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

Hellen Lesmann, Institute of Human Genetics, University of Bonn, Bonn, NRW, Germany.
Alexander Hustinx, Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, NRW, Germany.
Shahida Moosa, Division of Molecular Biology and Human Genetics, Stellenbosch University and Medical Genetics, Tygerberg Hospital, Stellenbosch, South Africa.
Hannah Klinkhammer, Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, NRW, Germany.
Elaine Marchi, New York State Institute for Basic Research in Developmental Disabilities, New York State, Albany, New York, USA.
Pilar Caro, Institute of Human Genetics, Heidelberg University, Heidelberg, Baden-Württemberg, Germany.
Ibrahim M. Abdelrazek, Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Alexandria, Egypt.
Jean Tori Pantel, Institute for Digitalization and General Medicine, University Hospital RWTH Aachen, Aachen, NRW, Germany.
Merle Ten Hagen, Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, NRW, Germany.
Meow-Keong Thong, Department of Paediatrics, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Rifhan Azwani Mazlan, Department of Paediatrics, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Sok Kun Tae, Department of Paediatrics, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Tom Kamphans, GeneTalk GmbH, Bonn, NRW, Germany.
Wolfgang Meiswinkel, GeneTalk GmbH, Bonn, NRW, Germany.
Jing-Mei Li, Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, NRW, Germany.
Behnam Javanmardi, Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, NRW, Germany.
Alexej Knaus, Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, NRW, Germany.
Annette Uwineza, College of Medicine and Health Sciences, University of Rwanda, and University Teaching Hospital of Kigali, Kigali, Rwanda.
Cordula Knopp, Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, NRW, Germany.
Tinatin Tkemaladze, Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi, Georgia.
Miriam Elbracht, Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, NRW, Germany.
Larissa Mattern, Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, NRW, Germany.
Rami Abou Jamra, Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Clara Velmans, Institute of Human Genetics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, NRW, Germany.
Vincent Strehlow, Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Maureen Jacob, Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich, Germany.
Angela Peron, Medical Genetics, Meyer Children's Hospital IRCCS, Firenze, Italy.
Cristina Dias, Department of Medical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
Beatriz Carvalho Nunes, Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
Thainá Vilella, Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
Isabel Furquim Pinheiro, Genetics Unit, Instituto da Criança, Universidade de São Paulo, São Paulo, Brazil.
Chong Ae Kim, Genetics Unit, Instituto da Criança, Universidade de São Paulo, São Paulo, Brazil.

Document Type

Journal Article

Publication Date

10-8-2024

Journal

medRxiv : the preprint server for health sciences

DOI

10.1101/2023.06.06.23290887

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.

Department

Pediatrics

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