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 Gassen & 18 others 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 B. A. de Vries, Vivian Hwa, Andrew Dauber, Jayne Y. Hehir-Kwa, Roland P. Kuiper, Marjolijn C. J. Jongmans

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)758-766
JournalAmerican journal of human genetics
Volume104
Issue number4
DOIs
Publication statusPublished - 2019

Cite this

Diets, I. J., van der Donk, R., Baltrunaite, K., Waanders, E., Reijnders, M. R. F., Dingemans, A. J. M., ... Jongmans, M. C. J. (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. https://doi.org/10.1016/j.ajhg.2019.02.023
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. / De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism. In: American journal of human genetics. 2019 ; Vol. 104, No. 4. pp. 758-766.
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title = "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.",
author = "Diets, {Illja J.} and {van der Donk}, Roos and Kristina Baltrunaite and Esm{\'e} Waanders and Reijnders, {Margot R. F.} and Dingemans, {Alexander J. M.} and Rolph Pfundt and {Vulto-van Silfhout}, {Anneke T.} and Laurens Wiel and Christian Gilissen and Julien Thevenon and Laurence Perrin and Alexandra Afenjar and Caroline Nava and Boris Keren and Sarah Bartz and Bethany Peri and Gea Beunders and Nienke Verbeek and {van Gassen}, Koen and Isabelle Thiffault and Maxime Cadieux-Dion and Lina Huerta-Saenz and Matias Wagner and Vassiliki Konstantopoulou and Julia Vodopiutz and Matthias Griese and Annekatrien Boel and Bert Callewaert and Brunner, {Han G.} and Tjitske Kleefstra and Nicoline Hoogerbrugge and {de Vries}, {Bert B. A.} and Vivian Hwa and Andrew Dauber and Hehir-Kwa, {Jayne Y.} and Kuiper, {Roland P.} and Jongmans, {Marjolijn C. J.}",
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Diets, IJ, van der Donk, R, Baltrunaite, K, Waanders, E, Reijnders, MRF, Dingemans, AJM, Pfundt, R, Vulto-van Silfhout, AT, Wiel, L, Gilissen, C, Thevenon, J, Perrin, L, Afenjar, A, Nava, C, Keren, B, Bartz, S, Peri, B, Beunders, G, Verbeek, N, van Gassen, K, Thiffault, I, Cadieux-Dion, M, Huerta-Saenz, L, Wagner, M, Konstantopoulou, V, Vodopiutz, J, Griese, M, Boel, A, Callewaert, B, Brunner, HG, Kleefstra, T, Hoogerbrugge, N, de Vries, BBA, Hwa, V, Dauber, A, Hehir-Kwa, JY, Kuiper, RP & Jongmans, MCJ 2019, '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. https://doi.org/10.1016/j.ajhg.2019.02.023

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.

In: American journal of human genetics, Vol. 104, No. 4, 2019, p. 758-766.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

AU - Diets, Illja J.

AU - van der Donk, Roos

AU - Baltrunaite, Kristina

AU - Waanders, Esmé

AU - Reijnders, Margot R. F.

AU - Dingemans, Alexander J. M.

AU - Pfundt, Rolph

AU - Vulto-van Silfhout, Anneke T.

AU - Wiel, Laurens

AU - Gilissen, Christian

AU - Thevenon, Julien

AU - Perrin, Laurence

AU - Afenjar, Alexandra

AU - Nava, Caroline

AU - Keren, Boris

AU - Bartz, Sarah

AU - Peri, Bethany

AU - Beunders, Gea

AU - Verbeek, Nienke

AU - van Gassen, Koen

AU - Thiffault, Isabelle

AU - Cadieux-Dion, Maxime

AU - Huerta-Saenz, Lina

AU - Wagner, Matias

AU - Konstantopoulou, Vassiliki

AU - Vodopiutz, Julia

AU - Griese, Matthias

AU - Boel, Annekatrien

AU - Callewaert, Bert

AU - Brunner, Han G.

AU - Kleefstra, Tjitske

AU - Hoogerbrugge, Nicoline

AU - de Vries, Bert B. A.

AU - Hwa, Vivian

AU - Dauber, Andrew

AU - Hehir-Kwa, Jayne Y.

AU - Kuiper, Roland P.

AU - Jongmans, Marjolijn C. J.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85063682658&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/30929739

U2 - 10.1016/j.ajhg.2019.02.023

DO - 10.1016/j.ajhg.2019.02.023

M3 - Article

VL - 104

SP - 758

EP - 766

JO - American journal of human genetics

JF - American journal of human genetics

SN - 0002-9297

IS - 4

ER -