Introduction: Following the well-established association between succinate dehydrogenase (SDH) deficiency and PGL, SDHA/B/C/D mutations have been associated with paraganglioma (PGL), renal cell carcinoma (RCC), gastrointestinal stromal tumour (GIST) and pituitary adenoma (PA).1,2 Some individuals/families have developed more than one tumour;3,4 however, no family has been reported with all tumours. A subset of phaeochromocytoma/PGL associated with germline SDHB mutations harbour somatic ATRX variants, suggesting digenic models of SDH-deficient tumorigenesis.5
Methods: A kindred presented with head and neck PGL in two siblings, GIST in a third sibling and macroprolactinoma in the fourth sibling. Their mother died from RCC. Despite loss of normal SDHB immunostaining in the PGL specimens, routine genetic testing of SDHB/C/D/AF2, as well as RET, VHL and TMEM127 failed to identify causative mutations. We performed in-house whole exome sequencing (WES) using germline DNA from the four siblings and tumour DNA from PGL and GIST formalin-fixed, paraffin-embedded specimens.
Results: WES yielded 199 germline variants that were: rare (<1% population); heterozygous in each sibling (consistent with autosomal dominant inheritance); likely damaging (by in silico analysis); and of high quality and depth of coverage (>30x). These included a novel deep intronic SDHC variant predicted to generate an alternate splice donor site with downstream frameshift, and a novel missense variant in PTCH2, a gene implicated in nevoid basal cell carcinoma syndrome (‘Gorlin’s syndrome’). Transcriptome analysis of whole blood by RNA-Seq is underway to confirm altered SDHC expression and to evaluate other candidate variants. Using similar filtration, we identified 437 somatic variants with involvement of known PGL- and GIST-predisposing genes, raising the possibility of multigenic tumorigenesis pathways.
Conclusions: The highly penetrant coexistence of PGL, RCC, GIST, PA and a novel segregating SDHC mutation describes a new paraganglioma syndrome, with possible contributions from germline and somatic variants in other genes.