American journal of human genetics · 2023

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

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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, Davis-Keppen Laura, Platt Dylan, Royer Erin, Leeuwen Lisette, Sinnema Margje, Stegmann Alexander P A, Stumpel Constance T R M, Tiller George E, Bosch Daniëlle G M, Potgieter Stephanus T, Joss Shelagh, Splitt Miranda, Holden Simon, Prapa Matina, Foulds Nicola, Douzgou Sofia, Puura Kaija, Waltes Regina, Chiocchetti Andreas G, Freitag Christine M, Satterstrom F Kyle, De Rubeis Silvia, Buxbaum Joseph, Gelb Bruce D, Branko Aleksic, Kushima Itaru, Howe Jennifer, Scherer Stephen W, Arado Alessia, Baldo Chiara, Patat Olivier, Bénédicte Demeer, Lopergolo Diego, Santorelli Filippo M, Haack Tobias B, Dufke Andreas, Bertrand Miriam, Falb Ruth J, Rieß Angelika, Krieg Peter, Spranger Stephanie, Bedeschi Maria Francesca, Iascone Maria, Josephi-Taylor Sarah, Roscioli Tony, Buckley Michael F, Liebelt Jan, Dagli Aditi I, Aten Emmelien, Hurst Anna C E, Hicks Alesha, Suri Mohnish, Aliu Ermal, Naik Sunil, Sidlow Richard, Coursimault Juliette, Nicolas Gaël, Küpper Hanna, Petit Florence, Ibrahim Veyan, Top Deniz, Di Cara Francesca, Genomics England Research Consortium, Louie Raymond J, Stolerman Elliot, Brunner Han G, Vissers Lisenka E L M, Kramer Jamie M, Kleefstra Tjitske

Аннотация

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.

Предметные рубрики MeSH

Humans Animals Facies Neurodevelopmental Disorders Phenotype Drosophila Intellectual Disability Jumonji Domain-Containing Histone Demethylases

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

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH