chemotherapy, Adjuvant, cancer screening, low penetrance, Cancer research, Female, Original Article, business, RB1
Abstract

Background Retinoblastoma (Rb) is a rare intraocular malignant tumor in children with high overall survival. Predisposition to Rb is linked to RB1 germline mutations with high penetrance, but rare RB1 low‐penetrance variants are also known. Rb survivors are at risk of second primary malignancies (SPMs), mostly osteosarcoma and soft‐tissue sarcoma. Nevertheless, the risk of primary osteosarcoma developing without prior Rb has not been reported in RB1 germline mutation carriers. Methods We report a patient in whom osteosarcoma developed at age 17 as a first primary malignancy within a family context of sarcoma. Results Unexpectedly, genetic testing identified a low‐penetrance germline mutation in RB1 [NM_000321.2: c.45_76dup; p.(Pro26Leufs*50)]. In eight additional similar cases from published and unpublished reports of families, first primary osteosarcomas and sarcomas mostly developed in RB1 low‐penetrance mutation carriers without prior Rb. Conclusion We propose that first primary sarcoma and osteosarcoma could be a novel clinical presentation of a RB1‐related hereditary predisposition syndrome linked to RB1 low‐penetrance germline mutations. In these families, careful screening of primary non‐Rb cancer and SPMs is required by maintaining enhanced clinical vigilance. Implementing lifelong periodic whole‐body MRI screening might be a complementary strategy for unaffected carrier relatives in these families., The risk of primary osteosarcoma developing without prior retinoblastoma has not been reported in RB1 germline mutation carriers. We report a patient in whom osteosarcoma developed at age 17 as a first primary malignancy within a family context of sarcoma. Unexpectedly, genetic testing identified a low‐penetrance germline mutation in RB1 [NM_000321.2: c.45_76dup, p.(Pro26Leufs*50)]. We propose that first primary sarcoma and osteosarcoma could be a novel clinical presentation of a RB1‐related hereditary predisposition syndrome linked to RB1 low‐penetrance germline mutations and discuss the screening strategy to implement for unaffected carrier relatives in these families.

Published
2019

8. No Association of Early-Onset Breast or Ovarian Cancer with Early-Onset Cancer in Relatives in BRCA1 or BRCA2 Mutation Families

Author

Tatiana Kogut Kubiak, Marc Ychou, Lucas Mizrahy, Jérôme Solassol, Carole Corsini, Virginie Galibert, Sandrine Akouete, Marion Imbert-Bouteille, Karen Baudry, David Geneviève, Antoine Maalouf, Pascal Pujol, Patrice Taourel, Remy Hobeika, Chloé Rideau, Frédéric Thomas, Helena Huguet, Yvette Macary, Alain Toledano, Jean-Pierre Daurès, Isabelle Coupier, Marie-Christine Picot, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Federal University of Juiz de Fora (UFIJ), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CIC Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches Ecologiques et Evolutives sur le Cancer (MIVEGEC-CREEC), Processus Écologiques et Évolutifs au sein des Communautés (PEEC), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut du Cancer de Montpellier (ICM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Clinique Hartmann [Neuilly-sur-Seine], and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, MESH: Mutation, MESH: Age of Onset, [SDV.CAN]Life Sciences [q-bio]/Cancer, QH426-470, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 03 medical and health sciences, Breast cancer, MESH: BRCA2 Protein, 0302 clinical medicine, BRCA2 Mutation, Ovarian cancer, MESH: Risk Factors, Genetics, medicine, Family history, MESH: Family, Genetics (clinical), MESH: BRCA1 Protein, Early onset, Early-onset, MESH: Humans, MESH: Middle Aged, business.industry, MESH: Genetic Predisposition to Disease, Cancer, MESH: Adult, MESH: Retrospective Studies, BRCA1, medicine.disease, BRCA2, MESH: France, MESH: Ovarian Neoplasms, Young age, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Multicenter study, MESH: Young Adult, 030220 oncology & carcinogenesis, business, MESH: Female, MESH: Breast Neoplasms
Abstract

