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Rots, D.* ; Jakub, T.E.* ; Keung, C.* ; Jackson, A.* ; Banka, S.* ; Pfundt, R.* ; de Vries, B.B.A.* ; van Jaarsveld, R.H.* ; Hopman, S.M.J.* ; van Binsbergen, E.* ; Valenzuela, I.* ; Hempel, M.* ; Bierhals, T.* ; Kortüm, F.* ; Lecoquierre, F.* ; Goldenberg, A.* ; Hertz, J.M.* ; Andersen, C.B.* ; Kibæk, M.* ; Prijoles, E.J.* ; Stevenson, R.E.* ; Everman, D.B.* ; Patterson, W.G.* ; Meng, L.* ; Gijavanekar, C.* ; De Dios, K.* ; Lakhani, S.* ; Levy, T.* ; Wagner, M. ; Wieczorek, D.* ; Benke, P.J.* ; Lopez Garcia, M.S.* ; Perrier, R.* ; Sousa, S.B.* ; Almeida, P.M.* ; Simões, M.J.* ; Isidor, B.* ; Deb, W.* ; Schmanski, A.A.* ; Abdul-Rahman, O.* ; Philippe, C.* ; Bruel, A.L.* ; Faivre, L.* ; Vitobello, A.* ; Thauvin, C.* ; Smits, J.J.* ; Garavelli, L.* ; Caraffi, S.G.* ; Peluso, F.* ; Davis-Keppen, L.* ; Platt, D.* ; Royer, E.* ; Leeuwen, L.* ; Sinnema, M.* ; Stegmann, A.P.A.* ; Stumpel, C.T.R.M.* ; Tiller, G.E.* ; Bosch, D.G.M.* ; Potgieter, S.T.* ; Joss, S.* ; Splitt, M.* ; Holden, S.* ; Prapa, M.* ; Foulds, N.* ; Douzgou, S.* ; Puura, K.* ; Waltes, R.* ; Chiocchetti, A.G.* ; Freitag, C.M.* ; Satterstrom, F.K.* ; De Rubeis, S.* ; Buxbaum, J.* ; Gelb, B.D.* ; Branko, A.* ; Kushima, I.* ; Howe, J.* ; Scherer, S.W.* ; Arado, A.* ; Baldo, C.* ; Patat, O.* ; Bénédicte, D.* ; Lopergolo, D.* ; Santorelli, F.M.* ; Haack, T.* ; Dufke, A.* ; Bertrand, M.* ; Falb, R.J.* ; Rieß, A.* ; Krieg, P.* ; Spranger, S.* ; Bedeschi, M.F.* ; Iascone, M.* ; Josephi-Taylor, S.* ; Roscioli, T.* ; Buckley, M.F.* ; Liebelt, J.* ; Dagli, A.I.* ; Aten, E.* ; Hurst, A.C.E.* ; Hicks, A.* ; Suri, M.* ; Aliu, E.* ; Naik, S.* ; Sidlow, R.* ; Coursimault, J.* ; Nicolas, G.* ; Küpper, H.* ; Petit, F.* ; Ibrahim, V.* ; Top, D.* ; Di Cara, F.* ; Louie, R.J.* ; Stolerman, E.* ; Brunner, H.G.* ; Vissers, L.E.L.M.* ; Kramer, J.M.* ; Kleefstra, T.*

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

Am. J. Hum. Genet. 110, 963-978 (2023)
Publ. Version/Full Text DOI PMC
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Compass ; Drosophila ; Kdm6b ; Mendelian Disorders ; De Novo Variants ; Missense Variants ; Neurodevelopmental Disorders; De-novo Variants; Structural Basis; Gene-expression; Histone; Drosophila; Sleep; Jmjd3; Demethylases; Mutations; Resource
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 110, Issue: 6, Pages: 963-978 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants
Canadian Institutes of Health Research
NSERC PGSD grant
Netherlands Organisation for Health Research and Development
Dutch Research Council