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GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases

Lesmann H 1 , Hustinx A 2 , Moosa S 3 , Klinkhammer H 2 , Marchi E 4 , Caro P 5 Show all authors , Abdelrazek IM 6 , Pantel JT 7 , Hagen MT 2 , Thong MK 8 , Binti Mazlan RA 8 , Tae SK 8 , Kamphans T 9 , Meiswinkel W 9 , Li JM 2 , Javanmardi B 2 , Knaus A 2 , Uwineza A 10 , Knopp C 11 , Tkemaladze T 12 , Elbracht M 11 , Mattern L 11 , Jamra RA 13 , Velmans C 14 , Strehlow V 13 , Jacob M 15 , Peron A 16 , Dias C 17 , Nunes BC 18 , Vilella T 18 , Pinheiro IF 19 , Kim CA 19 , Melaragno MI 18 , Weiland H 2 , Kaptain S 2 , Chwiałkowska K 20 , Kwasniewski M 21 , Saad R 22 , Wiethoff S 23 , Goel H 24 , Tang C 25 , Hau A 26 , Barakat TS 27 , Panek P 28 , Nabil A 6 , Suh J 11 , Braun F 29 , Gomy I 30 , Averdunk L 31 , Ekure E 32 , Bergant G 33 , Peterlin B 34 , Graziano C 35 , Gaboon N 36 , Fiesco-Roa M 37 , Spinelli AM 38 , Wilpert NM 39 , Phowthongkum P 40 , Güzel N 11 , Haack TB 41 , Bitar R 42 , Tzschach A 43 , Rodriguez-Palmero A 44 , Brunet T 15 , Rudnik-Schöneborn S 45 , Contreras-Capetillo SN 46 , Oberlack A 15 , Samango-Sprouse C 47 , Sadeghin T 48 , Olaya M 48 , Platzer K 13 , Borovikov A 49 , Schnabel F 13 , Heuft L 13 , Herrmann V 13 , Oegema R 50 , Elkhateeb N 51 , Kumar S 1 , Komlosi K 43 , Mohamed K 6 , Kalantari S 52 , Sirchia F 52 , Martinez-Monseny AF 53 , Höller M 43 , Toutouna L 43 , Mohamed A 6 , Lasa-Aranzasti A 54 , Sayer JA 55 , Ehmke N 56 , Danyel M 56 , Sczakiel H 56 , Schwartzmann S 56 , Boschann F 56 , Zhao M 56 , Adam R 56 , Einicke L 56 , Horn D 56 , Chew KS 57 , Kam CC 57 , Karakoyun M 58 , Pode-Shakked B 59 , Eliyahu A 60 , Rock R 61 , Carrion T 62 , Chorin O 63 , Zarate YA 64 , Conti MM 65 , Karakaya M 14 , Tung ML 66 , Chandra B 66 , Bouman A 27 , Lumaka A 67 , Wasif N 68 , Shinawi M 69 , Blackburn PR 70 , Wang T 71 , Niehues T 72 , Schmidt A 1 , Roth RR 73 , Wieczorek D 73 , Hu P 74 , Waikel RL 74 , Ledgister Hanchard SE 74 , Elmakkawy G 6 , Safwat S 6 , Ebstein F 75 , Krüger E 76 , Küry S 75 , Bézieau S 75 , Arlt A 2 , Olinger E 77 , Marbach F 5 , Li D 78 , Dupuis L 79 , Mendoza-Londono R 79 , Houge SD 80 , Weis D 81 , Chung BH 82 , Mak CCY 83 , Kayserili H 84 , Elcioglu N 85 , Aykut A 86 , Şimşek-Kiper PÖ 87 , Bögershausen N 88 , Wollnik B 88 , Bentzen HB 89 , Kurth I 11 , Netzer C 14 , Jezela-Stanek A 28 , Devriendt K 90 , Gripp KW 91 , Mücke M 7 , Verloes A 92 , Schaaf CP 5 , Nellåker C 93 , Solomon BD 74 , Nöthen MM 1 , Abdalla E 6 , Lyon GJ 94 , Krawitz PM 2 , Hsieh TC 2

