Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2
Víctor Faùndes, Stephanie Goh, Rhoda Akilapa, Heidre Bezuidenhout, Hans T. Björnsson, Lisa Bradley, Angela F. Brady, Elise Brischoux‐Boucher, Han G. Brunner, Saskia Bulk, Natalie Canham, Declan Cody, Maria Lisa Dentici, M. Cristina Digilio, Frances Elmslie, Andrew E. Fry, Harinder Gill, Jane A. Hurst, Diana Johnson, Sophie Julia, Katherine Lachlan, Robert Roger Lebel, Melissa Byler, Eric Gershon, Edmond G. Lemire, Maria Gnazzo, Francesca Romana Lepri, Antonia Marchèse, Meriel McEntagart, Julie McGaughran, Seiji Mizuno, Nobuhiko Okamoto, Claudine Rieubland, Jonathan Rodgers, Erina Sasaki, Emmanuel Scalais, Ingrid Scurr, Mohnish Suri, Ineke van der Burgt, Naomichi Matsumoto, Noriko Miyake, Valérie Benoît, Damien Lederer, Siddharth Banka
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.