Endocrine Abstracts

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary tumor syndrome. Common manifestations include more than 20 tumors of the parathyroid, pituitary and pancreatic glands and others non-endocrine tumors. The majority of patients carry a germline mutation in a tumor-suppressor gene MEN1, that encodes nuclear protein menin, ubiquitously expressed. So fare, more than 600 germline or somatic mutations have been reported over the entire coding region. Approximately 70% of mutations lead to premature truncation of menin (20% nonsense, 50% frame shift).

Subjects: In years 20015–2019 we have screened 72 basic patients with suspected MEN1 syndrome from the whole Czech republic and in positive findings we have examined their 20 direct relatives.

Methods: All 10 exons with introns flanking regions and 3´and 5´ UTR regions of MEN1 gene were analyzed by next generation sequencing (NGS) using kit Nextera XT on Miseq (Illumina).

Results: Sexteen germline mutations were identified in 18 of 72 basic patients with suspected MEN1 syndrome and in 12 of their 20 relatives. Six of detected variants have not been described yet: S113Qfs3X, D123Mfs31X, L267R, G281W, c.1049 + 9G > C and E392Gfs17X. In silico analysis detected these variants as pathogenic or probably pathogenic. Ten variants were previously described in families with MEN1 syndrome or familial primary hyperparathyroidism: I85Sfs32X, I85Lfs32X, T210Sfs13X, S226X, Q258X, c.784–9G > A, N374Tfs3X, D418H, C421R and R516Pfs15X. Furthermore, we have identified 3 intron variants with uncertain significance (by in silico analysis): c.–55C > T (pathogenic moderate), c.913–142C > T (likely benign) and c.913–159G > A (possible effect on splice site). We could not assess their clinical impact.

Conclusion: We confirmed the diagnosis of MEN1 syndrome in 25% of suspected basic patients and in 60% of their direct relatives. 62.5% from detected variants leaded to truncated menin (50% frame shift and 12.5% nonsense mutations), 25% were missense variants and 12.5% of the variants affected splice site. As regards newly detected genetic variants, we continue to examine other members of families to confirm the clinical impact of the variants.

Support: MHCR – RVO EÚ 00023761.