» What causes Cornelia de Lange Syndrome

Family Recurrence Risk

Genetic counselling should be offered to all families with a family member with CdLS. Genetic counselling is when prospective parents are given advice about the risks of having a child with a genetic disorder. The International CdLS Consensus Group advises that the recurrence risk of CdLS in a future child differs depending on which gene is involved.

The genes (NIPBL, SMC3, RAD21, BRD4 and ANKRD11) that are not on the X chromosome are autosomal (dominant) genes, meaning that if a mutation is fully present, the clinical effects will occur. Most of the time the mutation will be new in the family when a child is born with CdLS. Families have been reported to have more than one child with CdLS, with parents unaffected (47, 48). This is due to a small population of some of a parent’s eggs or sperm cells carrying the mutation (this is called germline mosaicism). For this reason, the recurrence risk for future children is never said to be zero. There also could be a very mildly affected parent, with a mutation in one of these genes, who would have a 50% (1 in 2) chance of passing on that mutation in each subsequent pregnancy. The authors’ joint experience based on 560 families having a child with a variant in NIPBL is that the recurrence risk due to germline mosaicism is 0.89% (slightly less than 1 in 100).

For the genes (SMC1A and HDAC8) on the X chromosome (X-linked), most of the time the mutation is new in the family. If the mother is unaffected but carries the mutation, the recurrence would be 50% (1 in 2) with each subsequent pregnancy. Sometimes genetic counselling is difficult, because affected siblings can be variably affected clinically (3, 35, 41, 42). This is also true for families with RAD21 mutations.

If no molecular testing has been done, the total overall recurrence risk for CdLS has been calculated in the past to be 1.5% (1½ in 100) (49) (R6).

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