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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)
Postprint DOI PMC
Open Access Green
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 110, Heft: 6, Seiten: 963-978 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort New York, NY
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503200-001
Förderungen
Canadian Institutes of Health Research
NSERC PGSD grant
Netherlands Organisation for Health Research and Development
Dutch Research Council
DOI 10.1016/j.ajhg.2023.04.008
WOS ID 001069581900001
Scopus ID 85160282099
PubMed ID 37196654
Erfassungsdatum 2023-10-06
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