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a Section of Medical
and Molecular Genetics, Department of Paediatrics and Child Health,
University of Birmingham, Birmingham B15 2TT, UK, b National
Cardiovascular Centre Research Institute, 5-7-1, Fuijshiro-dai, Suita,
Osaka 565, Japan, c Laboratory of Stem Cell Biology, Department of
Anatomy, Downing Street, Cambridge University, Cambridge CB2 3DY, UK, d Department
of Medical Genetics, St Mary's Hospital, Manchester, UK, e Laboratory of Developmental Genetics and
Imprinting, The Babraham Institute, Babraham Hall, Babraham, Cambridge
CB2 4AT, UK
Correspondence to: Professor Maher.
Received 19
November 1998;
Revised version accepted for publication 8 March 1999
Beckwith-Wiedemann syndrome (BWS) is a human imprinting
disorder with a variable phenotype. The major features are anterior abdominal wall defects including exomphalos (omphalocele), pre- and
postnatal overgrowth, and macroglossia. Additional less frequent complications include specific developmental defects and a
predisposition to embryonal tumours. BWS is genetically heterogeneous
and epigenetic changes in the IGF2/H19 genes resulting in
overexpression of IGF2 have been implicated in many cases. Recently
germline mutations in the cyclin dependent kinase inhibitor gene CDKN1C
(p57KIP2) have been reported in a variable minority of BWS
patients. We have investigated a large series of familial and sporadic
BWS patients for evidence of CDKN1C mutations by direct gene
sequencing. A total of 70 patients with classical BWS were
investigated; 54 were sporadic with no evidence of UPD and 16 were
familial from seven kindreds. Novel germline CDKN1C mutations were
identified in five probands, 3/7 (43%) familial cases and 2/54 (4%)
sporadic cases. There was no association between germline CDKN1C
mutations and IGF2 or H19 epigenotype abnormalities. The clinical
phenotype of 13 BWS patients with germline CDKN1C mutations was
compared to that of BWS patients with other defined types of molecular pathology. This showed a significantly higher frequency of exomphalos in the CDKN1C mutation cases (11/13) than in patients with an imprinting centre defect (associated with biallelic IGF2 expression and
H19 silencing) (0/5, p<0.005) or patients with uniparental disomy
(0/9, p<0.005). However, there was no association between germline
CDKN1C mutations and risk of embryonal tumours. No CDKN1C mutations
were identified in six non-BWS patients with overgrowth and Wilms
tumour. These findings (1) show that germline CDKN1C mutations are a
frequent cause of familial but not sporadic BWS, (2) suggest that
CDKN1C mutations probably cause BWS independently of changes in
IGF2/H19 imprinting, (3) provide evidence that aspects of the BWS
phenotype may be correlated with the involvement of specific imprinted
genes, and (4) link genotype-phenotype relationships in BWS and the
results of murine experimental models of BWS.
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