A five-year experience with fragile X testing: Setting laboratory standards of practice and a cost-effective protocol

During the years 1990-1994, our center tested 652 patients, with a broad range of referral indications, for fragile X syndrome using either cytogenetic analysis alone (Protocol 1) or, more recently, a combination of DNA analysis and routine karyotyping (Protocol 2). The overall positive rate for fragile X was 3.1% with an incidence of other chromosomal abnormalities (OCAs) of 3.2%. Breakdown of cases using each testing protocol along with percent positives is: Fragile X Positives Cases Definitive Equivocal OCA Protocol 1:322 (49,4%) 6 (1.9%) 7 (2.2%) 8 (2.5%) Protocol 2:330 (50.6%) 7 (2.1%) 0 13 (3.9%). Use of Protocol 2 yielded only definitive fragile X results, while more than half of the 'positives' using Protocol 1 were equivocal. Historically this has been problematic for both the laboratory and physician since interpretation is often dependent on an equally equivocal clinical picture. Protocol 2 eliminates these diagnostic dilemmas without compromising detection of other chromosomal abnormalities, the incidence of which appears to be unaffected by testing method used. The overall incidence of OCA of 3.2% underscores the value of routine karyotyping in this referral group and likely reflects the phenotypic variability of fragile X and its clinical overlap with other chromosomal abnormalities. We believe that a fragile X testing protocol combining routine karyotyping with definitive molecular technology represents the most cost-effective diagnostic approach to this clinically challenging patient population.