PREDICTIVE TESTING FOR MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A (MEN 2A) BASED ON THE DETECTION OF MUTATIONS IN THE RET PROTOONCOGENE

Background. The identification of inherited mutations in the RET proto oncogene (RET) associated with multiple endocrine neoplasia type 2A (M EN 2A) has enabled the development of a genetic test to identify asymp tomatic carriers of disease. Methods. Genomic DNA was extracted from 9 6 members of an MEN 2A kindred. The polymerase chain reaction was used to amplify the RET exon known to contain the associated mutation. The mutation results in a new restriction endonuclease site and is detect ed by digestion with the appropriate enzyme. Inheritance of the mutati on was verified with a previously developed genetic linkage test. Resu lts. We Sound that (1) mutations vary among kindreds but are consisten tly inherited within kindreds, (2) invariable correlation exists betwe en mutation and disease (43 mutations in 43 affected individuals), (3) determination of the genetic status by linkage-based testing was prec luded by recombination events and the informativeness of genetics mark ers, and (4) mutation analysis presymptomatically identified two genet ically affected individuals. Conclusions. Direct genetic analysis Sor mutations in RET circumvents the limitations of linkage-based genetic testing and current biochemical screening assays. This method will be the diagnostic test of choice Sor the identification of asymptomatic i ndividuals at risk for MEN 2A.