We studied 338 individuals from 60 kindred: 171 carried the SDHD mutation and 167 resulted wild type. Among the 171 mutation carriers, 88 were affected, 8 resulted asymptomatic after clinical screening, 17 are under investigation, while in 41 subjects the mutation were transmitted by the maternal branch and 17 were asymptomatic being unknown the parent of origin of the mutation. The penetrance resulted nearly complete (92%).
The phenotypic expression in the 88 affected carriers resulted: 30 single HNP, 57 multiple HNPs, 1 Pheo. All patients with single HNP presented a carotid body paraganglioma (CB). Among patients with multiple HNPs 95% presented CB, 33% jugular tympanic, 5% vagal and 5% thoracic PGLs.
To evaluate the prevalence of this mutation in the Trentino population we collected DNA from 4000 native. Preliminary results highlighted a high prevalence in healthy subjects (Val dei Mocheni 4%, Altopiano di Pine 2%).
We investigated the genetic history of this mutation by haplotype analysis using microsatellite markers and SNPs linked to SDHD gene. The analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and the study of the decay of LD, allowed the age estimation of the mutated common ancestor to the 13th-14th century.
The founder effect in an isolated population provides the explanation of the spread of SDHD c. 341 G>C mutation in Trentino. The peculiar transmission of the disease rather than the incomplete penetrance are responsible of the awareness in carriers of the presence of PGL 1 in relatives or ancestors.
An unusual high incidence of HNPs in Trentino was described more than fifty years ago but now we have discovered how, when and why PGL 1 became"epidemic" in Trentino, and we have the tool to predict the predisposition and to provide curative surgery with the least morbidity.