Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2
Bjornsson, Hans T.
Brady, Angela F.
Dentici, Maria Lisa
Digilio, Maria Cristina
Fry, Andrew E.
Lebel, Robert Roger
Lepri, Francesca Romana
van der Burgt, Ineke
Banka, Siddharth; orcid: 0000-0002-8527-2210; email: firstname.lastname@example.org
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AbstractAbstract: 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.
CitationGenetics in Medicine, volume 23, issue 7, page 1202-1210
PublisherNature Publishing Group US
DescriptionFrom Springer Nature via Jisc Publications Router
History: received 2020-10-09, rev-recd 2021-02-03, accepted 2021-02-03, registration 2021-02-03, pub-electronic 2021-03-05, online 2021-03-05, pub-print 2021-07
Publication status: Published
Funder: Kabuki Research Fund; doi: https://doi.org/10.13039/; Grant(s): 629396