Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory

Purpose: Based on results of diagnostic MEN1 testing, we have attempted to further define the mutational spectrum of the MEN1 gene and the clinical features most frequently associated with MEN1 mutations. Methods: Mutation testing was performed on blood samples by PCR amplification and sequencing of exons 2 to 10 of the MEN1 gene and the corresponding intron-exon junctions. Pedigree phenotypic information was obtained by written questionnaire. Results: Among 288 presumably unrelated pedigrees, 73 independent mutations were found in 89 families. Five mutations were found in 2 pedigrees, and 4 mutations were seen in more than 2 pedigrees. There were 17 nonsense mutations (23.3%), 2 in-frame deletions (2.7%), 18 frameshift-deletion mutations (24.7%), 10 frameshift-insertion or -duplication mutations (13.7%), 13 splice-site mutations (17.8%), and 13 presumptive missense mutations (17.8%). Thirty-nine of 56 pedigrees with parathyroid and pancreatic islet neoplasia tested positive, compared with 4/24 and 8/32 pedigrees affected with hyperparathyroidism or hyperparathyroidism and pituitary tumors. MEN1 mutations were found in 6/20 sporadic patients, all of whom had both parathyroid and pancreatic neoplasms. Of 14 mutation-negative sporadic patients, 10 exhibited hyperparathyroidism and pituitary tumors without islet cell neoplasia. Somatic mosaicism was detected in 1 sporadic patient. Conclusion: Patients from pedigrees with hyperparathyroidism and pancreatic islet tumors are most likely to test positive for MEN1 mutations. Mutations are less often detected in patients from pedigrees with hyperparathyroidism alone or in combination with pituitary tumors without pancreatic islet neoplasia. Sporadic cases are less likely to test positive than familial cases, in part due to somatic mosaicism.