Germline AIP variants are rare in sporadic unselected pituitary adenomas

Abstract

Context: Germline AIP variants are recognized causes of familial isolated pituitary adenoma, 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 2 patients (1.1%) harbored AIP variants, both variants of uncertain 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.

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BibTeX RIS

BibTeX

@article{rajab2026germline,
  title = {{Germline AIP variants are rare in sporadic unselected pituitary adenomas}},
  author = {Mohamed Rajab and Balgees Alghamdi and Allianah Benito and Burair Alsaihati and Mohamed Abouelhoda and Hindi Alhindi and Ali S Alzahrani},
  journal = {Journal of the Endocrine Society},
  year = {2026},
  month = oct,
  doi = {10.1210/jendso/bvag242},
  url = {https://europepmc.org/article/PMC/PMC13728844},
  note = {CC BY-NC-ND},
}

RIS

TY  - JOUR
TI  - Germline AIP variants are rare in sporadic unselected pituitary adenomas
AU  - Mohamed Rajab
AU  - Balgees Alghamdi
AU  - Allianah Benito
AU  - Burair Alsaihati
AU  - Mohamed Abouelhoda
AU  - Hindi Alhindi
AU  - Ali S Alzahrani
PY  - 2026
DA  - 2026/10/16
JO  - Journal of the Endocrine Society
DO  - 10.1210/jendso/bvag242
UR  - https://europepmc.org/article/PMC/PMC13728844
AB  - Context: Germline AIP variants are recognized causes of familial isolated pituitary adenoma, 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 2 patients (1.1%) harbored AIP variants, both variants of uncertain 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.
SN  - 2472-1972
ER  -

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