Large AIP deletions require copy-number testing to avoid missed familial pituitary adenoma diagnoses
The study reports a retrospective analysis of published data and two novel cases to characterize large AIP deletions in familial isolated pituitary adenoma. Investigators found that these copy-number variants account for approximately 8% to 10% of all AIP-positive pedigrees and produce clinical phenotypes comparable to point mutations. Because standard Sanger sequencing fails to detect these alterations, the authors recommend integrating multiplex ligation-dependent probe amplification or validated next-generation sequencing copy-number analysis into routine AIP testing workflows. This workflow adjustment is critical for laboratory directors to prevent underdiagnosis of AIP-related pituitary disorders.
The original study
Clinical and Genetic Spectrum of Large AIP Deletions.
- Authors
- Kolnikaj TS, Ruka M, Xhumari A, Babameto-Laku A, Siolos A, Drakos PA, et al.
- Journal
- Human mutation
- Type
- Journal Article
- PMID
- 42732373
Original abstract
Familial isolated pituitary adenoma (FIPA) accounts for approximately 2%-5% of all pituitary adenomas, with inactivating variants of the aryl hydrocarbon receptor-interacting protein (AIP) gene representing the most frequent known genetic cause. Clinically, patients with AIP variants often have young-onset macroadenomas with growth hormone hypersecretion, although disease severity and penetrance are variable. Most reported AIP variants are point mutations, whereas large deletions are rare and potentially underdiagnosed. Accurate detection of AIP copy-number variants requires methods such as multiplex ligation-dependent probe amplification or validated copy-number analysis of next-generation sequencing data, as Sanger sequencing alone may fail to identify these alterations. Due to the rarity of the disease, it is unknown whether large deletions in the ubiquitously expressed AIP gene are associated with potentially more severe phenotype. Available data suggest that large deletions may occur in 8%-10% of AIP mutation-positive pedigrees, highlighting the importance of incorporating copy-number variant detection into AIP testing workflows. We analysed data from all published patients with large AIP deletions (n = 25) and report here two novel large AIP deletions (Exons 3-4 and Exons 2-6 deletions) and three additional three families, including an Albanian kindred associated with metastatic Hürthle cell thyroid carcinoma. No major differences compared with other AIP variants were found in age at diagnosis, tumour size, hormonal profile, sex distribution or presence of other tumours. A role for AIP variants in thyroid carcinogenesis is unlikely.