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by Conny van Ravenswaaij
Although CHARGE syndrome is usually sporadic, there always has been evidence that it is caused by a genetic factor. The concordance rate in monozygotic twins is very high and affected sibling pairs do occur. We found a very small deletion of chromosome 8 in two children with CHARGE. This tiny region on chromosome 8 appeared to harbor a new gene: CHD7. Mutations in this gene were found in 16 of 17 well-selected patients. At present large groups of patients suspected for CHARGE syndrome are being studied and a mutation in CHD7 is found in about 60% of these patients. In the patients who fulfill the diagnostic clinical criteria, the mutation detection rate is as high as 90%. However, mutations can be found in patients who do not fulfill these criteria, and the mild end of the clinical spectrum is not yet known.
CHARGE syndrome has a recurrence risk of 1-2%. This can be explained by germ line mosaicism. That means that although the parent is not affected, some of his/her sperm or egg cells carry the same CHD7 mutation. Sometimes, in affected siblings, a mosaic mutation of CHD7 can be detected in one of the parents. In this situation the recurrence risk is increased. Therefore DNA studies are recommended in all parents of children with a CHD7 mutation. Prenatal diagnosis with 100% reliability is possible with chorionic villi sampling. A person with CHARGE syndrome has a risk of 50% to pass on the CHD7 mutation. However, infertility is very common in CHARGE syndrome and as a result parent-to-child transmission is rare. Further studies are in progress to determine if genes other than CHD7 can cause CHARGE syndrome.
Conny van Ravenswaaij is a clinical geneticist/cytogeneticist in the Department of Human Genetics at the University Medical Centre Groningen, the Netherlands.
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