Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2

Genet Med. 2021 Jul;23(7):1202-1210. doi: 10.1038/s41436-021-01119-8. Epub 2021 Mar 5.


Purpose: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood.

Methods: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed.

Results: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID.

Conclusion: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple
  • DNA-Binding Proteins / genetics
  • Face / abnormalities
  • Female
  • Genetic Association Studies
  • Hematologic Diseases
  • Histone Demethylases / genetics*
  • Humans
  • Infant, Newborn
  • Intellectual Disability* / genetics
  • Male
  • Neoplasm Proteins / genetics
  • Phenotype
  • Sex Characteristics*
  • Vestibular Diseases


  • DNA-Binding Proteins
  • Neoplasm Proteins
  • Histone Demethylases
  • KDM6A protein, human

Supplementary concepts

  • Kabuki syndrome