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Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes


Human chromosome 14q32.2 carries a cluster of imprinted genes including paternally expressed genes (PEGs) such as DLK1 and RTL1 and maternally expressed genes (MEGs) such as MEG3 (also known as GTL2), RTL1as (RTL1 antisense) and MEG8 (refs. 1,2), together with the intergenic differentially methylated region (IG-DMR) and the MEG3-DMR3,4,5. Consistent with this, paternal and maternal uniparental disomy for chromosome 14 (upd(14)pat and upd(14)mat) cause distinct phenotypes6,7. We studied eight individuals (cases 1–8) with a upd(14)pat-like phenotype and three individuals (cases 9–11) with a upd(14)mat-like phenotype in the absence of upd(14) and identified various deletions and epimutations affecting the imprinted region. The results, together with recent mouse data4,8,9,10, imply that the IG-DMR has an important cis-acting regulatory function on the maternally inherited chromosome and that excessive RTL1 expression and decreased DLK1 and RTL1 expression are relevant to upd(14)pat-like and upd(14)mat-like phenotypes, respectively.

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Figure 1: The pedigrees of two families.
Figure 2: The regional physical map of the human chromosome 14q32.2 imprinted region and the four deletion intervals identified in this study.
Figure 3: Methylation patterns of the IG-DMR (CG4 and CG6) (those of the MEG3-DMR (CG7) are shown in Supplementary Fig. 2b).
Figure 4: FISH results for the IG-DMR.
Figure 5: Examinations of placental samples.

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We would like to thank all the affected individuals and their family members who participated in this study. This work was supported by Grants for Child Health and Development (17C-2) and for Research on Children and Families (H18-005) from the Ministry of Health, Labor, and Welfare, and by Grants-in-Aid for Scientific Research (priority areas: 16086215 and 1508023; category B: 19390290) from the Ministry of Education, Culture, Sports, Science and Technology.

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Authors and Affiliations



Molecular analysis was performed by M.K., Y.S., M.I., F.K., M.O. and S.Y., placental sample collection and preparation by H.K., M.N., Y.T., K.M. and K. Ko., placental pathological examination by K.M., and blood sampling and phenotype assessment by G.N., T.T., M.N., Y.T., K.M., T.U., H.K., Y.K., H.O., K. Ku. and T.O. The study was designed and coordinated by F.I. and T.O. with later input from A.C.F.-S., and the results were interpreted and discussed by A.C.F.-S., F.I. and T.O. The paper was written by T.O.

Corresponding authors

Correspondence to Fumitoshi Ishino or Tsutomu Ogata.

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Supplementary Tables 1–5, Supplementary Figures 1–3 (PDF 1027 kb)

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Kagami, M., Sekita, Y., Nishimura, G. et al. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat Genet 40, 237–242 (2008).

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