The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder

Dmitrijs Rots , Taryn Jakub , Crystal Keung , Adam Jackson (1) , Siddharth Banka (2) , Rolph Pfundt (3) , Bert B.A. de Vries , Richard van Jaarsveld , Saskia M.J. Hopman , Ellen van Binsbergen , Irene Valenzuela (4) , Maja Hempel (5) , Tatjana Bierhals (5) , Fanny Kortüm (5) , Francois Lecoquierre (6, 7) , Alice Goldenberg (8) , Jens Michael Hertz (9) , Charlotte Brasch Andersen , Maria Kibæk (9) , Eloise Prijoles , Roger Stevenson , David Everman , Wesley Patterson , Linyan Meng , Charul Gijavanekar , Karl de Dios , Shenela Lakhani , Tess Levy , Matias Wagner , Dagmar Wieczorek , Paul Benke , María Soledad Lopez Garcia , Renee Perrier , Sergio Sousa , Pedro Almeida , Maria José Simões , Bertrand Isidor , Wallid Deb , Andrew Schmanski , Omar Abdul-Rahman , Christophe Philippe , Ange-Line Bruel , Laurence Faivre , Antonio Vitobello , Christel Thauvin , Jeroen Smits , Livia Garavelli , Stefano Caraffi , Francesca Peluso , Laura Davis-Keppen , Dylan Platt , Erin Royer , Lisette Leeuwen , Margje Sinnema , Alexander P.A. Stegmann , Constance T.R.M. Stumpel , George Tiller , Daniëlle G.M. Bosch , Stephanus Potgieter , Shelagh Joss , Miranda Splitt , Simon Holden , Matina Prapa , Nicola Foulds , Sofia Douzgou , Kaija Puura , Regina Waltes , Andreas Chiocchetti , Christine Freitag , F. Kyle Satterstrom , Silvia De Rubeis , Joseph Buxbaum , Bruce Gelb , Aleksic Branko , Itaru Kushima , Jennifer Howe , Stephen Scherer , Alessia Arado , Chiara Baldo , Olivier Patat , Demeer Bénédicte (10, 11) , Diego Lopergolo , Filippo Santorelli , Tobias Haack , Andreas Dufke , Miriam Bertrand , Ruth Falb , Angelika Rieß , Peter Krieg , Stephanie Spranger , Maria Francesca Bedeschi , Maria Iascone , Sarah Josephi-Taylor , Tony Roscioli , Michael Buckley , Jan Liebelt , Aditi Dagli , Emmelien Aten , Anna C.E. Hurst , Alesha Hicks , Mohnish Suri , Ermal Aliu , Sunil Naik , Richard Sidlow , Juliette Coursimault , Gaël Nicolas , Hanna Küpper , Florence Petit (12) , Veyan Ibrahim , Deniz Top , Francesca Di Cara , Raymond Louie , Elliot Stolerman , Han Brunner , Lisenka E.L.M. Vissers , Jamie Kramer , Tjitske Kleefstra

1 Edin. - University of Edinburgh
2 University of Manchester [Manchester]
3 Radboud University Medical Center [Nijmegen]
4 Vall d'Hebron University Hospital [Barcelona]
5 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
6 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
7 CHU Rouen
8 Service de génétique [Rouen]
9 Institute of Forensic Medicine [Odense]
10 CHU Amiens-Picardie
11 CHIMERE - CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516
12 RADEME - Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364

De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.

Mots clés: COMPASS; Drosophila; KDM6B; Mendelian disorders; de novo variants; missense variants; neurodevelopmental disorders

Domaines: Neurosciences [q-bio.NC]

Dmitrijs Rots, Taryn Jakub, Crystal Keung, Adam Jackson, Siddharth Banka, et al.. The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder. American Journal of Human Genetics, 2023, ⟨10.1016/j.ajhg.2023.04.008⟩. ⟨hal-04102199⟩