Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities

Nara Sobreira, Martha Brucato, Li Zhang, Christine Marie Ladd-Acosta, Chrissie Ongaco, Jane Romm, Kimberly Doheny, Regina C. Mingroni-Netto, Debora Bertola, Chong A. Kim, Ana Ba Perez, Maria I. Melaragno, David Valle, Vera A. Meloni, Hans Tomas Bjornsson

Research output: Contribution to journalArticle


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.

Original languageEnglish (US)
Pages (from-to)1335-1344
Number of pages10
JournalEuropean Journal of Human Genetics
Issue number12
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities'. Together they form a unique fingerprint.

  • Cite this

    Sobreira, N., Brucato, M., Zhang, L., Ladd-Acosta, C. M., Ongaco, C., Romm, J., Doheny, K., Mingroni-Netto, R. C., Bertola, D., Kim, C. A., Perez, A. B., Melaragno, M. I., Valle, D., Meloni, V. A., & Bjornsson, H. T. (2017). Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities. European Journal of Human Genetics, 25(12), 1335-1344.