Endocrine Abstracts

Introduction: Pituitary adenomas can cause severe life-long disease due to abnormal pituitary function. Identifying potentially causative germline variants in young-onset and familial cases is challenging and most cases remain unsolved.

Methods: Whole exome sequencing was performed on blood-derived DNA from 222 samples to identify rare germline disease-causing variants. 67 samples originated from 23 AIP-negative families and 99 cases were early-onset pituitary adenoma patients with no known family history. The phenotype-based variant prioritisation software Exomiser was used to curate a list of genes containing potentially contributing variants. Variants were filtered to only include those with an autosomal dominant mode of inheritance (for families) where the variant fully segregated and a heterozygous genotype for singletons, with a minor allele frequency less than 0.001%.

Results and Conclusions: 294 genes were found in three or more kindreds, with 39 of these being constrained with a loss-of-function observed/expected upper bound fraction less than 0.5, according to gnomAD, suggesting that these genes have a relatively lower frequency of loss-of-function variants in the general public. Twelve of these genes harboured shared rare variants where the variant itself was found in three or more kindreds, with two containing a shared, loss-of-function variant. While our pipeline has identified genes containing potentially novel disease-causing variants, further work is needed to confirm the presence of these variants by Sanger sequencing and before starting mechanistic studies for disease mechanism.

Acknowledgements: Special thanks to the FIPA consortium without whom this research would not be possible. https://www.qmul.ac.uk/fipa-patients/fipa-consortium/