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

Abstract

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.

DNA methylation episignature testing improves molecular diagnosis of Mendelian chromatinopathies

“…GDB836 is heterozygous for a de novo c.3743A>G; p.(Gln1248Arg) variant located within the JmjC functional domain of KDM6A. 19 and with confirmed inheritance, is reported as likely pathogenetic to further support the EpiSign result.…”

“…18 Both individuals presented with a history of infantile hypotonia, developmental delay, intellectual disability, and typical Kabuki syndrome dysmorphic features, leading to a definite clinical diagnosis. From a molecular point of view, GDB502 carries a de novo hemizygous c.2933A>T; p.(Asp980Val) variant located outside any known KDM6A domain 19 and is reported as a VUS based on ACMG/AMP guidelines. GDB836 is heterozygous for a de novo c.3743A>G; p.(Gln1248Arg) variant located within the JmjC functional domain of KDM6A.…”

Sex-biased and parental allele-specific gene regulation by KDM6A

“…Our study also provides evidence of a role of KDM6A in the regulation of sex-biased gene expression, which could have broad implications in understanding sex differences. Our CRISPR deletions encompass known pathogenic mutations seen in Kabuki syndrome, including loss of exons 1–2 [ 63 ]. Thus, results from this study may reveal therapeutic targets for individuals with Kabuki syndrome.…”

A homozygous frame‐shift variant in PROSER1 is associated with developmental delay, hypotonia, genitourinary malformations, and distinctive facial features

“…Furthermore, many other members of the enhancer‐associated KMT2C/KMT2D complexes have been linked to other neurodevelopmental disorders including KMT2A (Wiedemann–Steiner syndrome), 10 KMT2B (childhood‐onset dystonia), 11 KMT2C (Kleefstra syndrome 2), 12 KMT2D (Kabuki syndrome 1), 13 KDM6A (Kabuki syndrome 2), 14 and TET3 (Beck–Fahrner syndrome) 15 …”