Mutation Update for Kabuki Syndrome GenesKMT2DandKDM6Aand Further Delineation of X-Linked Kabuki Syndrome Subtype 2

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 Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel.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.

Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and <b><i>KDM6A</i></b> Haploinsufficiency

“…KDM6A is a lysine specific histone demethylase that controls tissue-specific expression of genes involved in development as well as the cell cycle [34–38]. Loss of function mutations of KDM6A which cause Kabuki Syndrome Type 2, KS2, are most often somatic mutations [18, 20, 22–25, 27]. Arnoux, et al, reported that hypoglycemia occurs in 11% of Kabuki Syndrome patients overall [39].…”

“…Arnoux, et al, reported that hypoglycemia occurs in 11% of Kabuki Syndrome patients overall [39]. Recent reports suggest that hypoglycemia may occur in a much higher proportion of patients with KS2 associated with KDM6A mutations [13, 20, 22, 26]. The mechanism by which haploinsufficiency for KDM6A causes hyperinsulinism in Kabuki Syndrome is not known, but has been suggested to involve disruption of epigenetic changes during pancreatic differentiation [28, 29].…”

Congenital Hypoglycemia Disorders: New Aspects of Etiology, Diagnosis, Treatment and Outcomes

“…After BWS, Kabuki syndrome is the second most common syndromic form of HI. Kabuki syndrome is caused by inactivating mutations in 2 genes: autosomal recessive mutations in KMT2D ( Lysine‐specific methyltransferase 2D ), which account for 70%‐75% of cases, and X‐linked mutations in KDM6A ( Lysine‐specific demethylase 6A ), which account for 1%‐9% of cases. These 2 genes encode a DNA methyltransferase and demethylase, respectively.…”

Holoprosencephaly in Kabuki syndrome

“…Heterozygous or hemizygous, pathogenic variants in either KMT2D (OMIM: 147920; 80% of cases) or KDM6A (OMIM: 300867; 8%), respectively, cause Kabuki syndrome (Banka et al, ; Bogershausen et al, ; Lederer et al, ; Miyake et al, ; Ng et al, ; Van Laarhoven et al, ). KMT2D encodes a H3K4 methyltransferase that associates with KDM6A, an H3K27 demethylase, and other proteins to form the activating signal co‐integrator 2 containing complex (ASCOM) responsible for chromatin regulation and transcription activation where loss of function leads to repressed transcription in a wide range of downstream genes (Demers, Chaturvedi, Ranish, et al, ; Van Laarhoven et al, ).…”