1. Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications
- Author
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Gioia Mastromoro, Alma Kuechler, Francesca Clementina Radio, Yoann Vial, Elena Andreucci, Tuula Rinne, Erika Leenders, Kara Ranguin, Emanuela Scarano, Marine Legendre, Marion Gérard, Julia Brinkmann, Alessandro De Luca, Paola Daniele, Kerstin Kutsche, Francesca Pantaleoni, Ineke van der Burgt, Christina Lissewski, Maria Cristina Digilio, Hélène Cavé, Yline Capri, Valérie Chune, Francesca Romana Lepri, Martin Zenker, Marco Tartaglia, Laura Mazzanti, Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Institute of Human Genetics (University Hospital Magdeburg), University Hospital of the Otto von Guericke University of Magdeburg, Radboud University Medical Center [Nijmegen], St. Orsola University Hospital, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Institut für Humangenetik, Universitätsklinikum Essen, Essen, Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Hôpital Pellegrin, CHU de Bordeaux, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Hôpital Robert Debré Paris, Hôpital Robert Debré, Anna Meyer Children's Hospital Florence, University of Florence, and Department of Experimental Medicine, Sapienza University of Rome (Italy)
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Adult ,Male ,Adolescent ,Medizin ,Bioinformatics ,Short stature ,Article ,Mapk signaling pathway ,Lymphatic System ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Genotype ,Genetics ,Humans ,Medicine ,In patient ,Child ,ComputingMilieux_MISCELLANEOUS ,Genetics (clinical) ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,0303 health sciences ,Protein function ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,business.industry ,Noonan Syndrome ,030305 genetics & heredity ,Infant ,medicine.disease ,Phenotype ,3. Good health ,Lymphatic system ,Child, Preschool ,Son of Sevenless Proteins ,Mutation ,Noonan syndrome ,Female ,medicine.symptom ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
RASopathies are caused by variants in genes encoding components or modulators of the RAS/MAPK signaling pathway. Noonan syndrome is the most common entity among this group of disorders and is characterized by heart defects, short stature, variable developmental delay, and typical facial features. Heterozygous variants in SOS2, encoding a guanine nucleotide exchange factor for RAS, have recently been identified in patients with Noonan syndrome. The number of published cases with SOS2-related Noonan syndrome is still limited and little is known about genotype-phenotype correlations. We collected previously unpublished clinical and genotype data from 17 individuals carrying a disease-causing SOS2 variant. Most individuals had one of the previously reported dominant pathogenic variants; only four had novel changes at the established hotspots for variants that affect protein function. The overall phenotype of the 17 patients fits well into the spectrum of Noonan syndrome and is most similar to the phenotype observed in patients with SOS1-related Noonan syndrome, with ectodermal anomalies as common features and short stature and learning disabilities as relatively infrequent findings compared to the average Noonan syndrome phenotype. The spectrum of heart defects in SOS2-related Noonan syndrome was consistent with the known spectrum of cardiac anomalies in RASopathies, but no specific heart defect was particularly predominating. Notably, lymphatic anomalies were extraordinarily frequent, affecting more than half of the patients. We therefore conclude that SOS2-related Noonan syndrome is associated with a particularly high risk of lymphatic complications that may have a significant impact on morbidity and quality of life.
- Published
- 2020
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