Introduction: Heterozygous mutations in the AIP gene are associated with young-onset pituitary adenomas while homozygous loss of AIP in animal models is lethal. As early diagnosis could lead to better outcomes, family members of AIP mutation-positive patients need follow up. The R304Q variant is commonly described as pathogenic based on clinical assessment. However, it is also present in the general population (minor-allele-frequency (MAF) 0.0007EVS, 0.0015ExAc) and the European population included homozygote subjects. Functional studies are unable to unequivocally identify abnormal function.
Method: Clinical, histological and family history data were collected on 30 R304Q cases (including four families and 13 known sporadic cases) from the literature, other centres and our own centre. Loss-of-heterozygosity (LOH) analysis was performed on tumour tissue. In silico and experimental data on protein function was reviewed and screening of our large patient cohort (FIPA consortium) was compared to general population databases.
Results: With nine affected patients, the MAF in our pituitary adenoma patient cohort (1149 probands) was not significantly different from that of the ExAc database (P=0.15). No LOH was detected in five tumour samples. In silico predictions using 11 different programs suggest that this is a benign variant, as do functional studies which found that R304Q was similar to the wild-type in 6/7 assays (PDE4A5-assay, AIP-RET interaction, two half-life studies and two fruit fly models), while an in vitro study assessing aryl hydrocarbon receptor-target Cyp1a1 expression showed intermediate results.
Conclusion: Several familial and young-onset sporadic pituitary adenoma cases carry the R304Q AIP variant. In vitro studies, in silico predictions and MAF data suggests that R304Q is a benign polymorphism. This discrepancy between clinical data and experimental results provides a controversial situation sometimes seen in clinical genetics which has potential implications for clinical practice, especially the screening of family members and follow up of carriers.