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De novo and inherited pathogenic variants in KDM3B cause intellectual disability, short stature, and facial dysmorphism

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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.
Keywords
RUBINSTEIN-TAYBI SYNDROME, DEMETHYLASE KDM3B, MYELOID-LEUKEMIA, WEAVER SYNDROME, MUTATIONS, PROTEIN, INDIVIDUALS, GENETICS, DELETION, JMJD1C

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MLA
Diets, Illja J., et al. “De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism.” AMERICAN JOURNAL OF HUMAN GENETICS, vol. 104, no. 4, 2019, pp. 758–66.
APA
Diets, I. J., van der Donk, R., Baltrunaite, K., Waanders, E., Reijnders, M. R., Dingemans, A. J., … Jongmans, M. C. (2019). De novo and inherited pathogenic variants in KDM3B cause intellectual disability, short stature, and facial dysmorphism. AMERICAN JOURNAL OF HUMAN GENETICS, 104(4), 758–766.
Chicago author-date
Diets, Illja J, Roos van der Donk, Kristina Baltrunaite, Esmé Waanders, Margot RF Reijnders, Alexander JM Dingemans, Rolph Pfundt, et al. 2019. “De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism.” AMERICAN JOURNAL OF HUMAN GENETICS 104 (4): 758–66.
Chicago author-date (all authors)
Diets, Illja J, Roos van der Donk, Kristina Baltrunaite, Esmé Waanders, Margot RF Reijnders, Alexander JM 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 Gassen, Isabelle 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 BA de Vries, Vivian Hwa, Andrew Dauber, Jayne Y Hehir-Kwa, Roland P Kuiper, and Marjolijn CJ Jongmans. 2019. “De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism.” AMERICAN JOURNAL OF HUMAN GENETICS 104 (4): 758–766.
Vancouver
1.
Diets IJ, van der Donk R, Baltrunaite K, Waanders E, Reijnders MR, Dingemans AJ, et al. De novo and inherited pathogenic variants in KDM3B cause intellectual disability, short stature, and facial dysmorphism. AMERICAN JOURNAL OF HUMAN GENETICS. 2019;104(4):758–66.
IEEE
[1]
I. J. Diets et al., “De novo and inherited pathogenic variants in KDM3B cause intellectual disability, short stature, and facial dysmorphism,” AMERICAN JOURNAL OF HUMAN GENETICS, vol. 104, no. 4, pp. 758–766, 2019.
@article{8625174,
  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.},
  author       = {Diets, Illja J and van der Donk, Roos and Baltrunaite, Kristina and Waanders, Esmé and Reijnders, Margot RF and Dingemans, Alexander JM and Pfundt, Rolph and Vulto-van Silfhout, Anneke T and Wiel, Laurens and Gilissen, Christian and Thevenon, Julien and Perrin, Laurence and Afenjar, Alexandra and Nava, Caroline and Keren, Boris and Bartz, Sarah and Peri, Bethany and Beunders, Gea and Verbeek, Nienke and van Gassen, Koen and Thiffault, Isabelle and Cadieux-Dion, Maxime and Huerta-Saenz, Lina and Wagner, Matias and Konstantopoulou, Vassiliki and Vodopiutz, Julia and Griese, Matthias and Boel, Annekatrien and Callewaert, Bert and Brunner, Han G and Kleefstra, Tjitske and Hoogerbrugge, Nicoline and de Vries, Bert BA and Hwa, Vivian and Dauber, Andrew and Hehir-Kwa, Jayne Y and Kuiper, Roland P and Jongmans, Marjolijn CJ},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keywords     = {RUBINSTEIN-TAYBI SYNDROME,DEMETHYLASE KDM3B,MYELOID-LEUKEMIA,WEAVER SYNDROME,MUTATIONS,PROTEIN,INDIVIDUALS,GENETICS,DELETION,JMJD1C},
  language     = {eng},
  number       = {4},
  pages        = {758--766},
  title        = {De novo and inherited pathogenic variants in KDM3B cause intellectual disability, short stature, and facial dysmorphism},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2019.02.023},
  volume       = {104},
  year         = {2019},
}

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