Language
English
Publication Date
6-1-2023
Journal
American Journal of Human Genetics
DOI
10.1016/j.ajhg.2023.04.008
PMID
37196654
PMCID
PMC10257005
PubMedCentral® Posted Date
5-16-2023
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Humans, Animals, Facies, Neurodevelopmental Disorders, Phenotype, Drosophila, Intellectual Disability, Jumonji Domain-Containing Histone Demethylases, neurodevelopmental disorders, COMPASS, Mendelian disorders, missense variants, de novo variants, Drosophila, KDM6B
Published Open-Access
yes
Recommended Citation
Rots, Dmitrijs; Jakub, Taryn E; Keung, Crystal; et al., "The Clinical and Molecular Spectrum of the KDM6B-Related Neurodevelopmental Disorder" (2023). Faculty and Staff Publications. 5178.
https://digitalcommons.library.tmc.edu/baylor_docs/5178
Included in
Genetic Phenomena Commons, Genetic Processes Commons, Genetic Structures Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Medical Specialties Commons
Comments
This article has been corrected. See Am J Hum Genet. 2025 Oct 18.