De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism
Diets, Illja J.; van der Donk, Roos; Baltrunaite, Kristina; Waanders, Esmé; Reijnders, Margot R.F.; Dingemans, Alexander J.M.; Pfundt, Rolph; Vulto-van Silfhout, Anneke T.; Wiel, Laurens; Gilissen, Christian; Thevenon, Julien; Perrin, Laurence; Afenjar, Alexandra; Nava, Caroline; Keren, Boris; Bartz, Sarah; Peri, Bethany; Beunders, Gea; Verbeek, Nienke; van Gassen, Koen; Thiffault, Isabelle; Cadieux-Dion, Maxime; Huerta-Saenz, Lina; Wagner, Matias; Konstantopoulou, Vassiliki; Vodopiutz, Julia; Griese, Matthias; Boel, Annekatrien; Callewaert, Bert; Brunner, Han G.; Kleefstra, Tjitske; Hoogerbrugge, Nicoline; de Vries, Bert B.A.; Hwa, Vivian; Dauber, Andrew; Hehir-Kwa, Jayne Y.; Kuiper, Roland P.; Jongmans, Marjolijn C.J.
(2019) American Journal of Human Genetics, volume 104, issue 4, pp. 758 - 766
(Article)
Abstract
By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding
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difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.
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Keywords: cancer predisposition, developmental delay, facial recognition, intellectual disability, KDM3B, leukemia, lymphoma, short stature, Genetics(clinical), Genetics, Research Support, Non-U.S. Gov't, Journal Article, Research Support, N.I.H., Extramural
ISSN: 0002-9297
Publisher: Cell Press
Note: Funding Information: I.J.D. was funded by the KiKa Foundation (project number 127 ). V.H. is funded by the National Institutes of Health (NIH) NICHHD R01 HD078592 . E.W. was funded by the Dutch Cancer Society ( KUN2012-5366 ). B.C. is a senior clinical investigator of the Fund for Scientific Research, Flanders . This work was partly supported by a research grant from the Research Foundation, Flanders : G028415N to B.C.. We thank Carol Saunders and Laura Cross for their contributions. Funding Information: I.J.D. was funded by the KiKa Foundation (project number 127). V.H. is funded by the National Institutes of Health (NIH) NICHHD R01 HD078592. E.W. was funded by the Dutch Cancer Society (KUN2012-5366). B.C. is a senior clinical investigator of the Fund for Scientific Research, Flanders. This work was partly supported by a research grant from the Research Foundation, Flanders: G028415N to B.C. We thank Carol Saunders and Laura Cross for their contributions. Publisher Copyright: © 2019 American Society of Human Genetics
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