Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing

Objective Diagnostic molecular genetic testing for multiple endocrine neoplasia type 1 (MEN1) has been available since the identification of the MEN1 gene in 1997. Mutation screening of the MEN1 gene has been recommended for patients who meet clinical criteria for MEN1 (at least two of the following: parathyroid hyperplasia, pancreatic endocrine tumour or pituitary adenoma) and those in whom a diagnosis of MEN1 is suspected. We examined the appropriateness of these clinical criteria. Patients and Methods A total of 292 patients were referred for diagnostic testing. The coding region of the MEN1 gene was sequenced in 186 index cases and mutation testing was requested for 106 subjects, including 83 asymptomatic relatives. Results MEN1 gene mutations were identified in 68/186 index cases (37%). Twenty-nine of the 60 MEN1 mutations reported are novel. The likelihood of finding a mutation was correlated with the number of MEN1-related tumours (mutation detection rate of 79%, 37% and 15% in patients with three, two and one main MEN1-related tumours; P less than or equal to 0.00001) and increased in the presence of a family history (mutation detection rate of 91%, 69% and 29%vs. 69%, 23% and 0% in sporadic cases with three, two or one main MEN1-related tumours, respectively; P less than or equal to 0.00001). The pick-up rate in the 83% of subjects who met proposed criteria for diagnostic testing was 42%, but in those who did not meet these criteria this fell to 0%. Conclusions The likelihood of finding an MEN1 mutation depends on the clinical features of the patient and their family. This large series supports present referral criteria for diagnostic mutation screening, but suggests that patients with sporadic isolated tumours rarely have MEN1 mutations.