Mutations in KMT2D, ZBTB24, and KMT2A in patients with clinical diagnosis of Kabuki syndrome lead to shared epigenetic abnormalities of target genes. N. Sobreira1, L. Zhang1, C. Ongaco2, J. Romm2, M. Baker1, K. Doheny2, D. Bertola3, K. Chong3, A. B. A. Perez4, M. Melaragno4, V. Meloni4, C. Ladd-Acosta5, D. Valle1, H. T. Bjornsson1 1) Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; 2) Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; 3) Unidade de Genética, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; 4) Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, Brazil; 5) Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

   Kabuki syndrome (KS) (MIM 147920) is a pleiotropic disorder characterized by intellectual disability, postnatal growth retardation, long palpebral fissures with eversion of the lateral third of the lower eyelids and persistence of the fetal fingerpads. About 60 to 74% of the individuals with KS are heterozygous for a LOF mutation in KMT2D (previously known as MLL2; MIM 602113) and about 6% have an X-linked dominant disorder caused by mutations KDM6A (MIM 300128). The genetic etiologies of the remaining cases are unknown. KMT2D is a histone methyltransferase that adds the open chromatin mark, H3K4me3 and KDM6A is a histone demethylase that removes the closed chromatin mark, H3K27me3. Both are components of the ASCOM complex involved in transcriptional coactivation of an undefined set of target genes. We used targeted next generation sequencing to sequence KMT2D, KDM6A, as well as two genes known to cause the ICF syndrome (ZBTB24, DNMT3B), a phenocopy of KS, plus 5 other candidate genes (KDM6B, MEN1, KMT2A, KMT2B, and HCFC1) selected on the basis of either interacting or having overlapping function with known KS genes on 29 individuals with a clinical diagnosis of KS. We identified 14 individuals with mutation in KMT2D (5/14 confirmed as de novo), 1 individual with a mutation in ZBTB24 and 3 individuals with missense mutations in KMT2A (2 confirmed as de novo). Wiedemann-Steiner syndrome (WSS; MIM 60513) with hairy elbows, short stature, facial dysmorphism, and developmental delay is a rare autosomal dominant disorder caused by heterozygous LOF mutations in KMT2A (MIM 159555). Our data suggest that a subset of mutations in KMT2A is responsible for a Kabuki like phenotype distinct from classical WSS. We next postulated that the overlapping clinical phenotype might reflect shared epigenetic abnormalities of target genes. Therefore, we investigated genome-scale DNA methylation patterns in our cohort using Infinium 450K BeadChips. We found significant hypermethylation (FWER < 0.1; adjusted for blood cell composition) at 3 genomic regions, near ZFP57, DEGS2 and LCLAT1, among our cohort compared to age and sex matched controls. Our results identify a new gene responsible for KS (KMT2A); suggest a mechanistic relationship between KS, ICF and WSS; and identify downstream methylation abnormalities in target genes that may be used as a marker of this clinical phenotype to guide the diagnostic process in this genetically heterogeneous group of patients.

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