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

Genomics England Research Consortium, Dmitrijs Rots, Taryn E. Jakub, Crystal Keung, Adam Jackson, Siddharth Banka, Rolph Pfundt, Bert B.A. de Vries, Richard H. van Jaarsveld, Saskia M.J. Hopman, Ellen van Binsbergen, Irene Valenzuela, Maja Hempel, Tatjana Bierhals, Fanny Kortüm, Francois Lecoquierre, Alice Goldenberg, Jens Michael Hertz, Charlotte Brasch Andersen, Maria KibækEloise J. Prijoles, Roger E. Stevenson, David B. Everman, Wesley G. Patterson, Linyan Meng, Charul Gijavanekar, Karl De Dios, Shenela Lakhani, Tess Levy, Matias Wagner, Dagmar Wieczorek, Paul J. Benke, María Soledad Lopez Garcia, Renee Perrier, Sergio B. Sousa, Pedro M. Almeida, Maria José Simões, Bertrand Isidor, Wallid Deb, Andrew A. Schmanski, Omar Abdul-Rahman, Christophe Philippe, Ange Line Bruel, Laurence Faivre, Antonio Vitobello, Christel Thauvin, Jeroen J. Smits, Livia Garavelli, Stefano G. Caraffi, Francesca Peluso, Kaija Puura

Research output: Contribution to journalArticleScientificpeer-review

2 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)963-978
Number of pages16
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - Jun 2023
Publication typeA1 Journal article-refereed


  • de novo variants
  • Drosophila
  • KDM6B
  • Mendelian disorders
  • missense variants
  • neurodevelopmental disorders

Publication forum classification

  • Publication forum level 3

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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