De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

Illja J Diets, Roos van der Donk, Kristina Baltrunaite, Esmé Waanders, Margot R F Reijnders, Alexander J M Dingemans, Rolph Pfundt, Anneke T Vulto-van Silfhout, Laurens Wiel, Christian Gilissen, Julien Thevenon, Laurence Perrin, Alexandra Afenjar, Caroline Nava, Boris Keren, Sarah Bartz, Bethany Peri, Gea Beunders, Nienke Verbeek, Koen van GassenIsabelle Thiffault, Maxime Cadieux-Dion, Lina Huerta-Saenz, Matias Wagner, Vassiliki Konstantopoulou, Julia Vodopiutz, Matthias Griese, Annekatrien Boel, Bert Callewaert, Han G Brunner, Tjitske Kleefstra, Nicoline Hoogerbrugge, Bert B A de Vries, Vivian Hwa, Andrew Dauber, Jayne Y Hehir-Kwa, Roland Kuiper, Marjolijn Jongmans

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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 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.

Originele taal-2Engels
Pagina's (van-tot)758-766
Aantal pagina's9
TijdschriftAmerican journal of human genetics
Volume104
Nummer van het tijdschrift4
DOI's
StatusGepubliceerd - 4 apr. 2019

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