Background: Mutation analysis with direct DNA sequencing is commonly used for the molecular diagnosis of multiple endocrine neoplasia type 1 (MEN1). However, a significant number of patients, despite clinical features of MEN1, do not show MEN1 mutations on direct DNA sequencing. Some of these patients may have gross gene deletions not detected by direct DNA sequencing or mutations in the noncoding regions of the gene not examined routinely.
Objective: To determine the prevalence of gross deletions in MEN1 in a large cohort of MEN1 patients.
Patients and methods: During 1997-2006, we screened MEN1 mutations by direct DNA sequencing in 368 probands referred to our diagnostic molecular genetic laboratory. Of these, 101 probands (23 familial, 78 sporadic) fulfilled the clinical criteria for MEN1 (presence of at least two of the parathyroid, pancreatic or pituitary tumours) but were negative for mutations on DNA sequencing. Their DNA samples were examined for gross deletions of one or more exons of MEN1 by using multiple ligation-dependent probe amplification (MLPA) and long-range polymerase chain reaction (PCR) amplification. We also sequenced the minimal promoter region of MEN1 for mutations in the familial cases.
Results: We identified a gross deletion involving exons 5 and 6 of MEN1 in one proband (prevalence rate 1%). The sequencing of the minimal promoter region in the familial cases revealed no mutations.
Conclusion: Gross deletion in the MEN1 gene is an uncommon cause of MEN1 and should be tested for in patients with a high clinical suspicion but without mutations on direct DNA sequencing.