Dataset Information

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

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.

SUBMITTER: Rots D

PROVIDER: S-EPMC10257005 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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

Rots Dmitrijs D Jakub Taryn E TE Keung Crystal C Jackson Adam A Banka Siddharth S Pfundt Rolph R de Vries Bert B A BBA van Jaarsveld Richard H RH Hopman Saskia M J SMJ van Binsbergen Ellen E Valenzuela Irene I Hempel Maja M Bierhals Tatjana T Kortüm Fanny F Lecoquierre Francois F Goldenberg Alice A Hertz Jens Michael JM Andersen Charlotte Brasch CB Kibæk Maria M Prijoles Eloise J EJ Stevenson Roger E RE Everman David B DB Patterson Wesley G WG Meng Linyan L Gijavanekar Charul C De Dios Karl K Lakhani Shenela S Levy Tess T Wagner Matias M Wieczorek Dagmar D Benke Paul J PJ Lopez Garcia María Soledad MS Perrier Renee R Sousa Sergio B SB Almeida Pedro M PM Simões Maria José MJ Isidor Bertrand B Deb Wallid W Schmanski Andrew A AA Abdul-Rahman Omar O Philippe Christophe C Bruel Ange-Line AL Faivre Laurence L Vitobello Antonio A Thauvin Christel C Smits Jeroen J JJ Garavelli Livia L Caraffi Stefano G SG Peluso Francesca F Davis-Keppen Laura L Platt Dylan D Royer Erin E Leeuwen Lisette L Sinnema Margje M Stegmann Alexander P A APA Stumpel Constance T R M CTRM Tiller George E GE Bosch Daniëlle G M DGM Potgieter Stephanus T ST Joss Shelagh S Splitt Miranda M Holden Simon S Prapa Matina M Foulds Nicola N Douzgou Sofia S Puura Kaija K Waltes Regina R Chiocchetti Andreas G AG Freitag Christine M CM Satterstrom F Kyle FK De Rubeis Silvia S Buxbaum Joseph J Gelb Bruce D BD Branko Aleksic A Kushima Itaru I Howe Jennifer J Scherer Stephen W SW Arado Alessia A Baldo Chiara C Patat Olivier O Bénédicte Demeer D Lopergolo Diego D Santorelli Filippo M FM Haack Tobias B TB Dufke Andreas A Bertrand Miriam M Falb Ruth J RJ Rieß Angelika A Krieg Peter P Spranger Stephanie S Bedeschi Maria Francesca MF Iascone Maria M Josephi-Taylor Sarah S Roscioli Tony T Buckley Michael F MF Liebelt Jan J Dagli Aditi I AI Aten Emmelien E Hurst Anna C E ACE Hicks Alesha A Suri Mohnish M Aliu Ermal E Naik Sunil S Sidlow Richard R Coursimault Juliette J Nicolas Gaël G Küpper Hanna H Petit Florence F Ibrahim Veyan V Top Deniz D Di Cara Francesca F Louie Raymond J RJ Stolerman Elliot E Brunner Han G HG Vissers Lisenka E L M LELM Kramer Jamie M JM Kleefstra Tjitske T

American journal of human genetics 20230516 6

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 ...[more]

PMID: 37196654

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Project description:BackgroundThe effects of prenatal alcohol exposure (PAE) are conceptualized as fetal alcohol spectrum disorder, with fetal alcohol syndrome (FAS) as the most severe. Many find it more difficult to characterize behavioral and cognitive effects of exposure on the central nervous system when physical signs are not present. In the current study, an operational definition of alcohol-related neurodevelopmental disorder (ARND) was examined to determine its usefulness in discrimination of children classified as ARND based on behavior (ARND/B) and cognition (ARND/C) from children in 4 contrast groups: (i) children exposed to study-defined "risky drinking"; (ii) children with any reported PAE; (iii) children classified as "Higher Risk" for developmental problems; and (iv) children classified as "Lower Risk."MethodsA total of 1,842 children seen as part of a surveillance study (J Am Med Assoc, 319, 2018, 474) were evaluated for alcohol exposure and physical characteristics of FAS, and completed neurodevelopmental testing. Ninety-one were identified as either ARND/B or ARND/C and contrasted with other groups to further identify distinguishing patterns. Multinomial logistic regression (MLR) was used to examine the accuracy of classification and to identify factors contributing to such classification.ResultsChildren described as ARND/C were distinct from other groups based on cognition and behavior as well as demographic factors (e.g., age, race, SES), child characteristics (e.g., gestational age; sex), and other drug exposures, while those described as ARND/B differed only on behavior and other drug exposures. MLR models successfully discriminated ARND groups from children in other groups with accuracy ranging from 79% (Higher Risk) to 86.7% (Low Risk).ConclusionsARND has been a subject of debate. This analysis suggests the effects of alcohol on behavior and cognition even in the absence of the characteristic facial features and growth deficiency that can be identified. The results also indicate that it may be possible to distinguish such children from those in other high-risk groups.

Dataset Information

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

Publications

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

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