DETECTION OF FRAGILE-X NON-PENETRANT MALES BY DNA MARKER ANALYSIS

Segregation analysis of the fragile-X [fra(X)] syndrome uncovered an unexpected 20% excess of normal males among sibships by Sherman et al. (Sherman SL, Morton NE, Jacobs PA, Turner G [1984]. Ann Hum Genet 48:21-37; Sherman SL, Jacobs PA, Morton NE, Froster-Iskenius U, Howard-Peebles PN, Nielsen KB, Partington MW, Sutherland GR, Turner G, Watson M [1985]: Hum Genet 63:289-299). This result predicts that about 17% (1/6) of normal sons of carrier fra(X) females will be non-penetrant. A way to test this prediction is by DNA markers. We analyzed DNA samples from 100 families with a set of flanking DNA markers linked to the fra(X) locus. Ten of 51 (19.6%) normal brothers, doubly informative and non-recombinant for flanking DNA markers, were found to be non-penetrant males. This result closely confirms the predictions of the segregation analysis indicating that about 1/6 of normal brothers are non-penetrant carrier males. The use of DNA markers to identify non-penetrant brothers and grandfathers can help to clarify the inheritance of the fra(X) mutation and be of considerable clinical usefulness. Using DNA markers, it was possible to study grandparental transmission in 71 of the families. In 39 families, DNA analysis confirmed the apparent pattern of inheritance. In 18 families, the grandparents had a single daughter with affected children. Of these, a new mutation at the time of their daughters' conception was possible in 15 and quite likely in 3. In 14 families with 2 or more daughters with affected fra(X) offspring, the grandparents had no affected sons or other relatives known to be positive for fra(X). In 6 of these families, only 2 daughters had affected sons and transmission was found to be from a non-penetrant grandfather in 3. In the other 8 families, 3 or more daughters had affected sons and the grandfather was found to be a transmitting male in 7. These results have allowed guidelines to be formulated to assist with genetic counseling in the use of DNA markers in detecting non-penetrant males.