Journal
JOURNAL OF MEDICAL GENETICS
Volume 58, Issue 6, Pages 422-425Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2020-106907
Keywords
epigenetics; imprinting
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Funding
- Japan Society for the Promotion of Science [16K09970, 17K08687]
- Japan Agency for Medical Research and Development (AMED) [17ek0109280h0001, 17ek0109234h0001, 17ek0109205h0001]
- Ministry of Health, Labor, and Welfare [H29--nanchitou(nan)--ippan-025]
- Grants-in-Aid for Scientific Research [16K09970, 17K08687] Funding Source: KAKEN
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Silver-Russell syndrome (SRS) is a representative imprinting disorder characterized by ICR1-LOM, with analysis showing variations in methylation patterns among different patients, emphasizing the importance of simultaneous analysis of multiple methylation sites for accurate molecular diagnosis.
Silver-Russell syndrome (SRS) is a representative imprinting disorder. A major cause is the loss of methylation (LOM) of imprinting control region 1 (ICR1) within the IGF2/H19 domain. ICR1 is a gametic differentially methylated region (DMR) consisting of two repeat blocks, with each block including three CTCF target sites (CTSs). ICR1-LOM on the paternal allele allows CTCF to bind to CTSs, resulting in IGF2 repression on the paternal allele and biallelic expression of H19. We analysed 10 differentially methylated sites (DMSs) (ie, seven CTSs and three somatic DMRs within the IGF2/H19 domain, including two IGF2-DMRs and the H19-promoter) in five SRS patients with ICR1-LOM. Four patients showed consistent hypomethylation at all DMSs; however, one exhibited a peculiar LOM pattern, showing LOM at the centromeric region of the IGF2/H19 domain but normal methylation at the telomeric region. This raised important points: there may be a separate regulation of DNA methylation for the two repeat blocks within ICR1; there is independent control of somatic DMRs under each repeat block; sufficient IGF2 repression to cause SRS phenotypes occurs by LOM only in the centromeric block; and the need for simultaneous methylation analysis of several DMSs in both blocks for a correct molecular diagnosis.
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