Germline mutations in young-onset sporadic pituitary macroadenomas: a multigene panel analysis

Objective: Mutations in several genes have been associated with familial forms of pituitary adenomas. Sporadic pituitary adenomas (i.e. with no family history or coexistent endocrine tumours) are also occasionally found to result from germline mutations in these genes, especially in young patients with larger tumours. The aim of this study was to determine the frequency of germline mutations in patients with young-onset sporadic pituitary macroadenomas. Methods: A cohort of 225 Portuguese patients with sporadic pituitary macroadenomas diagnosed before the age of 40 years was studied by whole exome sequencing (WES) followed by the analysis of a virtual panel of 29 genes that have been associated with predisposition to pituitary adenomas. Results: Pathogenic and likely pathogenic variants were identified in 16 (7.1%) of patients. The affected genes were AIP (n=4), PMS2 (n=4), MEN1 (n=2), VHL (n=2), CDH23 (n=1), MSH2 (n=1), SDHB (n=1), and TP53 (n=1). In patients diagnosed under the ages of 30 and 18 years, the frequency of mutations increased to 9.0% and 12.0%, respectively. Conclusion: This is so far the largest multigene analysis of patients with young-onset sporadic pituitary macroadenomas. We confirmed the AIP as the most frequently involved gene, but also uncovered rarer genetic causes of pituitary adenomas, including the first independent confirmation of a role of the CDH23 gene. The results may contribute to a better understanding of the genetic landscape of these tumours and help to decide which genes to include in the genetic screening of patients with young-onset pituitary macroadenomas. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded by the Portuguese Foundation for Science and Technology (FCT, project grants PTDC/MEC-MET/29489/2017 and UIDB/00709/2020). LM Gaspar was the recipient of a PhD fellowship from FCT (SFRH/BD/147160/2019). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee of the Faculty of Health Sciences, University of Beira Interior gave ethical approval for this work (Ref: CE-UBI-Pj-2018-027 and CE-FCS-2011-003) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data from this study are available from the corresponding author on reasonable request.