CONTEXT: Anecdotal evidence suggests a high incidence in Trentino, Italy, of head and neck paragangliomas (HNPGL), a rare autosomal dominant disease called paraganglioma type 1 syndrome and caused by germ-line mutations of the SDHD gene. OBJECTIVE: The aim of this study was to investigate the origin, spread, and clinical expression of the disease in this geographic region. DESIGN, SETTING, AND PARTICIPANTS: Trentino natives with HNPGL were recruited for establishing clinical expression of the disease, presence of a founder effect, and age of common ancestor. A large sample of the local population was recruited for determination of mutation prevalence and spread. MAIN OUTCOME MEASURES: SDHD genetic testing was offered to first-degree relatives, and clinical surveillance was offered to at-risk carriers. The hypothesis of a founder effect was explored by haplotype analysis, and time to the most recent common ancestor was estimated by decay of haplotype sharing over time. RESULTS: A total of 287 of the 540 recruited individuals from 95 kindreds carried the SDHD c.341A>G p.Tyr114Cys mutation. The prevalent phenotype was bilateral or multiple HNPGL, with low prevalence of pheochromocytoma and malignant forms. Penetrance was high. A common ancestor was dated between the 14th and 15th century, with the mutation spreading from the Mocheni Valley, a geographic, cultural and, presumably, a genetic isolate to 1.5% of the region's population. CONCLUSIONS: A combination of particular demographic, geographical, and historical conditions has resulted in the oldest and largest SDHD founder effect so far characterized and has transformed a rare disease into an endemic disease with major public health implications.
CONTEXT: Anecdotal evidence suggests a high incidence in Trentino, Italy, of head and neck paragangliomas (HNPGL), a rare autosomal dominant disease called paraganglioma type 1 syndrome and caused by germ-line mutations of the SDHD gene. OBJECTIVE: The aim of this study was to investigate the origin, spread, and clinical expression of the disease in this geographic region. DESIGN, SETTING, AND PARTICIPANTS: Trentino natives with HNPGL were recruited for establishing clinical expression of the disease, presence of a founder effect, and age of common ancestor. A large sample of the local population was recruited for determination of mutation prevalence and spread. MAIN OUTCOME MEASURES: SDHD genetic testing was offered to first-degree relatives, and clinical surveillance was offered to at-risk carriers. The hypothesis of a founder effect was explored by haplotype analysis, and time to the most recent common ancestor was estimated by decay of haplotype sharing over time. RESULTS: A total of 287 of the 540 recruited individuals from 95 kindreds carried the SDHD c.341A>G p.Tyr114Cys mutation. The prevalent phenotype was bilateral or multiple HNPGL, with low prevalence of pheochromocytoma and malignant forms. Penetrance was high. A common ancestor was dated between the 14th and 15th century, with the mutation spreading from the Mocheni Valley, a geographic, cultural and, presumably, a genetic isolate to 1.5% of the region's population. CONCLUSIONS: A combination of particular demographic, geographical, and historical conditions has resulted in the oldest and largest SDHD founder effect so far characterized and has transformed a rare disease into an endemic disease with major public health implications.
Authors: Berdine L Heesterman; Lisa M H de Pont; Andel Gl van der Mey; Jean-Pierre Bayley; Eleonora Pm Corssmit; Frederik J Hes; Berit M Verbist; Peter Paul G van Benthem; Jeroen C Jansen Journal: Eur J Hum Genet Date: 2018-05-18 Impact factor: 4.246
Authors: Laurence Amar; Karel Pacak; Olivier Steichen; Scott A Akker; Simon J B Aylwin; Eric Baudin; Alexandre Buffet; Nelly Burnichon; Roderick J Clifton-Bligh; Patricia L M Dahia; Martin Fassnacht; Ashley B Grossman; Philippe Herman; Rodney J Hicks; Andrzej Januszewicz; Camilo Jimenez; Henricus P M Kunst; Dylan Lewis; Massimo Mannelli; Mitsuhide Naruse; Mercedes Robledo; David Taïeb; David R Taylor; Henri J L M Timmers; Giorgio Treglia; Nicola Tufton; William F Young; Jacques W M Lenders; Anne-Paule Gimenez-Roqueplo; Charlotte Lussey-Lepoutre Journal: Nat Rev Endocrinol Date: 2021-05-21 Impact factor: 43.330
Authors: Marc Bennedbæk; Maria Rossing; Åse K Rasmussen; Anne-Marie Gerdes; Anne-Bine Skytte; Uffe B Jensen; Finn C Nielsen; Thomas V O Hansen Journal: Hered Cancer Clin Pract Date: 2016-06-08 Impact factor: 2.857
Authors: Serban Radian; Yoan Diekmann; Plamena Gabrovska; Brendan Holland; Lisa Bradley; Helen Wallace; Karen Stals; Anna-Marie Bussell; Karen McGurren; Martin Cuesta; Anthony W Ryan; Maria Herincs; Laura C Hernández-Ramírez; Aidan Holland; Jade Samuels; Elena Daniela Aflorei; Sayka Barry; Judit Dénes; Ida Pernicova; Craig E Stiles; Giampaolo Trivellin; Ronan McCloskey; Michal Ajzensztejn; Noina Abid; Scott A Akker; Moises Mercado; Mark Cohen; Rajesh V Thakker; Stephanie Baldeweg; Ariel Barkan; Madalina Musat; Miles Levy; Stephen M Orme; Martina Unterländer; Joachim Burger; Ajith V Kumar; Sian Ellard; Joseph McPartlin; Ross McManus; Gerard J Linden; Brew Atkinson; David J Balding; Amar Agha; Chris J Thompson; Steven J Hunter; Mark G Thomas; Patrick J Morrison; Márta Korbonits Journal: Hum Mutat Date: 2016-10-04 Impact factor: 4.700