Mosaic uniparental disomy in Beckwith-Wiedemann syndrome.

Abstract

1/23, p<O0OOl) and less likely to have exomphalos (0/9 versus 13123, p<OOl), but there were no significant differences between disomic and non-disomic cases in the incidence of hypoglycaemia, nephromegaly, neoplasia, and developmental delay. The detection of UlPD in BWS patients allows accurate genetic counselling to be provided and provides an insight into the molecular pathogenesis of BWS. (J Med Genet 1994;31:749-753)

Increased IGF-II protein affectsp57kip2expressionin vivoandin vitro: Implications for Beckwith–Wiedemann syndrome

“…This discordance can be the result of functional differences between human and mouse, be due to differences in genetic background, or reflect the fact that this group of patients with BWS has mutations in other critical genes involved in BWS. Finally, highly variable phenotypes have been associated with BWS, and, with the exception of correlations between somatic isodisomy and hemihypertrophy and between exomphalos and CDKINC mutation (47,48), no obvious correlation between phenotype and genotype has been established. It has been suggested that at least some tissues are highly sensitive to ratios of IGF-II and p57 KIP2 (40).…”

Beckwith–Wiedemann syndrome and uniparental disomy 11p: fine mapping of the recombination breakpoints and evaluation of several techniques

“…24 The extent of pUPD at chromosome 11p has been studied by means of STR markers; the critical region for pUPD is telomeric to chromosome 11p13 and always includes the region where map some BWS genes (IGF2, H19 and CDKN1C). 19,21,23 Some cases with mosaic pUPD for the whole chromosome 11 have been also described and the clinical findings did not differ from patients with pUPD restricted to a small part of 11p. 23,25 Although the extent of segmental disomy and proportion of cells with pUPD is variable, in all BWS cases the paternal UPD is isodisomic.…”

“…26 Clinically, a clear association between mosaic UPD and hemihyperplasia exists. 15,19,22,27 In addition, it was noted that neoplasias and Wilms' tumours are more frequent in BWS patients with pUPD or H19DMR hypermethylation than in BWS patients with other molecular defect. [27][28][29] Moreover, it has been hypothesized that extremely high levels of UPD might drive severe phenotypic expression of BWS; 30 but it is often difficult to determine if levels of UPD correlate with severity of the phenotype especially when the tissues/organs involved are not usually directly tested.…”

“…[15][16][17] Finally, another large category of BWS molecular alteration, 10-20% of cases, is represented by paternal uniparental disomy (pUPD), namely patients with two paternally derived copies of chromosome 11p15 and no maternal contribution for that region. 18,19 In these patients, in addition to the effects of IGF2 overexpression, a decreased level of the maternally expressed gene CDKN1C may contribute to the BWS phenotype. 9,12,20 It has been demonstrated that BWS patients with paternal UPD always show mosaicisms, suggesting that all cases had arisen as a postzygotic event 19,21,22 ; a possible explanation is that lack of one or more chromosome 11 maternally expressed genes may lead to embryonic lethality.…”

“…18,19 In these patients, in addition to the effects of IGF2 overexpression, a decreased level of the maternally expressed gene CDKN1C may contribute to the BWS phenotype. 9,12,20 It has been demonstrated that BWS patients with paternal UPD always show mosaicisms, suggesting that all cases had arisen as a postzygotic event 19,21,22 ; a possible explanation is that lack of one or more chromosome 11 maternally expressed genes may lead to embryonic lethality. 23 It was also suggested that the degree of mosaicism and the location of the genetic abnormality in different tissue is strongly associated with the pathological phenotype.…”