Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities. (December 2017)

• Record Type: Journal Article
• Authors: Sobreira, Nara; Brucato, Martha; Zhang, Li; Ladd-Acosta, Christine; Ongaco, Chrissie; Romm, Jane; Doheny, Kimberly; Mingroni-Netto, Regina; Bertola, Debora; Kim, Chong; Perez, Ana; Melaragno, Maria; Valle, David; Meloni, Vera; Bjornsson, Hans
• Is Part Of: European journal of human genetics. Volume 25:Number 12(2017)
• Page Start: 1335
• Page End: 1344
• Publication Date: 2017-12
• Subjects: Human genetics -- Periodicals; Medical genetics -- Periodicals; 616.042
• DOI: 10.1038/s41431-017-0023-0
• Languages: English
• ISSNs: 1018-4813

Abstract

Abstract Kabuki syndrome is a monogenic disorder caused by loss of function variants in either of two genes encoding histone-modifying enzymes. We performed targeted sequencing in a cohort of 27 probands with a clinical diagnosis of Kabuki syndrome. Of these, 12 had causative variants in the two known Kabuki syndrome genes. In 2, we identified presumptive loss of functionde novo variants inKMT2A (missense and splice site variants), a gene that encodes another histone modifying enzyme previously exclusively associated with Wiedermann-Steiner syndrome. Although Kabuki syndrome is a disorder of histone modification, we also find alterations in DNA methylation among individuals with a Kabuki syndrome diagnosis relative to matched normal controls, regardless of whether they carry a variant inKMT2A orKMT2D or not. Furthermore, we observed characteristic global abnormalities of DNA methylation that distinguished patients with a loss of function variant inKMT2D or missense or splice site variants in eitherKMT2D orKMT2A from normal controls. Our results provide new insights into the relationship of genotype to epigenotype and phenotype and indicate cross-talk between histone and DNA methylation machineries exposed by inborn errors of the epigenetic apparatus.