Background: Familial pituitary tumour syndromes account for approximately 5% of all pituitary tumours. The recent discovery of new players in pituitary tumorigenesis such as AIP and the SDHx genes together with increasing clinical experience with next generation sequencing (NGS) may unveil greater prevalence and better inform patient management.
Methods: We developed a custom NGS panel (Roche/Nimblegen) containing 8 known familial pituitary tumour genes, 25 genes involved in embryonic pituitary development and 267 genes implicated in various oncogenic pathways. Subjects had pituitary tumours suspected to be familial due to presentation below the age of 40 years, another multiple endocrine neoplasia 1 (MEN1) tumour, or family history of MEN1-related neoplasia. DNA was extracted from peripheral blood leucocytes and sequenced using our 300-gene panel (Illumina HiSeq 2500 sequencing). Sanger sequencing was performed for validation. Raw data was analysed by a custom bioinformatic pipeline and variants with a population frequency <1% were considered for pathogenicity. Variants were further evaluated by in silico analysis, comparison with genetic databases, and wider literature reviews.
Results: Clinical and genetic data were collated for 28 subjects with qualifying conditions including prolactinomas, acromegaly, gigantism, Cushing’s disease and non-functioning pituitary adenomas. NGS revealed potentially pathogenic germline mutations in seven patients, three with two rare variants, including AIP (p.F269F, p.A299V, p.R106C, p.R304*), MEN1 (p.R176Q), SDHA (p.D38V), and SDHB (p.A2V).
Conclusions: NGS has a high yield of genetic variants with potential pathogenicity. Individual patients had multiple relevant variants that may interact through digenic inheritance which would have been unrecognised in single or staged gene analysis. NGS data on well-described variants can be fed back to patient and clinician to guide therapeutic decisions and family screening, whilst novel genetic findings may elucidate new contributors to pituitary tumorigenesis and lead to novel treatment options.