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.

Figure 1

Spectrum of MLL2 mutations. Schematic representation of MLL2 mutations identified in this study. The gene structure shows all 54 coding exons and the protein structure shows the protein domains and motifs. Arrows indicate the exonic location of the mutations identified in the patients. Nonsense mutations are shown in red, frameshift in/dels are shown in green, splice-site mutations are shown in blue and missense mutations and in-frame deletions are shown in purple. Novel variants are underlined and variants of uncertain pathogenicity are highlighted by ^*.

Figure 2

Facial features of patients in this study. (a) Facial photograph of KS49, who has a MLL2 mutation, showing typical facial features of KS with interrupted high-arched eyebrows, long palpebral fissures, eversion of lateral part of lower eyelids, broad depressed nasal tip, large prominent earlobes and pillowed lower lip. (b) Facial photograph of KS45, who has a MLL2 mutation, showing deficient lateral eyebrows, long palpebral fissures, broad depressed nasal tip, large prominent earlobes, pillowed lower lip and oligodontia. (c) Facial photograph of KS36, who has a MLL2 mutation but is facially not typical for Kabuki syndrome. This demonstrates phenotypic variability of this condition indicating that MLL2 testing may be considered even in atypical patients. (d) Facial phenotype of KS110, which is typical of KS but MLL2 mutation was not found. She also has a history of severe feeding difficulties in infancy, coarctation of aorta, hypoplastic left ventricle, ventricular septal defect, aortic and sub-aortic stenosis, bilateral mild hydronephrosis, deep labial adhesions, right iris coloboma, bilateral choroido-retinal colobomas, single duplicated tooth, hypotonia and mild developmental delay.

Figure 3

Facial phenotype of KS changes with age. Both patients have MLL2 mutation. Mean and median scores for facial KS morphology are given in brackets. (a, b) Facial features of the same patient in neonatal period (2.64; 2) and later in infancy (4.45; 5, KS55). This patient has ‘grown into' KS. (c, d) Facial features of the same patient in childhood (4.32; 4, KS85) and later in adulthood (3.23; 3). This patient has ‘grown out of' KS.