RT Journal Article
SR Electronic
T1 Hypomethylation of a centromeric block of ICR1 is sufficient to cause Silver-Russell syndrome
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 422
OP 425
DO 10.1136/jmedgenet-2020-106907
VO 58
IS 6
A1 Ken Higashimoto
A1 Hijiri Watanabe
A1 Yuka Tanoue
A1 Hidefumi Tonoki
A1 Tomoharu Tokutomi
A1 Satoshi Hara
A1 Hitomi Yatsuki
A1 Hidenobu Soejima
YR 2021
UL http://jmg.bmj.com/content/58/6/422.abstract
AB 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.