Mutation Update for Kabuki Syndrome Genes<i>KMT2D</i>and<i>KDM6A</i>and Further Delineation of X-Linked Kabuki Syndrome Subtype 2

TLDR

Kabuki syndrome is a rare disorder characterized by a distinctive facial appearance, short stature, multiple organ malformations, and variable intellectual disability, with KMT2D mutations being the predominant cause and KDM6A mutations less frequent. The authors aim to provide an up‑to‑date summary of all reported KMT2D and KDM6A mutations, identify mutation hotspots, and outline strategies for molecular genetic testing. They screened 347 unpublished patients, discovering 12 novel KDM6A and 208 KMT2D mutations (132 novel), reported clinical data for 11 KS type 2 cases, and examined KDM6C in male KS patients. The study revealed numerous novel mutations, defined mutation hotspots, highlighted phenotype–genotype correlations and sex‑specific differences, and suggested a potential role for KDM6A in Kabuki‑like Turner syndrome.

Abstract

Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up-to-date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well-defined X-linked KS type 2, and comment on phenotype–genotype correlations as well as sex-specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki-like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.