Germline Variants in Sporadic Pituitary Adenomas

Abstract

Context Data on germline genetics of pituitary adenomas (PA) using whole exome sequencing (WES) are limited. This study investigated the germline genetic variants in patients with PA using WES. Patients and Methods We studied 134 consecutive functioning (80.6%) and non-functioning (19.4%) PA in 61 females (45.5%) and 73 males (54.5%). Their median age was 34 years (range 11-85) and 31 had microadenomas (23.0%) and 103 macroadenomas (77%). None of these patients had family history of PA or a known PA-associated syndrome. Peripheral blood DNA was isolated and whole exome sequenced. We used ACMG criteria and a number of in silico analysis tools to characterize genetic variant pathogenicity levels and focused on previously reported PA-associated genes. Results We identified 35 variants of unknown significance (VUS) in 17 PA-associated genes occurring in 40 patients (29.8%). Although designated VUS by the strict ACGM criteria, they are predicted to be pathogenic by in silico analyses and their extremely low frequencies in 1000 genome, gnomAD, and the Saudi Genome Project databases. Further analysis of these variants by the Alpha Missense analysis tool yielded 8 likely pathogenic variants in 9 patients in the following genes: AIP:c.767C > T (p.S256F), CDH23:c.906G > C (p.E302D), CDH23:c.1096G > A (p.A366T), DICER1: c.620C > T (p.A207 V), MLH1:c.955G > A (p.E319 K), MSH2:c.148G > A (p.A50T), and SDHA: c.869T > C (p.L290P) and USP48 (2 Patients): c.2233G > A (p.V745 M). Conclusions This study suggests that about 6.7% of patients with apparently sporadic PA carry likely pathogenic variants in PA-associated genes. These findings need further studies to confirm them.