Program Nr: 410 from the 2004 ASHG Annual Meeting

Clinical Testing for Hereditary Paraganglioma. J.A. Kant1, J. Uhrmacher1, B.E. Baysal2, F.A. Monzon1, A.B. Carter1. 1) Dept Pathology, Univ Pittsburgh, Pittsburgh, PA; 2) Dept OB-GYN, Univ Pittsburgh, Pittsburgh, PA.

   Hereditary paraganglioma (PGL) is an autosomal dominant neoplasia susceptibility syndrome. PGL has been associated with mutations in 3 proteins of the 4-subunit succinate-ubiquinone oxidoreductase (SDH) electron transport complex II - primarily the SDHD and SDHB genes. MRI can be used to follow high-risk mutation-positive patients. Molecular genetic testing for PGL has been offered clinically for several years to ~125 patients from North America with a history of benign or malignant paraganglioma. Bi-directional DNA sequencing of all exons and adjacent intron sequences is performed on the SDHD and/or SDHB genes. The usual reason for testing is to screen probands followed by testing of family members if a mutation is identified. Analysis is occasionally requested on patients with paraganglioma and no obvious family history; there has been one request for prenatal testing. SDHD or SDHB analysis is done after discussion with the submitting professional based on the location of paraganglioma(s) in the proband and family pedigree. SDHD is studied first in those with head and neck tumors and/or a history of paternal transmission. SDHB is studied first when there is maternal transmission and/or abdominal tumors. In the SDHD gene, 5 reported mutations and 6 new variants have been identified including 5 missense, 3 nonsense, 1 frameshift, and 2 splice site changes. In the SDHB gene, 7 reported mutations and 14 new variants have been identified including 11 missense, 3 nonsense, 2 frameshift, and 5 splice site changes. In addition, several polymorphisms have been identified in both genes. 17 probands have shown no mutation in either gene. The clinical significance of new variants is evaluated taking in account predicted effects on the protein, whether disease-associated mutations have been reported at the same amino acid, as well as calculated effects of splice variants on information content. Results are reported following ACMG Recommendations for Interpretation of Sequence Variations. A particularly interesting family without mutation in the SDHD gene demonstrates a haplotype of 3 neutral polymorphic markers which segregate with the paraganglioma phenotype.