Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations.
Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by somatic overgrowth, congenital malformations, and predisposition to childhood tumors. Aberrant expression of multiple imprinted genes, including H19, IGF2, KCNQ1OT1, and CDKN1C, has been observed in BWS patients. It has been estimated that mutations in CDKN1C occur in 12-17% of BWS patients. We have screened 10 autosomal dominant pedigrees and 65 sporadic BWS cases by PCR/heteroduplex analysis and DNA sequencing and have identified four mutations, 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 second 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 CDKN1C mutations in BWS to be only 4.9%. This is the first report of an analysis of the imprinting status of genes in the 11p15 region where CDKN1C mutations were associated with loss of IGF2 imprinting and maintenance of H19 and KCNQ1OT1 imprinting.
Li
M
M
Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
Squire
J
J
Shuman
C
C
Fei
Y L
YL
Atkin
J
J
Pauli
R
R
Smith
A
A
Nishikawa
J
J
Chitayat
D
D
Weksberg
R
R
D000595:Amino Acid Sequence; D001483:Base Sequence; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics* / Q000473:pathology; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; C094335:H19 long non-coding RNA; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II; D004247:DNA