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

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 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.

SUBMITTER: Diets IJ 

PROVIDER: S-EPMC6451728 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

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

American journal of human genetics 20190328 4

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.  ...[more]

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