Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities

Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities

Author Sobreira, Nara Google Scholar
Brucato, Martha Google Scholar
Zhang, Li Google Scholar
Ladd-Acosta, Christine Google Scholar
Ongaco, Chrissie Google Scholar
Romm, Jane Google Scholar
Doheny, Kimberly F. Google Scholar
Mingroni-Netto, Regina C. Google Scholar
Bertola, Debora Google Scholar
Kim, Chong A. Google Scholar
Perez, Ana B. A. Autor UNIFESP Google Scholar
Melaragno, Maria I. Autor UNIFESP Google Scholar
Valle, David Google Scholar
Meloni, Vera A. Google Scholar
Bjornsson, Hans T. Google Scholar
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 function de novo variants in KMT2A (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 in KMT2A or KMT2D or not. Furthermore, we observed characteristic global abnormalities of DNA methylation that distinguished patients with a loss of function variant in KMT2D or missense or splice site variants in either KMT2D or KMT2A 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.
xmlui.dri2xhtml.METS-1.0.item-coverage London
Language English
Sponsor NIH Director's Early Independence Award [DP5OD017877]
National Human Genome Research Institute [1U54HG006493]
Date 2017
Published in European Journal Of Human Genetics. London, v. 25, n. 12, p. 1335-1344, 2017.
ISSN 1018-4813 (Sherpa/Romeo, impact factor)
Publisher Nature Publishing Group
Extent 1335-1344
Access rights Closed access
Type Article
Web of Science ID WOS:000418403600005

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