AbstractMultiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited
endocrine tumor syndrome caused by inactivating variants of the MEN1
gene. The aim of this study is to explore the clinical and genetic
characteristics of four MEN1 patients. We isolated genomic deoxyribonucleic acid
from lymphocytes, parathyroid, and thymic tumoral tissue specimens from the MEN1
patients. All exons of the MEN1 and CDNK1B genes and adjacent
exon-intron sequences were amplified by polymerase chain reaction and
subsequently sequenced. Further, the splice alterations were studied by
sequencing the amplified RT-PCR products for MEN1 cDNA. We identified
four heterozygous MEN1 germline variants: c.564delC, c.1268G>A,
IVS5+5delG, and c.1546_1547insC. Both c.564delC and IVS5+5delG
were novel variants. The impact of the MEN1 splice variant,
IVS5+5delG, was evaluated using bioinformatics and in vitro analyses.
The analyses indicated that this variant resulted in skipping of the neighboring
exon and was disease-causing. Two novel somatic variants, c.249_252delGTCT and
c.313_314insC, were found. Additionally, loss of heterozygosity (LOH) for the
MEN1 locus (IVS5+5delG and c.564delC) was found in tumor
tissue samples from the MEN1 patients, consistent with Knudson’s two-hit
mechanism. We identified four MEN1 germline variants and two novel
somatic variants. Early recognition of the phenotype coupled with variant
screening of the MEN1 gene is the key to diagnosing and treating MEN1
effectively at an early stage.