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. Epub 2019 Mar 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Height
  • Child
  • Craniofacial Abnormalities / genetics*
  • Developmental Disabilities / genetics*
  • Dwarfism / genetics*
  • Exome
  • Face
  • Female
  • Genetic Association Studies
  • Genetic Variation*
  • Germ-Line Mutation
  • Haploinsufficiency
  • Histones / chemistry
  • Humans
  • Intellectual Disability / genetics*
  • Jumonji Domain-Containing Histone Demethylases / genetics*
  • Male
  • Musculoskeletal Abnormalities / genetics*
  • Mutation, Missense
  • Phenotype


  • Histones
  • Jumonji Domain-Containing Histone Demethylases
  • KDM3B protein, human