Background: A founder mutated AIP allele, R304* was previously identified in several Irish familial isolated pituitary adenoma (FIPA) pedigrees from a small region within Mid Ulster, Northern Ireland, but the alleles general population impact remains unknown.
Aims: To estimate R304* prevalence in the general population and pituitary adenoma (PA) patients and to calculate the alleles time to most recent common ancestor (tMRCA).
Methods: We tested for AIP mutations 116 somatotrophinoma patients from the Belfast and Dublin endocrine tertiary referral centres and studied additional R304*-positive pedigrees from our international FIPA database (five Irish/five non-Irish). We genotyped three population samples from Mid Ulster (n=936), Greater Belfast (n=1000) and Republic of Ireland (ROI, n=2094). Based on AIP-centred microsatellite haplotypes, we estimated through coalescent-based simulation the R304* alleles tMRCA and current number of allele carriers.
Results: R304* was very frequent in somatotrophinoma patients (12.6%/6.8% in Belfast/Dublin). General population prevalence estimates were 6/936 (95% CI: 0.00230.013; Mid Ulster), 1/1000 (95% CI: 0.0000250.0055; Greater Belfast) and 0/2094 (95% CI: 00·0014; ROI). All 18 Irish pedigrees (two identified through population screening) shared a recent common ancestor, while the non-Irish pedigrees were independent from each other and from the Irish founder. The Irish pedigrees median tMRCA was 2550 years (95% CI: 12755000). Forward simulation predicted 144 allele carriers/generation (95% CI: 301725).
Conclusions: R304* has a clinically-relevant prevalence in Ireland, especially in Mid Ulster, due to an approximately 2500-year old founder ancestor. While 40 affected carriers have already been identified, we estimated through forward simulation that 86 PA cases are currently alive (95% CI: 181035). Although R304* population screening cannot be currently advocated, our data strongly support the testing of Irish-origin young-onset somatotrophinoma patients. Our study generated increased disease awareness locally, possibly leading to early diagnosis of these typically aggressive AIP-related PAs, crucial to their effective management.