Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.
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
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
09
10
2020
accepted:
03
02
2021
revised:
03
02
2021
pubmed:
7
3
2021
medline:
13
8
2021
entrez:
6
3
2021
Statut:
ppublish
Résumé
The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood. Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed. 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. 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.
Identifiants
pubmed: 33674768
doi: 10.1038/s41436-021-01119-8
pii: S1098-3600(21)05027-9
pmc: PMC8257478
doi:
Substances chimiques
DNA-Binding Proteins
0
Neoplasm Proteins
0
Histone Demethylases
EC 1.14.11.-
KDM6A protein, human
EC 1.14.11.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1202-1210Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
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