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Recurrence, Germline Mosaicism


Can you explain how a family can have more than one child with CdLS, if neither parent has any features of CdLS?

Answer of our experts

We explain this by a phenomenon called 'germ line mosaicism' which refers to the presence in the germ cells (the eggs in a woman or the sperm in a man) of a number of eggs or sperm with a change in the CdLS gene

These eggs or sperm likely arose from an earlier progenitor cell (a cell that developed shortly after conception) that acquired the change and passed it onto the eggs or sperm that arose from it. Since the change in the CdLS gene is only in this small subset of cells and not in all of the cells of the parent, the parent would not have features of CdLS but would be at risk of passing on the gene with the change in it through those sperm or eggs that carried it to offspring

Depending on how many sperm or eggs had the change, the recurrence risk could be as high as 50% in each pregnancy. Now that we have found genes that cause CdLS we have confirmed that in families where a family with unaffected parents have multiple children with CdLS (or in those cases where a mother or father has more than one affected child through different partners), we have found the same change (or 'mutation') in the affected children but not in either parent's blood (where we generally collect samples for testing). We cannot easily test the sperm and the eggs for changes (well sperm may be easier to test), but if we did we would probably find the change in some of these cells in the parents. We take this potential scenario into account when we say the chance of having another child with CdLS is about 1.5% and not zero

IK/TK 7-13-10

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Mosaicism should be considered in individuals with CdLS in whom a variant in a gene known to cause CdLS cannot be detected in blood cells, in which case other tissues such as fibroblasts (skin), buccal (cheek) cells or bladder epithelial cells from urine should be studied.


Familial recurrence risk

Genetic counselling should be offered to all families with a family member with CdLS. Families should be counselled that the recurrence risk of CdLS differs depending on the gene involved. In the non-X-linked forms, the recurrence risk is 0.89% due to germline mosaicism. Autosomal dominant inheritance of CdLS does occur, meaning if one copy of the mutation is present, the individual will show clinical effects. In clinically diagnosed individuals with CdLS, the recurrence risk is 1.5%.

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