Endocrine Abstracts (2015) 38 P304 | DOI: 10.1530/endoabs.38.P304

The founder R304* AIP mutation is prevalent in Irish acromegaly and gigantism patients as well as in the general population of Ireland

Serban Radian1,2, Yoan Diekmann3, Plamena Gabrovska1, Brendan Holland1, Lisa Bradley4, Helen Wallace5, Karen Stals6, Anna-Marie Bussell6, Karen McGurren7, Martin Cuesta7, Anthony W Ryan8, Maria Herincs1, Laura C Hernández-Ramírez1, Aidan Holland1, Jade Samuels1, Elena Daniela Aflorei1, Sayka Barry1, Judit Dénes1, Ida Pernicova1, Craig E Stiles1, Giampaolo Trivellin1, Ronan McCloskey1, Michal Ajzensztejn9, Noina Abid9, Scott A Akker1, Moises Mercado10, Mark Cohen11, Rajesh V Thakker12, Stephanie Baldeweg13, Ariel Barkan14, Madalina Musat2, Miles Levy15, Steve Orme16, Martina Unterländer17, Joachim Burger17, Ajith V Kumar18, Sian Ellard6, Joseph McPartlin19, Ross McManus8, Gerard J Linden20, Brew Atkinson5, Mark G Thomas3, David J Balding3,21, Amar Agha7, Chris J Thompson7, Steve J Hunter5, Patrick J Morrison4,22 & Márta Korbonits1

1Department of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK; 2Department of Endocrinology, “C. Davila” University of Medicine and Pharmacy and C.I Parhon National Institute of Endocrinology, Bucharest, Romania; 3Research Department of Genetics, Evolution and Environment, University College London, London, UK; 4Department of Medical Genetics, Belfast HSC Trust, Belfast, UK; 5Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, UK; 6Department of Molecular Genetics, Royal Devon and Exeter Foundation Trust, Exeter, UK; 7Department of Endocrinology and Diabetes, Beaumont Hospital/RCSI Medical School, Dublin, Ireland; 8Department of Clinical Medicine and Institute of Molecular Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, St James’s Hospital, Dublin, Ireland; 9Royal Belfast Hospital for Sick Children, Belfast, UK; 10Endocrinology Service/Experimental Endocrinology Unit, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, IMSS, Mexico City, Mexico; 11Barnet General Hospital, London, UK; 12Academic Endocrine Unit, University of Oxford, Oxford, UK; 13University College London Hospitals, London, UK; 14University of Michigan, Ann Arbor, MI, USA; 15Department of Endocrinology, University Hospitals of Leicester, Leicester, UK; 16Department of Endocrinology, St James’s University Hospital, Leeds, UK; 17Institute of Anthropology, Johannes Gutenberg University, Mainz, Germany; 18North East Thames Regional Genetics Service, Great Ormond Street Hospital, London,UK; 19Trinity Biobank, Institute of Molecular Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, St James’s Hospital, Dublin, Ireland; 20Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK; 21Schools of Biosciences and of Mathematics & Statistics, University of Melbourne, Australia; 22Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK.

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 allele’s general population impact remains unknown.

Aims: To estimate R304* prevalence in the general population and pituitary adenoma (PA) patients and to calculate the allele’s 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* allele’s 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: 0.0023–0.013; Mid Ulster), 1/1000 (95% CI: 0.000025–0.0055; Greater Belfast) and 0/2094 (95% CI: 0–0·0014; 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: 1275–5000). Forward simulation predicted 144 allele carriers/generation (95% CI: 30–1725).

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: 18–1035). 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.

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