Comprehensive Genomic Analysis in Hereditary Adrenal and Extra-Adrenal Paragangliomas.

Pathogenic germline variants in paraganglioma predisposition genes, including structural variants such as an inverted tandem duplication of SDHA in a succinate dehydrogenase-deficient tumour.

Retrospective chart review of 110 individuals with adrenal or extra-adrenal paragangliomas managed in Toronto between 2011 and 2023, using targeted germline panel sequencing, whole genome sequencing (WGS) and optical genome mapping. Panel sequencing identified a pathogenic or likely pathogenic germline variant in 28.18% (31/110) of individuals, and five variants of uncertain significance were reclassified as pathogenic or likely pathogenic during the study period, bringing the total to 32.7% (36/110). Rates of variants of uncertain significance were comparable across groups (16.28%, 7/43 in the non-European group; 17.24%, 10/58 in the European group), but reclassification towards pathogenic was less frequent in the non-European group (28.57%, 2/7 vs 40.0%, 4/10). In seven individuals with succinate dehydrogenase-deficient tumours and uninformative panel testing, WGS identified a pathogenic variant in 6 of 7 cases (85.7%), and optical genome mapping resolved an inverted tandem duplication involving SDHA that WGS alone could not fully characterise. Incidental pathogenic variants were also found in genes without an established paraganglioma association, including TSC1 and PALB2.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The proposed strategy — broad panel plus tumour SDHB immunohistochemistry first, with WGS and optical genome mapping reserved for unresolved cases — largely matches current laboratory practice; the contribution is to quantify the yield of second-line techniques, but in only seven patients, too few to define a decision threshold. The difference in reclassification of variants of uncertain significance by self-reported ethnicity rests on 7 and 10 individuals and should be read as a signal to monitor rather than a demonstrated inequity. The series is single-centre and spans twelve years, during which interpretation criteria and technologies changed, which limits internal comparability.

Analysis by Dr Thibaut Benquey