According to clinical guidelines, the occurrence of very early-onset breast cancer (VEO-BC) (diagnosed ≤ age 30 years) or VEO ovarian cancer (VEO-OC) (diagnosed ≤ age 40 years) in families with BRCA1 or BRCA2 mutation (BRCAm) prompts advancing the age of risk-reducing strategies in relatives. This study aimed to assess the relation between the occurrence of VEO-BC or VEO-OC in families with BRCAm and age at BC or OC diagnosis in relatives. We conducted a retrospective multicenter study of 448 consecutive families with BRCAm from 2003 to 2018. Mean age and 5-year–span distribution of age at BC or OC in relatives were compared in families with or without VEO-BC or VEO-OC. Conditional probability calculation and Cochran–Mantel–Haenszel chi-square tests were used to investigate early-onset cancer occurrence in relatives of VEO-BC and VEO-OC cases. Overall, 15% (19/245) of families with BRCA1m and 9% (19/203) with BRCA2m featured at least one case of VEO-BC, 8% (37/245) and 2% (2/203) featured at least one case of VEO-OC, respectively. The cumulative prevalence of VEO-BC was 5.1% (95% CI 3.6–6.6) and 2.5% (95% CI 1.4–3.6) for families with BRCA1m and BRCA2m, respectively. The distribution of age and mean age at BC diagnosis in relatives did not differ by occurrence of VEO-BC for families with BRCA1m or BRCA2m. Conditional probability calculations did not show an increase of early-onset BC in VEO-BC families with BRCA1m or BRCA2m. Conversely, the probability of VEO-BC was not increased in families with early-onset BC. VEO-BC or VEO-OC occurrence may not be related to young age at BC or OC onset in relatives in families with BRCAm. This finding—together with a relatively high VEO-BC risk for women with BRCAm—advocates for MRI breast screening from age 25 regardless of family history.

Published
2021

9. Report on three additional patients and genotype–phenotype correlation in SLC25A22-related disorders group

Author

Pierre Rustin, Emilie Carme, camille lemattre, Yannis Duffourd, Vincent Meyer, Patricia Blanchet, François Rivier, Jean-Baptiste Rivière, Anne Boland, Thomas Guignard, Paule Bénit, Emmanuelle Haquet, Julien Thevenon, Elodie Sanchez, David Geneviève, Marion Imbert-Bouteille, Jean-François Deleuze, Doris Lechner, Agathe Roubertie, Frédéric Tran Mau-Them, Constance Wells, Florence Molinari, Vincent Gatinois, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Robert Debré, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Groupe d'Études et de Recherche Interdisciplinaire en Information et COmmunication - ULR 4073 (GERIICO ), Université de Lille, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Saclay, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Aix Marseille Université (AMU), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and MORNET, Dominique

Subjects
Male, Adolescent, Protein domain, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Compound heterozygosity, Bioinformatics, Mitochondrial Membrane Transport Proteins, Article, 03 medical and health sciences, Epilepsy, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Genetics, medicine, Humans, Ictal, Exome, Genetic Predisposition to Disease, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Child, Gene, Genetics (clinical), Exome sequencing, Genetic Association Studies, Skin, 0303 health sciences, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Base Sequence, business.industry, 030305 genetics & heredity, Electroencephalography, Fibroblasts, medicine.disease, Phenotype, 3. Good health, Pedigree, Transmembrane domain, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, Spasms, Infantile
Abstract

International audience; Early infantile epileptic encephalopathy (EIEE) is a heterogeneous group of severe forms of age-related developmental and epileptic encephalopathies with onset during the first weeks or months of life. The interictal electroencephalogram (EEG) shows a “suppression burst” (SB) pattern. The prognosis is usually poor and most children die within the first two years or survive with very severe intellectual disabilities. EIEE type 3 is caused by variants affecting function, in SLC25A22, which is also responsible for epilepsy of infancy with migrating focal seizures (EIMFS). We report a family with a less severe phenotype of EIEE type 3. We performed exome sequencing and identified two unreported variants in SLC25A22 in the compound heterozygous state: NM_024698.4: c.[813_814delTG];[818 G>A] (p.[Ala272Glnfs*144];[Arg273Lys]). Functional studies in cultured skin fibroblasts from a patient showed that glutamate oxidation was strongly defective, based on a literature review. We clustered the 18 published patients (including those from this family) into three groups according to the severity of the SLC25A22-related disorders. In an attempt to identify genotype–phenotype correlations, we compared the variants according to the location depending on the protein domains. We observed that patients with two variants located in helical transmembrane domains presented a severe phenotype, whereas patients with at least one variant outside helical transmembrane domains presented a milder phenotype. These data are suggestive of a continuum of disorders related to SLC25A22 that could be called SLC25A22-related disorders. This might be a first clue to enable geneticists to outline a prognosis based on genetic molecular data regarding the SLC25A22 gene.

