Long-term follow-up and novel splice donor mutation in in a Chinese family.

Heterozygous germline mutation of the tumor suppressor gene is responsible for multiple endocrine neoplasia type 1. Parathyroid and thoracic neuroendocrine tumor specimens and DNA from two Han Chinese MEN1 family patients were analyzed using whole exome and Sanger sequencing. The proband (II-3) was sequentially diagnosed with pituitary adenoma, pancreatic tumor, adrenal cortical tumor, abdominal lipoma, and parathyroid adenoma during the 6-year follow-up. The son of the proband (III-6) was also diagnosed with a thoracic neuroendocrine tumor and a parathyroid adenoma during this period. Splice alterations were studied by RT-PCR and sequencing. The mutation impact was evaluated using bioinformatics. Sequence analysis revealed a novel splice donor mutation, IVS9 + 1G > C, that changed the splicing mode of MEN1 to halt translation before two nuclear localization signals in the menin protein. Novel somatic mutations, c.1402_1405delGAGG and c.286 C > T, were identified in the parathyroid adenoma of II-3 and thoracic neuroendocrine tumor of III-6, respectively, indicating a two-hit etiology of MEN1 syndrome. Our study revealed the clinical and genetic basis of MEN1 in this Han Chinese family and provides insight into MEN1 mechanisms, diagnosis, and management.