Germline AIP Variants Are Rare in Sporadic Unselected Pituitary Adenomas

Abstract Context Germline AIP variants are recognized causes of familial isolated pituitary adenoma (FIPA), associated with young-onset and aggressive pituitary adenomas (PA). In this study, we evaluated the prevalence and phenotype of AIP variants in sporadic PA in the highly consanguineous population of Saudi Arabia. Methods In this prospective cross-sectional study, 188 non-selected patients (53% males, 44% ≤ 30-year-old, 80.3% macroadenomas) with PAs underwent Sanger sequencing of all exons and exon–intron boundaries of the AIP gene. We also evaluated all curated AIP variants in a local population database of 18,360 whole-exome sequences. Results Among 188 successfully sequenced cases, only two patients (1.1%) harbored AIP variants, both of unknown significance (VUS). The first was a 17-year-old male with a giant prolactinoma, consistent with the classical AIP-associated phenotype, who had a previously reported variant (NM_003977.4:c.563G > A, p.Arg188Gln). The second was a 60-year-old woman with a gonadotroph macroadenoma, atypical for AIP-related disease, who had a variant (c.767C > T, p.Ser256Phe). Neither tumor showed loss of heterozygosity, repeated twice on carefully selected tumor tissue. Thus, the prevalence of VUS was only 2/188 but of pathogenic/likely pathogenic AIP variants was 0/188 (95% CI, 0%–1.9%) overall and 0/151 (95% CI, 0%–2.4%) among macroadenomas. The institutional database showed only 8 AIP VUS in 20 unrelated subjects (0.11%). Conclusion Although this cohort included a high proportion of young patients and macroadenomas, no pathogenic or likely pathogenic AIP variant was found. AIP variants are rare in sporadic PAs in this population, supporting highly selective testing for AIP variants in patients with PA.