Increased Population Risk ofAIP-Related Acromegaly and Gigantism in Ireland

Abstract

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.

Three Reportedly Unrelated Families With Liddle Syndrome Inherited From a Common Ancestor

“…With the present study, we infer the evolutionary history of the disease-causing allele detected in all three affected families, building on an approach developed for another successful prediction of under-diagnosed cases of a rare disease [25, 26].…”

“…Indeed, estimating the number of generations that separate reportedly unrelated patients, has important consequences on the prediction of the number of additional affected individuals yet to be diagnosed in a given population source. Previously, successful strategies were deployed to apply evolutionary inference to tackle this problem [25, 26]. Particularly, approaches based on coalescent theory were adopted, where the convergence of the alleles of a given locus to their common ancestor from an earlier time is used to make inferences on the evolutionary history of the examined DNA sequence and, hence, on the genetic relationships of the screened probands.…”

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

“…However, often limited information is available due to medical histories not being shared between family members; geographical or social separation of the kindred; relatives dying prematurely of causes unrelated to the disorder; incomplete or variable disease penetrance; small kindred size with insufficient family members to establish clear pedigrees; or instances of nonpaternity. Knowledge of the geographical origin of the kindred may also be important and indicate the presence of a known founder mutation (eg acromegaly/gigantism due to the Arg304Ter AIP variant in Ireland; MEN2A due to Cys611Tyr RET mutation in Denmark) . A relevant family history will be absent in instances of de novo mutation (eg the majority of patients with MEN2B, female cases with XLAG), disorders associated with somatic mosaicism (eg McCune‐Albright syndrome, sporadic male cases with XLAG), and is often absent for autosomal recessive disorders and disorders with reduced disease penetrance.…”

“…As such, the penetrance estimates above are intended to be illustrative. References relevant to specific genes include AIP 19,42 ; CDC73 123,124 ; MEN1 26,125 ; SDH complex genes 11,12,120,121 ; PRKAR1A 28 ; RET 23,24,126 ; and VHL. 127 Penetrance estimates for MEN4 due to CDKN1B mutations are not available due to low numbers of reported cases.…”

Genetics of pituitary adenomas

“…The majority of AIP mutations are truncating mutations (stop codon, splice mutations, frameshifts). A few hotspot mutations have been described, such as the R304Stop mutation, which has been shown to be a founder mutation in Ireland [72,73] and Italy, [74] but has also been identified in India, UK, and Mexico; [75,76] or the R81Stop or the R271W, which has been identified in several independent cases. It is important to remember that only ~20% of AIP mutation carriers actually develop the disease, which usually occurs in teenage years, and patients over the age of 30 years with normal MRI and biochemistry results are unlikely to develop the disease later.…”