De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism
Illja Diets
(1)
,
Roos van der Donk
(1)
,
Kristina Baltrunaite
(2, 3)
,
Esmé Waanders
(4)
,
Margot Reijnders
,
Alexander Dingemans
(1)
,
Rolph Pfundt
(1)
,
Anneke Vulto-van Silfhout
(1)
,
Laurens Wiel
(1, 5)
,
Christian Gilissen
(1, 5)
,
Julien Thevenon
(6)
,
Laurence Perrin
(6)
,
Alexandra Afenjar
(7)
,
Caroline Nava
(7, 8)
,
Boris Keren
(7)
,
Sarah Bartz
(9)
,
Bethany Peri
(9)
,
Gea Beunders
(10)
,
Nienke Verbeek
(11)
,
Koen van Gassen
(11)
,
Isabelle Thiffault
(12)
,
Maxime Cadieux-Dion
(12)
,
Lina Huerta-Saenz
(12)
,
Matias Wagner
(13, 14)
,
Vassiliki Konstantopoulou
(15)
,
Julia Vodopiutz
(15)
,
Matthias Griese
(16)
,
Annekatrien Boel
(17)
,
Bert Callewaert
(17)
,
Han Brunner
(1, 18, 19)
,
Tjitske Kleefstra
(1, 18, 19)
,
Nicoline Hoogerbrugge
(1)
,
Bert de Vries
(1)
,
Vivian Hwa
(2, 3)
,
Andrew Dauber
(2, 20)
,
Jayne Hehir-Kwa
(4)
,
Roland Kuiper
(1)
,
Marjolijn Jongmans
(1, 4, 11)
1
Radboud University Medical Center [Nijmegen]
2 Cincinnati Children's Hospital Medical Center
3 University of Cincinnati College of Medicine
4 Princess Máxima Center for Pediatric Oncology
5 Radboud Institute for Molecular Life Sciences [Nijmegen, the Netherlands]
6 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
7 GRC 19 ConCer-LD - Pathologies Congénitales du Cervelet-LeucoDystrophies
8 ICM - Institut du Cerveau = Paris Brain Institute
9 Children’s Hospital Colorado
10 VU University Medical Center [Amsterdam]
11 UMCU - University Medical Center [Utrecht]
12 Children's Mercy Hospital [Kansas City]
13 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
14 HMGU - Helmholtz Zentrum München = German Research Center for Environmental Health
15 Medizinische Universität Wien = Medical University of Vienna
16 University-Hospital Munich-Großhadern [München]
17 Ghent University Hospital
18 Radboud University [Nijmegen]
19 MUMC - Maastricht University Medical Centre
20 Children’s National Health System [Washington, DC, USA]
2 Cincinnati Children's Hospital Medical Center
3 University of Cincinnati College of Medicine
4 Princess Máxima Center for Pediatric Oncology
5 Radboud Institute for Molecular Life Sciences [Nijmegen, the Netherlands]
6 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
7 GRC 19 ConCer-LD - Pathologies Congénitales du Cervelet-LeucoDystrophies
8 ICM - Institut du Cerveau = Paris Brain Institute
9 Children’s Hospital Colorado
10 VU University Medical Center [Amsterdam]
11 UMCU - University Medical Center [Utrecht]
12 Children's Mercy Hospital [Kansas City]
13 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
14 HMGU - Helmholtz Zentrum München = German Research Center for Environmental Health
15 Medizinische Universität Wien = Medical University of Vienna
16 University-Hospital Munich-Großhadern [München]
17 Ghent University Hospital
18 Radboud University [Nijmegen]
19 MUMC - Maastricht University Medical Centre
20 Children’s National Health System [Washington, DC, USA]
Illja Diets
- Fonction : Auteur
- PersonId : 1378774
- ORCID : 0000-0001-7603-8898
Margot Reijnders
- Fonction : Auteur
Résumé
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.