MLL2 and KDM6A mutations in patients with Kabuki syndrome

Abstract

Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.

A novel de novo mutation involving the MLL2 gene in a Kabuki syndrome patient presenting with seizures

“…Since then there have been several reports of patient series describing MLL2 mutations in 52-76% of the cases [9][10][11][22][23][24] . MLL2 is a 36.3 kb gene located on chromosome 12q13.12 21 , and encodes a protein of 5537 amino acids which is located in a multiprotein complex.…”

“…Exon 39 contains several regions that encode long polyglutamine tracts suggesting the presence of a mutational hot spot, which could explain the high rate of mutations in this exon. About 300 mutations have been demonstrated in MLL2 gene so far 11 . The mutation identified in the present patient which leads to a truncated protein and thus most likely to haploinsufficiency of MLL2 has not yet been described in the literature.…”

“…Although it has been first described in the Japanese population, there have been numerous reports from other ethnic groups 4 , including patients of Turkish descent [5][6][7][8] . It generally occurs because of a "de novo" mutation, involving either the myeloid/ lymphoid or mixed-lineage leukemia 2 (MLL2) gene 9 or less frequently the lysine (K)-specific demethylase 6A (KDM6A) gene 10,11 . Here we report on a Turkish KS patient with epilepsy carrying a novel heterozygous mutation in the MLL2 gene.…”

Kabuki Syndrome with Multiple Associated Surgical Anomalies (Cleft Palate, Anorectal Anomaly and Diaphragmatic Hernia): Case Report and Literature Review

“…The gene identified as responsible are MLL2 3) and KDM6A 3) , and a molecular genetic test for MLL2 is clinically available. The MLL2 gene mutation has been found in 61.7% and the KDM6A gene mutation in 6.2% of patients clinically diagnosed as having KS 7) . Because MLL2 and KDM6A are histone methyltransferases for H3K4 and H3K27, respectively, KS appears to be related to aberrant histone methylation.…”

“…The associated malformations observed in our case were cleft palate, anorectal malformation, and diaphragmatic hernia (i.e., Morgagni hernia). The prevalence of a combination of KS and cleft palate is high, at 35% among the patients with KS 4) , half of those with this combination present with an MLL2 gene mutation 7) . A combination of KS and anorectal malformation has been reported in 9 patients [8][9][10][11][12] including ours, as shown in Table 1, and the prevalence of this combination is reported to range from 5% to 25% 4)13)14)…”