In December, 1993, we initiated a pilot project in which DNA fragile X (fraX) testing was offered during routine prenatal or genetic counseling to all pregnant women seen at the Genetics & IVF Institute, most of whom were referred for the indication of advanced maternal age. A brochure on fragile X syndrome was sent to each patient prior to her appointment and was reviewed by a counselor or physician during the counseling session. As of June 1995, 3,345 patients were offered testing; 474 women with no identified family history of mental retardation or learning disability and 214 women with a positive family history accepted the test on a self‐pay basis. The second population screened was 271 potential donors in our anonymous egg donor program. DNA from blood was tested by Southern blot using EcoRI/EagI and StB12.3. If an expansion was detected, CGG repeat number was determined by PCR‐based analysis. Among the 474 patients with unremarkable family histories, three fraX carriers were identified (repeat sizes = 60+), whereas none were found in the 214 patients with a positive family history. Among the potential egg donors, two high borderline patients were identified (repeat sizes = between 50 and 59). Our ongoing study indicates that screening of pregnant or preconceptual populations for fraX carrier status using DNA testing is accepted by many patients and is an important addition to current medical practice. © 1996 Wiley‐Liss, Inc.

In December, 1993, we initiated a pilot project in which DNA fragile X (fraX) testing was offered during routine prenatal or genetic counseling to all pregnant women seen at the Genetics & IVF Institute, most of whom were referred for the indication of advanced maternal age. A brochure on fragile X syndrome was sent to each patient prior to her appointment and was reviewed by a counselor or physician during the counseling session. As of June 1995, 3,345 patients were offered testing; 474 women with no identified family history of mental retardation or learning disability and 214 women with a positive family history accepted the test on a self-pay basis. The second population screened was 271 potential donors in our anonymous egg donor program. DNA from blood was tested by Southern blot using EcoRI/EagI and StB12.3. If an expansion was detected, CGG repeat number was determined by PCR-based analysis. Among the 474 patients with unremarkable family histories, three fraX carriers were identified (repeat sizes = 60+), whereas none were found in the 214 patients with a positive family history. Among the potential egg donors, two high borderline patients were identified (repeat sizes = between 50 and 59). Our ongoing study indicates that screening of pregnant or preconceptual populations for fraX carrier status using DNA testing is accepted by many patients and is an important addition to current medical practice.

Individuals with developmental delay who are found to have only fragile X premutations present an interpretive dilemma. The presence of the premutation could be an unrelated coincidence, or it could be a sign of mosaicism involving a full mutation in other tissues. To investigate three cases of this type, buccal epithelium was collected on cytology brushes for Southern blot analysis. In one notable case, the blood specimen of a boy with developmental delay was found to have a premutation of 0.1 extra kb, which was shown by PCR to be an allele of 60 ± 3 repeats. There was no trace of a full mutation. Mosaicism was investigated as an explanation for his developmental delay, although the condition was confounded by prematurity and other factors. The cheek epithelium DNA was found to contain the premutation, plus a methylated full mutation with expansions of 0.9 and 1.5 extra kb. The three populations were nearly equal in frequency but the 1.5 kb expansion was the most prominent. Regardless of whether this patient has clinical signs of fragile X syndrome, he illustrates that there can be gross tissue‐specific differences in molecular subpopulations in mosaic individuals. Because brain and epithelium are more closely related embryonically than are brain and blood, cryptic full mutations in affected individuals may be evident in epithelial cells while being absent or difficult to detect in blood. This phenomenon may explain some atypical cases of the fragile X phenotype associated with premutations or near‐normal DNA findings. © 1996 Wiley‐Liss, Inc.

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