How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum

Abstract

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.

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.…”

“…The MLL2 gene is comprised of 54 exons and its mutations lead to loss of protein function and therefore repressed transcription of a variety of developmental genes, thus causing multiple organ involvement and characteristic phenotype of the syndrome. Mutations can be observed throughout the gene, however, a great majority of them are located in exons 39 and 48 9,23 . Most mutations of the gene are nonsense, leading to formation of a truncated protein.…”

“…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.…”

Descrição de uma forma autossômica dominante de síndrome de Kabuki por mutação no gene <i>MLL2</i>

“…3,7,8 A principal característica dos indivíduos com SK é a presença dos dismorfismos faciais característicos, 3,6 tal como observado nos três casos descritos neste artigo. Apesar de a identificação do gene MLL2 em doentes com SK ser recente, alguns estudos sugerem que mutações nesse gene associam-se mais frequentemente a características faciais clássicas da síndrome, 8,12 bem como a uma maior incidência de baixa estatura, 13 de dificuldades alimentares e de luxações articulares, 14 achados também presentes nos casos descritos. Perante essa mutação, estão também descritas frequências significativamente superiores de anomalias renais, 12 fendas labio-alvéolo-palatinas e telarca precoce.…”

Epigenetics, Autism Spectrum, and Neurodevelopmental Disorders

“…More than 30 different mutations in MLL2 have been defined, most being nonsense or frameshift mutations, which are predicted to result in haploinsufficiency [134]. Mutation of MLL2 only accounts for about 70 % of cases of KS suggesting genetic heterogeneity [135,136]. Recently, deletions or point mutations in the lysine (K)-specific demethylase 6A (KDM6A) gene, which encodes a histone demethylase that interacts with MLL2, were found in patients with KS [137].…”