Journal Article

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

Gill, Harinder, Mizuno, Seiji, Rieubland, Claudine, Fry, Andrew E., Suri, Mohnish, Rodgers, Jonathan, Johnson, Diana, Marchese, Antonia, Scalais, Emmanuel, Byler, Melissa, Bezuidenhout, Heidre, Bulk, Saskia, Brischoux-Boucher, Elise, Lachlan, Katherine, Akilapa, Rhoda, Brady, Angela F., Hurst, Jane, Lederer, Damien, Gershon, Eric, Dentici, Maria Lisa, Elmslie, Frances, McEntagart, Meriel, Sasaki, Erina, Banka, Siddharth, Lepri, Francesca Romana, Bjornsson, Hans T., Miyake, Noriko, Gnazzo, Maria, van der Burgt, Ineke, Digilio, Maria Cristina, Okamoto, Nobuhiko, Scurr, Ingrid, Matsumoto, Naomichi, Lemire, Edmond, Canham, Natalie, Bradley, Lisa, McGaughran, Julie, Brunner, Han, Julia, Sophie, Lebel, Robert Roger, Benoit, Valérie, Faundes, Víctor, Goh, Stephanie, Cody, Declan

2021

Overview

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.

• Publisher: Elsevier Inc,Nature Publishing Group US,Elsevier Limited,Nature Publishing Group
• Subject: Abnormalities, Multiple / Biomedical and Life Sciences / Biomedicine / DNA-Binding Proteins - genetics / Face - abnormalities / Female / Genetic Association Studies / Genetics / Genetics & genetic processes / Genotype & phenotype / Génétique & processus génétiques / Hematologic Diseases / Histone Demethylases - genetics / Human Genetics / Humans / Infant, Newborn / Intellectual Disability - genetics / Laboratory Medicine / Life Sciences / Male / Neoplasm Proteins - genetics / Phenotype / Physical growth / Sciences du vivant / Sex Characteristics / Vestibular Diseases