Analysis of CDKN1C in Beckwith Wiedemann Syndrome

In this study we have examined 32 patients with Beckwith Wiedemann Syndrome (BWS) for mutations affecting the CDKN1C gene, including seven cases of fa milial BWS. Mutations were not detected in the coding region of the CDKN1C gene in any individual with BWS. However in two patients, two G/A base subs titutions at adjacent positions in the 5'UTR were detected. These substitut ions were also found in normal controls. Expression of CDKN1C in somatic ti ssues was examined in 18 of the 32 cases using semi-quantitative RT-PCR. CD KN1C expression was significantly reduced in the peripheral blood of three cases compared with controls. These results suggest that, although coding r egion mutations in the CDKN1C gene are rare in BWS, mutations disrupting CD KN1C expression may be found. Three of five informative patients exhibited biallelic CDKN1C expression in lymphocytes, cord blood, and kidney tissue, respectively. Biallelic expression was not associated with overall CDKN1C l evels significantly different to those in controls. Patients who expressed CDKN1C biallelically, or who were low CDKN1C expressors, maintained monoall elic methylation in the Differentially Methylated Region 2 (DMR2) of the IG F2 locus. One patient expressing CDKN1C biallelically, maintained imprinted gene expression at the IGF2 locus. These results suggest that biallelic CD KN1C expression does not significantly perturb the overall levels of CDKN1C expression in somatic tissue. They also confirm other studies showing that the mechanisms associated with regulating CDKN1C expression and imprinting are separate from those regulating IGF2 imprinting. Hum Mutat 15:4 97-508, 2000. (C) 2000 Wiley-Liss, Inc.