IMPE Abstracts

[Introduction] Genomic imprinting refers to the process by which a single allele is expressed in a parent-of-origin dependent manner. This parent-of-origin dependent expression is regulated by methylation patterns of differentially methylated region (DMRs). Here, we focus on two imprinting disorders, Kagami-Ogata syndrome (KOS14) and Temple syndrome (TS14). [Chromosome 14q32.2 imprinted region] This region harbors paternally expressed protein-coding genes such as DLK1 and RTL1 and maternally expressed non-coding genes such as MEG3 and RTL1as, along with the germline-derived MEG3-DLK1:IG-DMR and the postfertilization-derived MEG3:TSS-DMR. Both DMRs are methylated after paternal transmission and unmethylated after maternal transmission. The unmethylated MEG3-DLK1:IG-DMR and MEG3:TSS-DMR of maternal origin function as the imprinting centers in the placenta and body respectively, with a hierarchical interaction regulated by the MEG3-DLK1:IG-DMR for the methylation pattern of the MEG3:TSS-DMR in the body. RTL1 expression level becomes ~2.5 times increased in the absence of RTL1as-encoded microRNAs. [KOS14] KOS14 is caused by paternal uniparental disomy 14 (upd(14)pat), epimutations (hypermethylations) affecting the DMR(s), and microdeletions involving the DMRs and/or RTL1as of maternal origin, and chromosomal breakage disrupting the continuity of MEGs, which are accompanied by increased RTL1 expression in common. KOS14 is associated with characteristic face and a small bell-shaped thorax with coat-hanger appearance of the ribs as the unique pathognomonic features, abdominal wall defects, placentomegaly, and polyhydramnios as the characteristic but not specific features, and other non-specific features such as relatively large birth body size and developmental delay. [TS14] TS14 is caused by upd(14)mat, epimutations (hypomethylations) affecting the DMR(s), microdeletions involving DLK1 (and RTL1), and pathogenic variants of DLK1, which are accompanied by loss of DLK1 expression in common. TS14 usually exhibits Silver-Russell syndrome-like and/or Prader-Willi syndrome-like features in infancy, and gonadotropin-dependent precocious puberty in a later age. TS14 also appears to be associated with abnormal glucose and lipid metabolism.