TY - JOUR
T1 - ZNF445
T2 - a homozygous truncating variant in a patient with Temple syndrome and multilocus imprinting disturbance
AU - Kagami, Masayo
AU - Hara-Isono, Kaori
AU - Matsubara, Keiko
AU - Nakabayashi, Kazuhiko
AU - Narumi, Satoshi
AU - Fukami, Maki
AU - Ohkubo, Yumiko
AU - Saitsu, Hirotomo
AU - Takada, Shuji
AU - Ogata, Tsutomu
N1 - Funding Information:
We are grateful to the patients and their parents for their cooperation. We thank Drs. Keisuke Nagasaki, Tomonobu Hasegawa, Yasuyuki Fukuhara, and Yuko Akutsu for providing us with clinical data and materials for molecular studies. We also thank Drs. Sayaka Kawashima, Takanobu Inoue, Shinichiro Sano, Kanako Tanase-Nakao, Ms. Fumiko Kato, Saori Miyasako, Tamae Tanji, and Aki Ueda for their support in molecular analyses.
Funding Information:
This work was supported by Grants from the Japan Society for the Promotion of Science (JSPS) (18K06356), the National Center for Child Health and Development (2019B-4), the Japan Agency for Medical Research and Development (AMED) (JP20ek0109373 and JP21ek0109549), and Takeda Science Foundation.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Background: ZNF445, as well as ZFP57, is involved in the postfertilization methylation maintenance of multiple imprinting-associated differentially methylated regions (iDMRs). Thus, ZNF445 pathogenic variants are predicted to cause multilocus imprinting disturbances (MLIDs), as do ZFP57 pathogenic variants. In particular, the MEG3/DLK1:IG-DMR would be affected, because the postzygotic methylation imprint of the MEG3/DLK1:IG-DMR is maintained primarily by ZNF445, whereas that of most iDMRs is preserved by both ZFP57 and ZNF445 or primarily by ZFP57. Results: We searched for a ZNF445 variant(s) in six patients with various imprinting disorders (IDs) caused by epimutations and MLIDs revealed by pyrosequencing for nine iDMRs, without a selection for the original IDs. Re-analysis of the previously obtained whole exome sequencing data identified a homozygous ZNF445 variant (NM_181489.6:c.2803C>T:p.(Gln935*)) producing a truncated protein missing two of 14 zinc finger domains in a patient with Temple syndrome and MLID. In this patient, array-based genomewide methylation analysis revealed severe hypomethylation of most CpGs at the MEG3:TSS-DMR, moderate hypomethylation of roughly two-thirds of CpGs at the H19/IGF2:IG-DMR, and mild-to-moderate hypomethylation of a few CpGs at the DIRAS3:TSS-DMR, MEST:alt-TSS-DMR, IGF2:Ex9-DMR, IGF2:alt-TSS, and GNAS-AS1:TSS-DMR. Furthermore, bisulfite sequencing analysis for the MEG3/DLK1:IG-DMR delineated a markedly hypomethylated segment (CG-A). The heterozygous parents were clinically normal and had virtually no aberrant methylation pattern. Conclusions: We identified a ZNF445 pathogenic variant for the first time. Since ZNF445 binds to the MEG3/DLK1:IG-DMR and other iDMRs affected in this patient, the development of Temple syndrome and MLID would primarily be explained by the ZNF445 variant. Furthermore, CG-A may be the target site for ZNF445 within the MEG3/DLK1:IG-DMR.
AB - Background: ZNF445, as well as ZFP57, is involved in the postfertilization methylation maintenance of multiple imprinting-associated differentially methylated regions (iDMRs). Thus, ZNF445 pathogenic variants are predicted to cause multilocus imprinting disturbances (MLIDs), as do ZFP57 pathogenic variants. In particular, the MEG3/DLK1:IG-DMR would be affected, because the postzygotic methylation imprint of the MEG3/DLK1:IG-DMR is maintained primarily by ZNF445, whereas that of most iDMRs is preserved by both ZFP57 and ZNF445 or primarily by ZFP57. Results: We searched for a ZNF445 variant(s) in six patients with various imprinting disorders (IDs) caused by epimutations and MLIDs revealed by pyrosequencing for nine iDMRs, without a selection for the original IDs. Re-analysis of the previously obtained whole exome sequencing data identified a homozygous ZNF445 variant (NM_181489.6:c.2803C>T:p.(Gln935*)) producing a truncated protein missing two of 14 zinc finger domains in a patient with Temple syndrome and MLID. In this patient, array-based genomewide methylation analysis revealed severe hypomethylation of most CpGs at the MEG3:TSS-DMR, moderate hypomethylation of roughly two-thirds of CpGs at the H19/IGF2:IG-DMR, and mild-to-moderate hypomethylation of a few CpGs at the DIRAS3:TSS-DMR, MEST:alt-TSS-DMR, IGF2:Ex9-DMR, IGF2:alt-TSS, and GNAS-AS1:TSS-DMR. Furthermore, bisulfite sequencing analysis for the MEG3/DLK1:IG-DMR delineated a markedly hypomethylated segment (CG-A). The heterozygous parents were clinically normal and had virtually no aberrant methylation pattern. Conclusions: We identified a ZNF445 pathogenic variant for the first time. Since ZNF445 binds to the MEG3/DLK1:IG-DMR and other iDMRs affected in this patient, the development of Temple syndrome and MLID would primarily be explained by the ZNF445 variant. Furthermore, CG-A may be the target site for ZNF445 within the MEG3/DLK1:IG-DMR.
KW - MEG3/DLK1:IG-DMR
KW - Multilocus imprinting disturbance
KW - Postzygotic genomic imprint
KW - Temple syndrome
KW - ZNF445
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UR - http://www.scopus.com/inward/citedby.url?scp=85106928600&partnerID=8YFLogxK
U2 - 10.1186/s13148-021-01106-5
DO - 10.1186/s13148-021-01106-5
M3 - Article
C2 - 34039421
AN - SCOPUS:85106928600
SN - 1868-7075
VL - 13
JO - Clinical Epigenetics
JF - Clinical Epigenetics
IS - 1
M1 - 119
ER -