Presymptomatic identification of carriers of the multiple endocrine neoplasia type 2A gene using flanking DNA markers.

Abstract

Because the predisposition locus for multiple endocrine neoplasia type 2A (MEN2A) has been mapped to chromosome 10 by genetic linkage analysis, it has become possible to identify gene carriers by following the transmission of linked genetic markers from affected parents to offspring at risk for MEN2A. We have applied a highly accurate genetic test to presymptomatic diagnosis of gene carriers in several large kindreds with MEN2A. DNA was extracted from 300 individuals in six kindreds with MEN2A and used for genotyping studies with DNA markers flanking the MEN2A locus. Genotype data were used to predict the inheritance of the MEN2A gene in kindred members at risk according to previously calculated map distances and the program LINKAGE: Ninety-five percent of individuals were informative with markers flanking the MEN2A locus. Of 130 patients at risk, 26 (20%) were predicted to be MEN2A gene carriers, 100% (77%) were noncarriers, and 4 (3%) were recombinant and their gene carrier status could not be determined. Gene carrier prediction probabilities were calculated at greater than 98% in 94% of these patients. We conclude that genetic testing with flanking DNA markers is a highly accurate method for the presymptomatic identification of MEN2A gene carriers and allows for diagnosis at an earlier stage than does traditional calcitonin testing.