Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities

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

Rannsóknarafurð: Framlag til fræðitímaritsGreinritrýni

27 Tilvitnanir (Scopus)


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.

Upprunalegt tungumálEnska
Síður (frá-til)1335-1344
FræðitímaritEuropean Journal of Human Genetics
Númer tölublaðs12
ÚtgáfustaðaÚtgefið - 1 des. 2017


Funding Information:
Acknowledgements We would like to thank all the families that participated in this study. We also thank Maggie Baker for assistance in selecting the candidate genes for the amplicon study. This work was supported by a grant to H.T.B. by the NIH Director’s Early Independence Award (DP5OD017877) and a grant to D.V. from the National Human Genome Research Institute (1U54HG006493).

Publisher Copyright:
© 2017 European Society of Human Genetics.


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