CDKN1C hyperexpression in two patients with severe growth failure and microdeletions affecting the paternally inherited KCNQ1OT1:TSS-DMR. Issue 12 (29th July 2022)

• Record Type: Journal Article
• Authors: Hara-Isono, Kaori; Yamazawa, Kazuki; Tanaka, Satsuki; Nishi, Eriko; Fukami, Maki; Kagami, Masayo
• Is Part Of: Journal of medical genetics. Volume 59:Issue 12(2022)
• Page Start: 1241
• Page End: 1246
• Publication Date: 2022-07-29
• Subjects: epigenomics -- human genetics; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmg-2022-108700
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Two imprinting control centres, H19/IGF2 :IG-differentialy methylated region (DMR) and KCNQ1OT1 :TSS-DMR, reside on chromosome 11p15.5. Paternal deletions involving the KCNQ1OT1 :TSS-DMR result in variable phenotypes, namely, normal phenotype, Silver-Russel syndrome (SRS) and fetal demise. However, expression analyses for CDKN1C in these patients are very limited. Cases: Patient 1 (adult woman) and patient 2 (boy in early childhood) showed prenatal and postnatal growth failure and clinical suspicion of SRS. Molecular analyses: Both patients showed hypermethylation of the KCNQ1OT1 :TSS-DMR caused by the paternal heterozygous de novo deletions involving the KCNQ1OT1 :TSS-DMR, but not including CDKN1C enhancers. The deletion sizes were 5 kb and 12 kb for patients 1 and 2, respectively. CDKN1C gene expressions in immortalised leucocytes of both patients were increased compared with those of controls. Conclusion: Paternal deletions involving the KCNQ1OT1 :TSS-DMR, but not including CDKN1C enhancers, disrupt KCNQ1OT1 expression, strongly activate CDKN1C expression and consequently cause severe growth failure.