ESPE Abstracts (2015) 84 P-1-95

Various Imprinting Disorders Underlying Silver-Russell Syndrome-Compatible Phenotype

Masayo Kagamia, Keiko Matsubaraa, Shinichiro Sanoa, Akie Nakamuraa, Seiji Mizunob, Naoki Hamajimac, Atsuhiro Yanagisawad, Miyuki Hashimotod, Akira Yukotee, Maki Fukamia & Tsutomu Ogataa,f

aDepartment of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; bDepartment of Pediatrics, Aichi Human Service Center, Central Hospital, Aichi, Japan; cDepartment of Pediatrics, Nagoya City West Medical Center, Aich, Japan; dDepartment of Pediatrics, Yaizu City Hospital, Shizuoka, Japan; eDepartment of Neurology, Fukuoka University Faculty of Medicine, Fukuoka, Japan; fDepartment of Pediatrics, Hamamatsu University School of Medicine, Shizuoka, Japan

Background: Silver-Russell syndrome (SRS) is a rare congenital developmental disorder characterised by pre- and postnatal growth failure, relative macrocephaly, triangular face, hemihypotrophy, and fifth finger clinodactyly. Hypomethylation of the H19-DMR and maternal uniparental disomy chromosome 7 (UPD(7)mat) were identified in about 30 and 10% of SRS patients respectively. Genetic causes of the remaining 60% of the patients are unknown. Growth failure, small hands, and hypotonia in neonate and early infancy which are observed in SRS patients are also identified in patients with the other imprinting disorders such as Temple syndrome (TS14) and Prader-Willi syndrome (PWS).

Objective and hypotheses: To clarify the relevance of imprinting disorders other than SRS to SRS-like phenotypes.

Method: We examined the methylation status of the six differential methylated regions (DMRs); KvDMR on chromosome 11, the IG-DMR and the MEG3-DMR on chromosome 14, the SNRPN-DMR on chromosome 15, the PLGLA1-DMR on chromosome 6, and the GNAS exon A/B-DMR on chromosome 20, using pyrosequencing methods. We studied 81 Japanese patients who satisfied the SRS diagnostic criteria proposed by Netchine et al in 2007 and had neither epimutation of the H19-DMR nor UPD(7)mat. For patients with abnormal methylation status in these six DMRs, we performed microsatellite analysis, aCGH, and MLPA to determine the genetic causes of the imprinting disorders in each patient.

Results: We identified three TS14 patients with epimutation, two PWS patients with maternal uniparental disomy chromosome 15 and one patient with maternal uniparental disomy chromosome six in 81 patients with SRS-like phenotypes. These results suggest that the imprinting disorders other than SRS also demonstrate SRS-compatible phenotype.

Funding: This work was supported by Grants-in-Aid for Scientific Research Research (B) (23390083) from the JSPS, and by Grants for Research on Intractable Diseases (H22-161) from the MHLW, and by Grants from the NCCHD (25–10).