Abstract
Although recent studies have often revealed the presence of multilocus imprinting disturbance (MLID) at differentially methylated regions (DMRs) in patients with imprinting disorders (IDs), most patients exhibit clinical features of the original ID only. Here we report a Japanese female patient with Beckwith–Wiedemann syndrome and pseudohypoparathyroidism type Ib. Molecular studies revealed marked methylation defects (MDs) at the Kv-DMR and the GNAS-DMRs and variable MDs at four additional DMRs, in the absence of a mutation in ZFP57, NLRP2, NLRP7, KHDC3L and NLRP5. It is likely that the MDs at the Kv-DMR and the GNAS-DMRs were sufficient to cause clinically recognizable IDs, whereas the remaining MDs were insufficient to result in clinical consequences or took place at DMRs with no disease-causing imprinted gene(s). The development of MLID and the two IDs of this patient may be due to a mutation in a hitherto unknown gene for MLID, or to a reduced amount of DNA methyltransferase-1 (DNMT1) available for the methylation maintenance of DMRs because of the consumption of DNMT1 by the maintenance of X-inactivation. In support of the latter possibility, such co-existence of two IDs has primarily been identified in female patients, and MLID has predominantly been identified as loss of methylations.
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Acknowledgements
We thank Dr Hiromi Kamura (Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Japan) for her technological assistance. This work was supported by Grants-in-Aid for Scientific Research (A) (25253023), Grants-in-Aid for Scientific Research (C) (26461537) and Grants-in-Aid for Challenging Exploratory Research (15K15096) from the Japan Society for the Promotion of Science (JSPS), by Grants from the National Center for Child Health and Development (25-10), and by Grant from Takeda Science Foundation.
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Sano, S., Matsubara, K., Nagasaki, K. et al. Beckwith–Wiedemann syndrome and pseudohypoparathyroidism type Ib in a patient with multilocus imprinting disturbance: a female-dominant phenomenon?. J Hum Genet 61, 765–769 (2016). https://doi.org/10.1038/jhg.2016.45
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DOI: https://doi.org/10.1038/jhg.2016.45
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