Novel KDM6A (UTX) mutations and a clinical and molecular review of the X‐linked Kabuki syndrome (KS2)

Abstract

We describe seven patients with KDM6A (located on Xp11.3 and encodes UTX) mutations, a rare cause of Kabuki syndrome (KS2, MIM 300867) and report, for the first time, germ-line missense and splice-site mutations in the gene. We demonstrate that less than 5% cases of Kabuki syndrome are due to KDM6A mutations. Our work shows that similar to the commoner Type 1 Kabuki syndrome (KS1, MIM 147920) caused by KMT2D (previously called MLL2) mutations, KS2 patients are characterized by hypotonia and feeding difficulties during infancy and poor postnatal growth and short stature. Unlike KS1, developmental delay and learning disability are generally moderate-severe in boys but mild-moderate in girls with KS2. Some girls may have a normal developmental profile. Speech and cognition tend to be more severely affected than motor development. Increased susceptibility to infections, join laxity, heart, dental and ophthalmological anomalies are common. Hypoglycaemia is more common in KS2 than in KS1. Facial dysmorphism with KDM6A mutations is variable and diagnosis on facial gestalt alone may be difficult in some patients. Hypertrichosis, long halluces and large central incisors may be useful clues to an underlying KDM6A mutation in some 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].…”

Neurobehavioral features in individuals with Kabuki syndrome

“…() who reported mutations in KMT2D (MIM#602113) as the major genetic cause of the disorder. More recently, deletions or mutations of KDM6A (MIM#300128) have been reported to underlie a small proportion of affected individuals (Banka et al., ; Bögershausen, Bruford, & Wollnik, ; Lederer et al., ).…”

Kabuki syndrome

“…A small number of patients have also been reported in whom Kabuki syndrome is attributed to mosaic small or whole KMT2D gene deletions, or intragenic multi-exon duplication (Banka et al, 2013). Causative missense and splice-site mutations in, and deletions involving, the KDM6A (lysine-specific demethylase 6A) gene, located at Xp11.3, have been infrequently reported (Lederer et al, 2012;Miyake et al, 2013;Cheon et al, 2014;Banka et al, 2015). KMT2D and KDM6A are trithorax proteins which interact to modulate histone lysine methylation, thereby epigenetically regulating gene expression (Kim et al, 2014;Adam, 2015).…”