CDKN1Chyperexpression in two patients with severe growth failure and microdeletions affecting the paternally inheritedKCNQ1OT1:TSS-DMR

Abstract

BackgroundTwo imprinting control centres,H19/IGF2:IG-differentialy methylated region (DMR) andKCNQ1OT1:TSS-DMR, reside on chromosome 11p15.5. Paternal deletions involving theKCNQ1OT1:TSS-DMR result in variable phenotypes, namely, normal phenotype, Silver-Russel syndrome (SRS) and fetal demise. However, expression analyses forCDKN1Cin these patients are very limited.CasesPatient 1 (adult woman) and patient 2 (boy in early childhood) showed prenatal and postnatal growth failure and clinical suspicion of SRS.Molecular analysesBoth patients showed hypermethylation of theKCNQ1OT1:TSS-DMR caused by the paternal heterozygous de novo deletions involving theKCNQ1OT1:TSS-DMR, but not includingCDKN1Cenhancers. The deletion sizes were 5 kb and 12 kb for patients 1 and 2, respectively.CDKN1Cgene expressions in immortalised leucocytes of both patients were increased compared with those of controls.ConclusionPaternal deletions involving theKCNQ1OT1:TSS-DMR, but not includingCDKN1Cenhancers, disruptKCNQ1OT1expression, strongly activateCDKN1Cexpression and consequently cause severe growth failure.