Published
2019

10. Ovarian Clear Cell Carcinoma in Cowden Syndrome

Author

Clothilde Lindet-Bourgeois, Pascal Pujol, Carole Corsini, Maud Blanluet, Michel Longy, Pierre Vande Perre, Gaëtan MacGrogan, Marion Imbert-Bouteille, Gauthier Rathat, Karen Baudry, Virginie Bubien, Kevin Yauy, Julie Tinat, Didier Bessis, Stéphanie Baert-Desurmont, and Hélène Perrochia

Subjects
Adult, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, medicine, PTEN, Humans, Medical History Taking, Ovarian Neoplasms, biology, business.industry, Macrocephaly, PTEN Phosphohydrolase, Cancer, Cowden syndrome, medicine.disease, Pedigree, Oncology, 030220 oncology & carcinogenesis, Clear cell carcinoma, Cancer research, biology.protein, Adenocarcinoma, Female, medicine.symptom, Ovarian cancer, business, Hamartoma Syndrome, Multiple, Adenocarcinoma, Clear Cell
Abstract

Cowden syndrome (CS) is an autosomal dominant mendelian disease related to germline pathogenic variants affecting the PTEN-gene. CS is characterized by macrocephaly, mucocutaneous lesions, and an increased risk of breast and thyroid cancers. Rare ovarian cancer cases (mostly embryonic tumors) associated with PTEN have been described in the literature, but no current CS guidelines are available for ovarian cancer risk management. We report on a woman diagnosed with ovarian clear cell carcinoma (OCCC) at 28 years of age. The patient displayed macrocephaly, trichilemmomas, oral papillomatosis, and acral keratosis. A family history of multiple cancer cases within the PTEN-related tumor spectrum was identified. In addition, PET scan and fine-needle biopsy results led to a diagnosis of thyroid follicular neoplasia. PTEN sequencing revealed that she carried a germline inherited pathogenic variant in exon 5 c.388C>T, p.(Arg130*) (NM_000314). Somatic mismatch repair immunohistochemistry analysis showed normal expression, and germline BRCA1/2 sequencing did not reveal pathogenic or likely pathogenic variants. An ovarian cell immunohistochemistry analysis reported total loss of PTEN expression, which strongly suggested the role of PTEN in the oncogenesis of this cancer. Hence, a total thyroid resection was performed instead of thyroid lobectomy and a risk-reducing bilateral mastectomy was discussed. Co-occurrence of this pathogenic germline mutation in PTEN in this patient, early development of OCCC at age 28 years, and total loss of PTEN expression in the tumor might support the involvement of PTEN in the carcinogenesis of her ovarian cancer. We describe a new ovarian cancer case with an atypical histologic type-clear cell carcinoma-in CS. This observation might be the first indication of the need to expand the PTEN-related tumor spectrum to incorporate OCCC. The CS diagnosis significantly changed the therapeutic outcome of this patient.

Published
2018

11. LARP7 variants and further delineation of the Alazami syndrome phenotypic spectrum among primordial dwarfisms: 2 sisters

Author

Anne Boland, Marjolaine Willems, Jean-Baptiste Rivière, Florence Apparailly, Elodie Sanchez, Frédéric Tran Mau Them, Julien Thevenon, David Geneviève, Marion Imbert-Bouteille, Thomas Guignard, Vincent Gatinois, Vincent Meyer, Jean-François Deleuze, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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, Université Bourgogne Franche-Comté [COMUE] (UBFC), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Plateau technique de Biologie [CHU de Dijon], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Philips, Alexandre, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-IFR3, and Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
medicine.medical_specialty, Heart malformation, [SDV]Life Sciences [q-bio], Dwarfism, 03 medical and health sciences, Loss of Function Mutation, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Child, Genetics (clinical), Exome sequencing, Loss function, 030304 developmental biology, 0303 health sciences, business.industry, Siblings, 030305 genetics & heredity, General Medicine, Syndrome, medicine.disease, Dermatology, Phenotype, [SDV] Life Sciences [q-bio], Ribonucleoproteins, Etiology, Microcephaly, Female, Primordial dwarfism, business, Mild microcephaly
Abstract

Alazami syndrome (AS) (MIM# 615071 ) is an autosomal recessive microcephalic primordial dwarfism (PD) with recognizable facial features and severe intellectual disability due to depletion or loss of function variants in LARP7. To date, 15 patients with AS have been reported. Here we describe two consanguineous Algerian sisters with Alazami PD due to LARP7 homozygous pathogenic variants detected by whole exome sequencing. By comparing these two additional cases with those previously reported, we strengthen the key features of AS: severe growth restriction, severe intellectual disability and some distinguishing facial features such as broad nose, malar hypoplasia, wide mouth, full lips and abnormally set teeth. We also report significant new findings enabling further delineation of this syndrome: disproportionately mild microcephaly, stereotypic hand wringing and severe anxiety, thickened skin over the hands and feet, and skeletal, eye and heart malformations. From previous reviews, we summarize the main etiologies of PD according to the involved mechanisms and cellular pathways, highlighting their clinical core features.

