Recurrence of Marfan syndrome as a result of parental germ-line mosaicism for an FBN1 mutation

Mutations in the FBN1 gene cause Marfan syndrome (MFS), a dominantly inheri ted connective tissue disease. Almost all the identified FBN1 mutations hav e been family specific, and the rate of new mutations is high. We report he re a de novo FBN1 mutation that was identified in two sisters with MFS born to clinically unaffected parents. The paternity and maternity were unequiv ocally confirmed by genotyping. Although one of the parents had to be an ob ligatory carrier for the mutation, we could not detect the mutation in the leukocyte DNA of either parent. To identify which parent was a mosaic for t he mutation we analyzed several tissues from both parents, with a quantitat ive and sensitive solid-phase mini-sequencing method. The mutation was not, however, detectable in any of the analyzed tissues. Although the mutation could not be identified in a sperm sample from the father or in samples of multiple tissue from the mother, we concluded that the mother was the likel y mosaic parent and that the mutation must have occurred during the early d evelopment of her germ-line cells. Mosaicism confined to germ-line cells ha s rarely been reported, and this report of mosaicism for the FBN1 mutation in MFS represents an important case, in light of the evaluation of the recu rrence risk in genetic counseling of families with MFS.