Mutation spectrum of MLL2 in a cohort of Kabuki syndrome patients

Abstract

Background: Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause.

Methods: Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools.

Results: We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site.

Conclusions: This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management.

Figure 1

Facial features of Kabuki syndrome patients. Representative images of Kabuki patients with MLL2 mutations.

Figure 2

Mutation spectrum of MLL2 in our cohort of Kabuki syndrome patients. Upper panel: genomic structure of the MLL2 gene including 54 coding exons (black rectangles), the 3'untranslated region (red rectangle) and introns (black horizontal line). Mutations are represented in black (nonsense = 16), red (indel = 3), blue (splice sites = 3), and green (frameshift = 13). Middle figure: MLL2 protein domain structures, PHD, plant homeodomain finger; HMG-box, high mobility group; CC, Coiled Coil; LXXLL domain, FYRN, FY-rich domain, N-terminal region; FYRC, FY-rich domain, C-terminal region; SET, (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain; PostSET: PostSET domain. Lower panel: evolutionary comparison of the protein sequences flanking the 7 missense mutations identified in the human MLL2 protein with their orthologous counterparts in seven species. The position of the amino acid change is indicated with a star.