TY  - JOUR
AU  - Radian, S
AU  - Diekmann, Y
AU  - Gabrovska, P
AU  - Holland, B
AU  - Bradley, L
AU  - Wallace, H
AU  - Stals, K
AU  - Bussell, A-M
AU  - McGurren, K
AU  - Cuesta, M
AU  - Ryan, AW
AU  - Herincs, M
AU  - Hernandez-Ramirez, LC
AU  - Holland, A
AU  - Samuels, J
AU  - Aflorei, ED
AU  - Barry, S
AU  - Denes, J
AU  - Pernicova, I
AU  - Stiles, CE
AU  - Trivellin, G
AU  - McCloskey, R
AU  - Ajzensztejn, M
AU  - Abid, N
AU  - Akker, SA
AU  - Mercado, M
AU  - Cohen, M
AU  - Thakker, RV
AU  - Baldeweg, S
AU  - Barkan, A
AU  - Musat, M
AU  - Levy, M
AU  - Orme, SM
AU  - Unterlaender, M
AU  - Burger, J
AU  - Kumar, AV
AU  - Ellard, S
AU  - McPartlin, J
AU  - McManus, R
AU  - Linden, GJ
AU  - Atkinson, B
AU  - Balding, DJ
AU  - Agha, A
AU  - Thompson, CJ
AU  - Hunter, SJ
AU  - Thomas, MG
AU  - Morrison, PJ
AU  - Korbonits, M
Y2  - 2021/02/05
Y1  - 2017/01/01
SN  - 1059-7794
UR  - http://hdl.handle.net/11343/260428
AB  - The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304* ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.
LA  - English
PB  - WILEY-BLACKWELL
T1  - Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland
DO  - 10.1002/humu.23121
IS  - Human Mutation
VL  - 38
IS  - 1
SP  - 78-85
L1  - /bitstream/handle/11343/260428/PMC5215436.pdf?sequence=1&isAllowed=y
ER  -