Published
2017

12. An Incidental Finding of Maternal Multiple Myeloma by Non Invasive Prenatal Testing

Author

Joris Vermeesch, Peter Vandenberghe, Sanae Finge, Véronique Dorvaux, Eric Legius, Marion Imbert-Bouteille, Pascal Bourquard, Vincent Gatinois, Lucille Altounian, Jean Chiesa, Jean-Baptiste Gaillard, E Mousty, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and University Hospitals Leuven [Leuven]

Subjects
Adult, 0301 basic medicine, Oncology, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 03 medical and health sciences, 0302 clinical medicine, Text mining, Pregnancy, Internal medicine, Research Letter, medicine, Humans, Genetic Testing, Genetics (clinical), Multiple myeloma, Genetic testing, Incidental Findings, medicine.diagnostic_test, Maternal Serum Screening Tests, business.industry, Non invasive, Obstetrics and Gynecology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Sequence Analysis, DNA, medicine.disease, Research Letters, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Multiple Myeloma, business, Pregnancy Complications, Neoplastic
Abstract

What is already known about this subject? Non invasive prenatal testing for fetal trisomies 13, 18, and 21 occasionally identifies maternal cancer. What does this study add? A further case of maternal cancer incidentally diagnosed by routine NIPT. Extensive NIPT abnormalities are unlikely to be of fetal origin. Information given to patients should also adequately advise patients on potential incidental findings and might offer the option to opt out of receiving results beyond the trisomy report. International guidelines would improve patient counseling. ispartof: Prenatal Diagnosis vol:37 issue:12 pages:1257-1260 ispartof: location:England status: published

Published
2017

13. Le DPNI sur sang maternel : les pièges du cffDNA

Author

Franck Pellestor, Elodie Guagliardo, Emmanuelle Haquet, Anouck Schneider, Jacques Puechberty, Jean-Baptiste Gaillard, Marion Imbert-Bouteille, Kevin Yauy, Emmanuelle Vintejoux, and Vincent Gatinois

Subjects
Anatomy
Abstract

Le depistage prenatal non invasif (DPNI) des anomalies cytogenetiques fœtales sur le sang maternel represente une revolution dans la prise en charge des femmes enceintes. Avec une sensibilite et une specificite inegalees pour un depistage de masse, il permet d’eviter de nombreux gestes invasifs et rend les grossesses a risque plus sereines. Ce test est fonde sur la presence d’ADN fœtal libre (cffDNA) dans le sang maternel dont la demi-vie, tres courte, le rend representatif de la grossesse en cours. Le cffDNA etant issu des cellules trophoblastiques, les mosaiques confinees au placenta seront retrouvees, au meme titre qu’un examen de villosites choriales. Dans le sang, le cffDNA se trouve melange a l’ADN circulant maternel en tres large majorite. La proportion de cffDNA est appelee « fraction fœtale » et depend notamment du terme de la grossesse et de l’indice de masse corporelle de la mere. Si cette fraction fœtale est trop faible, il existe un risque d’echec voire d’erreur d’interpretation. De plus, l’interpretation peut etre faussee par des sources tierces d’ADN libre : la presence d’un second placenta, l’existence d’une tumeur meme infra-clinique chez la mere liberant un ADN tumoral libre ou encore une greffe d’organe ou l’administration de therapies cellulaires. Ces sources apportent un ADN libre different qui peut donner lieu a des faux-positifs, des faux-negatifs ou a la decouverte d’incidentalomes. La mise en place du DPNI de la trisomie 21 au CHU de Montpellier nous a permis de comprendre la cinetique du cffDNA lors de la grossesse et d’estimer l’influence des parametres physiopathologiques maternels sur la fraction fœtale. Ainsi, nous pouvons optimiser la date de prelevement au contexte de chaque de patiente. De plus, nous avons identifie les principaux pieges a eviter pour ce test dans la pratique courante d’un laboratoire de cytogenetique.

Published
2017

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