<i>CDKN1C</i> hyperexpression in two patients with severe growth failure and microdeletions affecting the paternally inherited <i>KCNQ1OT1</i>:TSS-DMR.

Abstract

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