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Weksberg Lab

Clinical diagnosis and genetics

What is the Beckwith-Wiedemann syndrome?

Disease characteristics:

Beckwith-Wiedemann syndrome (BWS) is a disorder of growth characterized by :

macrosomia

macroglossia

visceromegaly

omphalocele

neonatal hypoglycemia

hemihyperplasia

embryonal tumors

or large body size

or large tongue

or enlargement of internal organs (especially liver and kidneys)

or defects in the abdominal wall

or low blood sugar after birth

or asymmetric enlargement of one side or one area of the body ear creases/pits

i.e., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma

BWS syndrome is caused by mutation in the chromosome 11p15.5 region. Duplication in this region appears to be involved in the pathogenesis and imprinting results in anomalous patterns of transmission.

Clinical Diagnosis and Genetics of BWS

The diagnosis of Beckwith-Wiedemann syndrome relies heavily on clinical findings. Chromosome abnormalities involving 11p15 are found in 1% or less of cases. Molecular genetic testing available through service laboratories can identify several different types of 11p15 abnormalities in patients with BWS: in 50% of patients, loss of methylation at KCNQ1OT1 is observed; in 10-20% of patients, paternal uniparental disomy for chromosome 11p15 is observed. Research testing reveals mutations in the CDKN1C gene (previously called p57 KIP2 ) in 5-10% of sporadic cases and 40% of familial cases. Detection of these molecular abnormalities are adjuncts to clinical diagnosis and genetic counselling.

Molecular Characteristics:

The molecular basis of the BWS phenotype is heterogeneous. It can be caused by a variety of genetic or epigenetic aberrations in a 2 MB region of chromosome 11p15.5. This region, housing a cluster of 12 imprinted genes and 4 imprinted noncoding RNA transcripts, is subdivided into 2 imprinted domains each containing putative imprinting control centers.

These imprinting centers are differentially methylated regions of DNA (DMRs) modified in a parent of origin-specific manner and postulated to control expression in cis of clusters of imprinted genes via a novel type of coordinate regulation.