WBSinv1 As a Risk Factor for Having a Child With WBS

The finding that one-fourth to one-third of transmitting WBS parents are carriers for the WBSinv-1 polymorphism suggests that it predisposes to unequal meiotic recombination. A thorough evaluation of the population frequency is needed in order to accurately assign a numerical risk factor to carrier status for WBSinv-1, but preliminary data do support a significant increase in risk associated with the inverted chromosome. The population frequency has been estimated at 5% based on the analysis of200 families with a classic WBS deletion member, where both transmitting and nontransmitting parents had their WBSinv-1 carrier status determined (70). The same study took the frequency of WBS to be 1 in 7500 (based on data from ref. 10) and generated a risk factor of 4.5-fold for an inversion carrier. This gives an overall chance of having an affected child of 1 in 2000 for WBSinv-1 carriers and 1 in 9200 for noncarriers.

A second study looked at the WBSinv-1 status of the transmitting parent in two families with multiple affected children (71). In one family, there were no inversion carriers, but in the second family, both affected siblings had inherited a deleted WBSinv-1 chromosome from their father, who was a carrier for WBSinv-1.

Together, these data indicate that the WBSinv-1 polymorphism seems to be a significant risk factor for WBS. Although the increase in risk associated with the inversion is substantial, the absolute risk of having a child with WBS is still well below the risk of fetal loss associated with prenatal diagnosis procedures, making widespread carrier testing unfeasible at this time. However, as prenatal diagnostic techniques improve and their associated risks decrease, carrier testing for WBSinv-1 may become part of a standard screening panel for those planning families (72).

Fig. 5. A model for the generation of WBSinv-1 and the subsequent Williams-Beuren syndrome (WBS) deletion. (A) Generation of the WBSinv-1 chromosome. The region predicted to undergo nonallelic homologous recombination (NAHR) is indicated by X. Unique DNA within the WBS region is represented by a black line and the 1.5-Mb commonly deleted region between the centromeric and medial low-copy repeats (LCRs) and is represented by a blue line. The LCRs are indicated by green (for block A), red (for block B), and yellow (for block C) lines. They are labeled with the respective block letter where the suffix indicates whether the block is centromeric (c), medial (m), or telomeric (t). (B) Generation of the WBS deletion in a WBSinv-1 carrier. The predicted alignment of the WBSinv-1 and normal chromosomes is shown. The two regions that are predicted to correctly align and enable recombination to occur, are indicated with X. The products of such a recombination event are shown. The NAHR event depicted should result in the generation of both a deleted and a duplicated chromosome.

Fig. 5. A model for the generation of WBSinv-1 and the subsequent Williams-Beuren syndrome (WBS) deletion. (A) Generation of the WBSinv-1 chromosome. The region predicted to undergo nonallelic homologous recombination (NAHR) is indicated by X. Unique DNA within the WBS region is represented by a black line and the 1.5-Mb commonly deleted region between the centromeric and medial low-copy repeats (LCRs) and is represented by a blue line. The LCRs are indicated by green (for block A), red (for block B), and yellow (for block C) lines. They are labeled with the respective block letter where the suffix indicates whether the block is centromeric (c), medial (m), or telomeric (t). (B) Generation of the WBS deletion in a WBSinv-1 carrier. The predicted alignment of the WBSinv-1 and normal chromosomes is shown. The two regions that are predicted to correctly align and enable recombination to occur, are indicated with X. The products of such a recombination event are shown. The NAHR event depicted should result in the generation of both a deleted and a duplicated chromosome.

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