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Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by mutations of the tumor suppressor gene  MEN1 . Most of the germline  MEN1  gene mutations have been small mutations, and the whole gene deletion is rarely observed. In the present study, we revealed  Alu  retrotransposon-mediated  de novo  germline deletion of the whole  MEN1  gene and somatic copy-neutral loss of heterozygosity (LOH) in a patient with MEN1. The patient is a 39-year-old woman who was referred to our department for the management of prolactinoma. She was also diagnosed with primary hyperparathyroidism and suspected of MEN1. Although nucleotide sequencing did not detect any  MEN1  gene mutations, multiplex ligation-dependent probe amplification (MLPA) revealed a large germline deletion of the  MEN1  gene. Subsequent quantitative polymerase chain reaction (qPCR)–based copy number mapping showed a monoallelic loss of approximately 18.5-kilobase region containing the whole  MEN1  gene. Intriguingly, the 2 breakpoints were flanked by  Alu  repetitive elements, suggesting the contribution of  Alu / Alu -mediated rearrangements (AAMR) to the whole  MEN1  gene deletion. Furthermore, copy number mapping using MLPA and qPCR in combination with single nucleotide polymorphism analysis revealed copy-neutral LOH as a somatic event for parathyroid tumorigenesis. In conclusion, copy number mapping revealed a novel combination of  Alu / Alu -mediated  de novo  germline deletion of the  MEN1  gene and somatic copy-neutral LOH as a cytogenetic basis for the MEN1 pathogenesis. Moreover, subsequent in silico analysis highlighted the possible predisposition of the  MEN1  gene to  Alu  retrotransposon-mediated genomic deletion.

Alu-Mediated MEN1 Gene Deletion and Loss of Heterozygosity in a Patient with Multiple Endocrine Neoplasia Type 1