Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized b y somatic overgrowth, congenital malformations, and predisposition to child hood tumors. Aberrant expression of multiple imprinted genes, including H19 , IGF2, KCNQ1OT1, and CDKN1C, has been observed in BWS patients. It has bee n estimated that mutations in CDKN1C occur in 12-17% of BWS patients. We ha ve screened 10 autosomal dominant pedigrees and 65 sporadic BWS cases by PC R/heteroduplex analysis and DNA sequencing and have identified four mutatio ns, two of which were associated with biallelic IGF2 expression and normal H19 and KCNQ1OT1 imprinting. One patient demonstrated phenotypic expression of paternally transmitted mutation in this maternally expressed gene, a se cond proband is the child of one of a pair of monozygotic twin females who carry the mutation:de novo, and a third patient exhibited unusual skeletal changes more commonly found in other overgrowth syndromes. When considered with other studies published to date, this work reveals the frequency of CD KN1C mutations in BWS to be only 4.9%. This is the first report of an analy sis of the imprinting status of genes in the 11p15 region where CDKN1C muta tions were associated with loss of IGFS imprinting and maintenance of H19 a nd KCNQ1OT1 imprinting. (C) 2001 Academic Press.