In:
The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 97, No. 4 ( 2012-04-01), p. E637-E641
Abstract:
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 & gt;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.
Type of Medium:
Online Resource
ISSN:
0021-972X
,
1945-7197
DOI:
10.1210/jc.2011-2597
Language:
English
Publisher:
The Endocrine Society
Publication Date:
2012
detail.hit.zdb_id:
2026217-6
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