The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder
Genomics England Research Consortium; Rots, Dmitrijs; Jakub, Taryn E.; Keung, Crystal; Jackson, Adam; Banka, Siddharth; Pfundt, Rolph; de Vries, Bert B.A.; van Jaarsveld, Richard H.; Hopman, Saskia M.J.; van Binsbergen, Ellen; Valenzuela, Irene; Hempel, Maja; Bierhals, Tatjana; Kortüm, Fanny; Lecoquierre, Francois; Goldenberg, Alice; Hertz, Jens Michael; Andersen, Charlotte Brasch; Kibæk, Maria; Prijoles, Eloise J.; Stevenson, Roger E.; Everman, David B.; Patterson, Wesley G.; Meng, Linyan; Gijavanekar, Charul; De Dios, Karl; Lakhani, Shenela; Levy, Tess; Wagner, Matias; Wieczorek, Dagmar; Benke, Paul J.; Lopez Garcia, María Soledad; Perrier, Renee; Sousa, Sergio B.; Almeida, Pedro M.; Simões, Maria José; Isidor, Bertrand; Deb, Wallid; Schmanski, Andrew A.; Abdul-Rahman, Omar; Philippe, Christophe; Bruel, Ange Line; Faivre, Laurence; Vitobello, Antonio; Thauvin, Christel; Smits, Jeroen J.; Garavelli, Livia; Caraffi, Stefano G.; Peluso, Francesca; Puura, Kaija (2023-06)
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Genomics England Research Consortium
Rots, Dmitrijs
Jakub, Taryn E.
Keung, Crystal
Jackson, Adam
Banka, Siddharth
Pfundt, Rolph
de Vries, Bert B.A.
van Jaarsveld, Richard H.
Hopman, Saskia M.J.
van Binsbergen, Ellen
Valenzuela, Irene
Hempel, Maja
Bierhals, Tatjana
Kortüm, Fanny
Lecoquierre, Francois
Goldenberg, Alice
Hertz, Jens Michael
Andersen, Charlotte Brasch
Kibæk, Maria
Prijoles, Eloise J.
Stevenson, Roger E.
Everman, David B.
Patterson, Wesley G.
Meng, Linyan
Gijavanekar, Charul
De Dios, Karl
Lakhani, Shenela
Levy, Tess
Wagner, Matias
Wieczorek, Dagmar
Benke, Paul J.
Lopez Garcia, María Soledad
Perrier, Renee
Sousa, Sergio B.
Almeida, Pedro M.
Simões, Maria José
Isidor, Bertrand
Deb, Wallid
Schmanski, Andrew A.
Abdul-Rahman, Omar
Philippe, Christophe
Bruel, Ange Line
Faivre, Laurence
Vitobello, Antonio
Thauvin, Christel
Smits, Jeroen J.
Garavelli, Livia
Caraffi, Stefano G.
Peluso, Francesca
Puura, Kaija
06 / 2023
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:tuni-202307057079
https://urn.fi/URN:NBN:fi:tuni-202307057079
Kuvaus
Peer reviewed
Tiivistelmä
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.
Kokoelmat
- TUNICRIS-julkaisut [18911]