De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism PMID: 30929739

RQC and Longevity Regulation

2026-09-03

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

Am J Hum Genet. 2019 Apr 4;104(4):758-766. doi: 10.1016/j.ajhg.2019.02.023.

Illja J Diets ¹ , Roos van der Donk ² , Kristina Baltrunaite ³ , Esmé Waanders ⁴ , Margot R F Reijnders ⁵ , Alexander J M Dingemans ¹ , Rolph Pfundt ¹ , Anneke T Vulto-van Silfhout ¹ , Laurens Wiel ⁶ , Christian Gilissen ⁶ , Julien Thevenon ⁷ , Laurence Perrin ⁸ , Alexandra Afenjar ⁹ , Caroline Nava ¹⁰ , Boris Keren ¹¹ , Sarah Bartz ¹² , Bethany Peri ¹² , Gea Beunders ¹³ , Nienke Verbeek ¹⁴ , Koen van Gassen ¹⁴ , Isabelle Thiffault ¹⁵ , Maxime Cadieux-Dion ¹⁶ , Lina Huerta-Saenz ¹⁷ , Matias Wagner ¹⁸ , Vassiliki Konstantopoulou ¹⁹ , Julia Vodopiutz ¹⁹ , Matthias Griese ²⁰ , Annekatrien Boel ²¹ , Bert Callewaert ²¹ , Han G Brunner ²² , Tjitske Kleefstra ²³ , Nicoline Hoogerbrugge ¹ , Bert B A de Vries ¹ , Vivian Hwa ³ , Andrew Dauber ²⁴ , Jayne Y Hehir-Kwa ⁴ , Roland P Kuiper ² , Marjolijn C J Jongmans ²⁵

Affiliations

1. Department of Human Genetics, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
2. Department of Human Genetics, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands; Princess Máxima Center for Pediatric Oncology, 3584CS Utrecht, the Netherlands.
3. Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
4. Princess Máxima Center for Pediatric Oncology, 3584CS Utrecht, the Netherlands.
5. Department of Human Genetics, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, 6229HX Maastricht, the Netherlands.
6. Department of Human Genetics, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands; Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
7. Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, 21079 Dijon, France; Equipe Génétique des Anomalies du Développement, Université de Bourgogne-France Comté, 21070 Dijon, France.
8. Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, 21079 Dijon, France.
9. APHP, Département de Génétique et Embryologie Médicale, Centre de Référence Déficiences Intellectuelles de Causes Rares, GRC n°19, ConCer-LD, Hôpital Armand Trousseau, 75012 Paris, France.
10. APHP, Hôpital Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France; Sorbonne Universités, Institut du Cerveau et de la Moelle épinière, ICM, Institut National de la Santé et de la Recherche Médicale U1127, Centre National de la Recherche Scientifique UMR 7225, 75013, Paris, France.
11. APHP, Hôpital Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France.
12. Division of Endocrinology, Children's Hospital of Colorado, Aurora, CO 80045, USA.
13. Department of Clinical Genetics, VU University Medical Center, 1081HV Amsterdam, the Netherlands.
14. Department of Genetics, University Medical Center Utrecht, 3508AB Utrecht, the Netherlands.
15. Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 66211, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO 66211, USA; University of Missouri, Kansas City School of Medicine, Kansas City, MO 66211, USA.
16. Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 66211, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO 66211, USA.
17. Children's Mercy Hospital, Kansas City, MO 66211, USA; Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Penn State Hershey Children's Hospital, Hershey, PA 17033, USA.
18. Institute of Human Genetics, Technische Universität München, 80333 Munich, Germany; Institute for Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute for Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
19. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria.
20. Dr. von Hauner Children's Hospital, Division of Pediatric Pneumology, University Hospital Munich, German Center for Lung Research, 80333 Munich, Germany.
21. Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
22. Department of Human Genetics, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, 6525GA Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202AZ Maastricht, the Netherlands.
23. Department of Human Genetics, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, 6525GA Nijmegen, the Netherlands.
24. Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Endocrinology, Children's National Health System, Washington, DC 20010, USA.
25. Department of Human Genetics, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands; Princess Máxima Center for Pediatric Oncology, 3584CS Utrecht, the Netherlands; Department of Genetics, University Medical Center Utrecht, 3508AB Utrecht, the Netherlands. Electronic address: [email protected].

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

KDM3B; cancer predisposition; developmental delay; facial recognition; intellectual disability; leukemia; lymphoma; short stature.