4.6 Article

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

Journal

GENETICS IN MEDICINE
Volume 23, Issue 7, Pages 1202-1210

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-021-01119-8

Keywords

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Funding

  1. CONICYT, Chile's National Commission for Scientific and Technological Research [72160007]
  2. Kabuki Research Fund at Manchester University NHS Foundation Trust [629396]
  3. Health Innovation Challenge Fund [HICF-1009-003]
  4. Wellcome Trust
  5. National Institute for Health Research through the Comprehensive Clinical Research Network, UK
  6. Louma G. Foundation
  7. AKABE (Belgian Kabuki association)
  8. AMED [JP20ek0109280, JP20dm0107090, JP20ek0109301, JP20ek0109348, JP20kk0205012]
  9. JSPS KAKENHI [JP17H01539, JP19H06321]
  10. Ministero della Salute [RC2020]

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The study revealed that clinical features common in KS2 patients include neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, intellectual disability, microcephaly, congenital heart anomalies, among others. Males were more likely to be born prematurely, have shorter stature, and experience severe developmental delay/ID.
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.

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