Endocrine Abstracts

Background: Mutations in the AIP gene cause Familial Isolated Pituitary Adenomas (FIPA). While two specific AIP mutations in Northern Ireland and England suggest a shared ancestor, the clinical impact of this shared ancestry remains unknown. We aimed to analyse common AIP mutations, determine their origin from shared ancestors and assess their impact on clinical features.

Methods: We analysed 389 carriers with 54 unique AIP mutations from the International FIPA Consortium. We also reviewed the UK Biobank population cohort for additional families. We determined shared ancestral origins using identity-by-descent analysis of array genotyping data. We then compared clinical features between carriers with and without a shared ancestral haplotype.

Results: We identified four recurrent mutations in multiple unrelated families in the FIPA consortium with additional families in the UK Biobank: p.R304* (97 carriers / 35 pedigrees), p.F269_H275dup (21 carriers / 13 pedigrees), p.R271W (9 carriers / 8 pedigrees), and p.R81* (4 carriers / 2 pedigrees). Analysis showed 23/35 (66%) families with the p.R304* variant shared a single haplotype. Of these, 16 (70%) families originated from Northern Ireland, and 3 (13%) from Scotland, and 4 (17%) from England. Additionally, 11 (85%) families with the p.F269_H275dup variant shared a haplotype and were all from England. In contrast, p.R271W and p.R81* variants showed no evidence of a shared ancestral origin. Clinical comparison of p.R304* carriers with (n = 106) and without (n = 27) the shared haplotype revealed no significant differences in individuals with and without adenoma, age at diagnosis/symptom onset, tumour size, tumour invasiveness, or need for multiple surgeries (P > 0.05).

Conclusion: The p.R304* and p.F269_H275dup AIP variants originate from shared ancestral haplotypes with distinct geographical distributions across the UK and Ireland. However, the shared ancestry does not appear to significantly alter disease severity suggesting the absence of major modifier variant in the AIP gene.