Affiliations 

  • 1 Institute of Human Genetics, University of Bonn, Bonn, NRW, Germany
  • 2 Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, NRW, Germany
  • 3 Division of Molecular Biology and Human Genetics, Stellenbosch University and Medical Genetics, Tygerberg Hospital, Stellenbosch, South Africa
  • 4 New York State Institute for Basic Research in Developmental Disabilities, New York State, Albany, New York, USA
  • 5 Institute of Human Genetics, Heidelberg University, Heidelberg, Baden-Württemberg, Germany
  • 6 Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Alexandria, Egypt
  • 7 Institute for Digitalization and General Medicine, University Hospital RWTH Aachen, Aachen, NRW, Germany
  • 8 Department of Paediatrics, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
  • 9 GeneTalk GmbH, Bonn, NRW, Germany
  • 10 College of Medicine and Health Sciences, University of Rwanda, and University Teaching Hospital of Kigali, Kigali, Rwanda
  • 11 Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, NRW, Germany
  • 12 Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi, Georgia
  • 13 Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
  • 14 Institute of Human Genetics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, NRW, Germany
  • 15 Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich, Germany
  • 16 Medical Genetics, Meyer Children's Hospital IRCCS, Firenze, Italy
  • 17 Department of Medical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK
  • 18 Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil
  • 19 Genetics Unit, Instituto da Criança, Universidade de São Paulo, São Paulo, Brazil
  • 20 Centre for Bioinformatics and Data Analysis, Medical University of Bialystok, Bialystok, Poland
  • 21 IMAGENE.ME SA, Bialystok, Poland
  • 22 North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, Great Ormond Street, London, UK
  • 23 Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, NRW, Germany
  • 24 School of Medicine and Public Health, University of Newcastle, Callaghan NSW, Australia
  • 25 Kabuki Syndrome Foundation, Northbrook, IL, USA
  • 26 Hunter Genetics, Hunter New England Health Service, Newcastle, Australia
  • 27 Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
  • 28 Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
  • 29 Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, NRW, Germany
  • 30 Department of Genetics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Sao Paulo, Brazil
  • 31 Department of General Pediatrics and Neonatology, University Children's Hospital, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany
  • 32 Department of Paediatrics, College of Medicine, University of Lagos, Lagos, Nigeria
  • 33 Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
  • 34 Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana
  • 35 Medical Genetics Unit, Ausl Romagna, Cesena, Italy
  • 36 Medical Genetics Center, Faculty of Medicine, Ain Shams University, Cairo, Egypt
  • 37 Programa de Maestría y Doctorado en Ciencias Médicas, Odontológicas y de la Salud, Universidad Nacional Autónoma de México, México City, Mexico
  • 38 Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
  • 39 NeuroCure Cluster of Excellence; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, D-10117 Berlin, Germany
  • 40 Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand
  • 41 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
  • 42 Pediatric Gastroenterology Department, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
  • 43 Institute of Human Genetics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • 44 Paediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain
  • 45 Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
  • 46 Universidad Autonoma de Yucatan (University Autonomus of Yucatan), Merida, Yucatan, Mexico
  • 47 Department of Pediatrics, George Washington University, 2121 I St. NW, Washington D.C. 2005
  • 48 Department of Research, The Focus Foundation, 2772 Rutland Road P.O. Box 190, Davidsonville, MD 21035
  • 49 Research Centre for Medical Genetics (RCMG), Moscow, Russia
  • 50 Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
  • 51 Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  • 52 Department of Molecular Medicine, University of Pavia, Pavia, Italy
  • 53 Department of Clinical Genetics, SJD Barcelona Children's Hospital, Esplugues del Llobregat (Barcelona), Spain
  • 54 Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Catalunya, Spain
  • 55 Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, UK
  • 56 Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
  • 57 Department of Paediatrics, Faculty of Medicine, University Malaya, 59100 Kuala Lumpur, Malaysia
  • 58 Ege University, Faculty of Medicine, Department of Pediatric Gastroenterology Hepatology and Nutrition, Izmir, Turkey
  • 59 The Institute of Rare Diseases, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
  • 60 The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Israel
  • 61 Metabolic Diseases Clinic, Edmond and Lily Safra Children's Hospital, Sheba Medical Center
  • 62 Rare diseases Unit, Pediatric Department, Hospital Universitari Son Espases, Palma de Mallorca, Spain
  • 63 The Institute of Rare Diseases, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
  • 64 Department of Pediatrics, Section of Genetics and Metabolism, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR, USA
  • 65 Project Director AI for Health at Foundation 29, Foundation 29, Madrid, Spain
  • 66 University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA 52242, USA
  • 67 Center for Human Genetics, Faculty of Medicine, University of Kinshasa, Kinshasa, DR Congo
  • 68 Institute of Human Genetics, University of Ulm, Ulm, Baden-Württemberg, Germany
  • 69 Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
  • 70 Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
  • 71 Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, Beijing 100191, China
  • 72 Department of Pediatrics, Helios Klinik Krefeld, Krefeld 47805, Germany
  • 73 Institute of Human Genetics, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
  • 74 Medical Genomics Unit, Medical Genetics Branch, National Human Genome Research Institute, Bethesda, USA
  • 75 Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France
  • 76 Insitute for Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Greifswald, Germany
  • 77 Center for Human Genetics, Cliniques Universitaires Saint-Luc, Brussels, Belgium
  • 78 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  • 79 Department to Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital of Sick Children, Toronto, Ontario, Canada
  • 80 Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
  • 81 Institue for Medical Genetics, Kepler University Hospital, Linz, Austria
  • 82 Hong Kong Genome Institute, Hong Kong, China
  • 83 Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
  • 84 Medical Genetics Department, Koç University School of Medicine (KUSoM), 34010, Istanbul, Türkiye
  • 85 Department of Pediatric Genetics, Marmara University School of Medicine, Istanbul, Türkiye
  • 86 Department of Medical Genetics, Ege University Faculty of Medicine, Izmir, Türkiye
  • 87 Hacettepe University Faculty of Medicine, Department of Pediatric Genetics, Ankara, Türkiye
  • 88 Institut of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
  • 89 Centre for Medical Ethics, Faculty of Medicine, University of Oslo, Oslo, Norway
  • 90 Center for Human Genetics, KU Leuven, Leuven, Belgium
  • 91 Division of Medical Genetics, A.I. du Pont Hospital for Children/Nemours, USA, Wilmington, Delaware, USA
  • 92 Department of Clinical Genetics, Robert-Debré Hospital, Paris, France
  • 93 Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK
  • 94 Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America
Res Sq, 2024 Jun 10.
PMID: 38903062 DOI: 10.21203/rs.3.rs-4438861/v1

Abstract

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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