TY - JOUR
T1 - Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature
AU - van Jaarsveld, Richard H
AU - Reilly, Jack
AU - Cornips, Marie-Claire
AU - Hadders, Michael A
AU - Agolini, Emanuele
AU - Ahimaz, Priyanka
AU - Anyane-Yeboa, Kwame
AU - Bellanger, Severine Audebert
AU - van Binsbergen, Ellen
AU - van den Boogaard, Marie-Jose
AU - Brischoux-Boucher, Elise
AU - Caylor, Raymond C
AU - Ciolfi, Andrea
AU - van Essen, Ton A J
AU - Fontana, Paolo
AU - Hopman, Saskia
AU - Iascone, Maria
AU - Javier, Margaret M
AU - Kamsteeg, Erik-Jan
AU - Kerkhof, Jennifer
AU - Kido, Jun
AU - Kim, Hyung-Goo
AU - Kleefstra, Tjitske
AU - Lonardo, Fortunato
AU - Lai, Abbe
AU - Lev, Dorit
AU - Levy, Michael A
AU - Lewis, M E Suzanne
AU - Lichty, Angie
AU - Mannens, Marcel M A M
AU - Matsumoto, Naomichi
AU - Maya, Idit
AU - McConkey, Haley
AU - Megarbane, Andre
AU - Michaud, Vincent
AU - Miele, Evelina
AU - Niceta, Marcello
AU - Novelli, Antonio
AU - Onesimo, Roberta
AU - Pfundt, Rolph
AU - Popp, Bernt
AU - Prijoles, Eloise
AU - Relator, Raissa
AU - Redon, Sylvia
AU - Rots, Dmitrijs
AU - Rouault, Karen
AU - Saida, Ken
AU - Schieving, Jolanda
AU - Tartaglia, Marco
AU - Tenconi, Romano
AU - Uguen, Kevin
AU - Verbeek, Nienke
AU - Walsh, Christopher A
AU - Yosovich, Keren
AU - Yuskaitis, Christopher J
AU - Zampino, Giuseppe
AU - Sadikovic, Bekim
AU - Alders, Mariëlle
AU - Oegema, Renske
N1 - Funding Information:
The authors would like to thank all the involved patients and their families for contributing to this study. In addition, they thank Yohei Misumi and Koen van Gassen for their contribution to this study and the genome diagnostic laboratory at the UMC Utrecht for facilitating cohort collection and variant interpretation. This work was funded by the government of Canada through GenomeCanada and the Ontario Genomics Institute (OGI-188). N.M. is supported by Japan Agency for Medical Research and Development (AMED) (JP20ek0109486, JP21ek0109549, JP21cm0106503, and JP21ek0109493 to N. Matsumoto). B.P. is supported by the Deutsche Forschungsgemeinschaft (DFG) through grant PO2366/2–1. C.A.W. is supported by a grant from the National Institute of Neurological Disorders and Stroke (NINDS) (R01NS035129) and is an investigator at the Howard Hughes Medical Institute . M.T. is supported by the Italian Ministry of Health (5x1000_2019, RCR-2021-23671215, and RCR-2022-23682289 to M.T.). M.E.S.L. is supported by an Investigator Grant Award from B.C. Children’s Hospital Research Institute.
Funding Information:
The authors would like to thank all the involved patients and their families for contributing to this study. In addition, they thank Yohei Misumi and Koen van Gassen for their contribution to this study and the genome diagnostic laboratory at the UMC Utrecht for facilitating cohort collection and variant interpretation. This work was funded by the government of Canada through GenomeCanada and the Ontario Genomics Institute (OGI-188). N.M. is supported by Japan Agency for Medical Research and Development (AMED) (JP20ek0109486, JP21ek0109549, JP21cm0106503, and JP21ek0109493 to N. Matsumoto). B.P. is supported by the Deutsche Forschungsgemeinschaft (DFG) through grant PO2366/2–1. C.A.W. is supported by a grant from the National Institute of Neurological Disorders and Stroke (NINDS) (R01NS035129) and is an investigator at the Howard Hughes Medical Institute. M.T. is supported by the Italian Ministry of Health (5x1000_2019, RCR-2021-23671215, and RCR-2022-23682289 to M.T.). M.E.S.L. is supported by an Investigator Grant Award from B.C. Children's Hospital Research Institute. R.Oe. designed and coordinated the study. R.Oe. R.H.v.J. and M.-C.C. collected and analyzed clinical and genetic data. J.R. J.Ke. M.A.L. B.S. and M.A. were involved in creating the episignature. M.A.H. depicted the 3D domain structures. R.H.v.J. J.R. M.-C.C. and R.Oe. wrote the manuscript. R.H.v.J. J.R. M.-C.C. M.A.H. E.A. P.A. K.A.-Y. S.A.B. E.v.B. M.-J.v.d.B. E.B.-B. R.C. A.C. T.A.J.v.E. P.F. S.H. M.I. M.M.J. E.-J.K. J.Ke. J.Ki. H.-G.K. T.K. F.L. A.La. D.L. M.A.L. M.E.S.L. A.Li. M.M.A.M.M. N.M. I.M. H.M. A.M. V.M. E.M. M.N. A.N. R.On. R.P. B.P. E.P. R.R. S.R. D.R. K.R. K.S. J.S. M.T. R.T. K.U. N.V. C.A.W. K.Y. C.J.Y. G.Z. B.S. M.A. and R.Oe. contributed to the data generation or analysis and reviewed/edited the manuscript. In memoriam: Ton A.J. van Essen. This study was approved by the medical ethical committee installed by the University Medical Centre Utrecht (TCBIO 20/714, March 18, 2021). All individuals were included after informed consent forms, stating that they agree to participate in research efforts and publication of their clinical and genetic data and photos, for relevant cases, were signed and received by the respective institutions. Patient privacy was respected during the exchange of data among researchers and/or clinicians.
Publisher Copyright:
© 2022 The Authors
PY - 2023/1
Y1 - 2023/1
N2 - PURPOSE: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD.METHODS: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature.RESULTS: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism.CONCLUSION: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.
AB - PURPOSE: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD.METHODS: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature.RESULTS: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism.CONCLUSION: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.
KW - Human Genetics
KW - KDM2B
KW - MDEMs
KW - Methylation signatures
KW - Neurodevelopmental disorders
UR - http://www.scopus.com/inward/record.url?scp=85141320488&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2022.09.006
DO - 10.1016/j.gim.2022.09.006
M3 - Article
C2 - 36322151
SN - 1098-3600
VL - 25
SP - 49
EP - 62
JO - Genetics in medicine : official journal of the American College of Medical Genetics
JF - Genetics in medicine : official journal of the American College of Medical Genetics
IS - 1
ER -