Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

Niels Vos, Liselot van der Laan, Perle K. M. Russel, Saskia M. Maas, Mariet W. Elting, Johanna M. van Hagen, Phillis Lakeman, Sandra Jansen, Floor A. M. Duijkers, Marcel M. A. M. Mannens, Mariëlle Alders, Peter Henneman & Mieke M. van Haelst

Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands

Niels Vos, Liselot van der Laan, Perle K. M. Russel, Saskia M. Maas, Mariet W. Elting, Johanna M. van Hagen, Phillis Lakeman, Sandra Jansen, Floor A. M. Duijkers, Marcel M. A. M. Mannens, Mariëlle Alders, Peter Henneman & Mieke M. van Haelst

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, N6A 5W9, Canada

Sadegheh Haghshenas, Kathleen Rooney, Michael A. Levy, Raissa Relator, Jennifer Kerkhof, Haley McConkey & Bekim Sadikovic

Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 3K7, Canada

Kathleen Rooney, Haley McConkey & Bekim Sadikovic

Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands

Lisenka E. L. M. Vissers, Bert B. A. de Vries & Rolph Pfundt

Department of Genetics, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands

Nienke E. Verbeek, Marjolijn C. J. Jongmans & Marie-José H. van den Boogaard

Center for Medical Genetics, Antwerp University Hospital, University of Antwerp, Drie Eikenstraat 655, 2650, Edegem, Belgium

Lynne Rumping

Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

Danielle G. M. Bosch, Laura Donker-Kaat & Kyra E. Stuurman

Université de Bourgogne, Inserm U1231, Equipe GAD, Dijon, France

Antonio Vitobello, Christel Thauvin-Robinet, Laurence Faivre, Sophie Nambot & Aurore Garde

CHU Dijon Bourgogne, FHU-TRANSLAD, Unité Fonctionnelle Innovation en Diagnostic Génomique Des Maladies Rares, 21000, Dijon, France

Antonio Vitobello, Christel Thauvin-Robinet & Sophie Nambot

CHU Dijon Bourgogne, Centre de Génétique, Centre de Référence Maladies Rares «Déficiences Intellectuelles de Causes Rares», FHU-TRANSLAD, Dijon, France

Christel Thauvin-Robinet & Aurore Garde

CHU Dijon Bourgogne, Centre de Génétique, Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs», FHU-TRANSLAD, Dijon, France

Laurence Faivre & Sophie Nambot

INserm U1183, Department of Clinical Genetics, Montpellier University, 34090 CHU Montpellier, Montpellier, France

Marjolaine Willems & David Genevieve

Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, Univ Rouen Normandie, 76000, Rouen, France

Gaël Nicolas

Department of Medical Genetics, Timone Hospital, Marseille, France

Tiffany Busa

Genetics Department, University Hospital, UMR 1253, iBrain, University of Tours, Inserm, Tours, France

Annick Toutain

APHP, Department of Genetics, Robert Debré Hospital, 75019, Paris, France

Marion Gérard

Clinical Genetics and Neurodevelopmental Disorders, Centre Hospitalier de L’Estran, 50170, Pontorson, France

Varoona Bizaoui

Service de Génétique Médicale, CHU de Nantes, 44000, Nantes, France

Bertrand Isidor

Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Foggia, Italy

Giuseppe Merla

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy

Giuseppe Merla

Servizio di Genetica Medica, Ospedale Cardinale G. Panico, Tricase, LE, Italy

Maria Accadia

Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA

Charles E. Schwartz

Department of Clinical Genetics, Genetic and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia

Katrin Ounap

Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia

Katrin Ounap

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

Mariëtte J. V. Hoffer

Genetics Program, North York General Hospital, Toronto, ON, M2K 1E1, Canada

Marjan M. Nezarati

Greenwood Genetic Center, Greenwood, SC, 29646, USA

Matthew L. Tedder & Curtis Rogers

Department of Medical Sciences, University of Torino, Via Santena 19, 10126, Turin, Italy

Alfredo Brusco & Slavica Trajkova

Unit of Medical Genetics, Città Della Salute e Della Scienza Hospital, Turin, Italy

Alfredo Brusco

Department of Clinical and Biological Science, University of Torino, Turin, Italy

Giovanni B. Ferrero

Service de Génétique, CRMR AnDDI-Rares, CHU Reims, Reims, France

Marta Spodenkiewicz

Department of Medical Genetics and Metabolism, Valley Children’s Hospital, Madera, CA, USA

Richard Sidlow

Department of Public Health and Pediatric Sciences, University of Torino, Turin, Italy

Alessandro Mussa

Pediatric Clinical Genetics Unit, Regina Margherita Childrens’ Hospital, Turin, Italy

Alessandro Mussa

Liverpool Center for Genomic Medicine, Liverpool Women’s Hospital, Liverpool, UK

Emma McCann

Department of Pediatrics, Le Bonheur Children’s Hospital, Memphis, TN, USA

Henry J. Mroczkowski

Division of Genetics, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA

Henry J. Mroczkowski

Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, VIC, 3052, Australia

Susan M. White

Department of Paediatrics, University of Melbourne, Melbourne, Australia

Susan M. White

Amsterdam UMC, Department of Paediatrics, Emma Children’s Hospital, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

Mieke M. van Haelst

Amsterdam UMC, Emma Center for Personalized Medicine, Amsterdam, The Netherlands

Mieke M. van Haelst

All authors reviewed the final version of the manuscript. All authors read and approved the final manuscript. MMvH. and PH designed the project. NV, LvdL, PR, MMvH, MWE, LELMV, BBAdV, LR, PL, DGMB, JMvH, NEV, MCCJ, SM, GM, CES, KO, SMW, MH, and MMN contributed to the sample collection. NV, PR, MMvH, MA, MWE, LELMV, BBAdV, LR, PL, DGMB, JMvH, NEV, MCCJ, SM, AV, CT, LF, MW, DG, and VB contributed to the clinical assessment of the participants and diagnostic laboratory investigations. LvdL and JK performed the laboratory experiments. BS oversaw the analytic and bioinformatic aspects of this study. SH, LvdL, MAL, and RR performed the bioinformatic analysis. N.V., SH. and LvdL wrote the manuscript. MMAMM, MMvH, PH, HM and BS supervised the project.