Whole-exome sequencing identifies RXRG and TH germline variants in familial isolated prolactinoma

Abstract

Pituitary adenomas are common intracranial tumors that occur sporadically. In some rare cases this condition is identified in familial clusters and has no involvement with other endocrine tumors, a disorder identified as Familial Isolated Pituitary Adenoma (FIPA). FIPA development has been associated with genetic abnormalities, especially in AIP gene, where germline mutations have been reported in approximately 20% of cases. Mutations in the MEN1 gene have been described in a subset of pituitary adenoma families, but with bona fide multiple endocrine neoplasia type 1 feature. Mutations in prolactin receptor (PRLR) have also been associated to pituitary adenoma in animal models. Thus, in most FIPA cases the exact genetic defect that lead to disease development remains unknown. Therefore, the aim of this work is to determine the genetic basis of FIPA in a Brazilian family. The studied family is composed of three siblings presented with isolated prolactinsecreting pituitary adenoma diagnosed through clinical, biochemical and imaging testing. Sanger sequencing was used to genotype candidate genes AIP, MEN1 and PRLR. Further mutation screening was performed using whole-exome sequencing. In silico analysis and additional predictive algorithms were applied to prioritize likely pathogenic variants. No mutations in the coding and flanking intronic regions in the MEN1, AIP and PRLR genes were detected. Whole-exome sequencing revealed novel, predicted damaging, heterozygous variants in three different genes: RXRG, REXO4 and TH. The RXRG and TH possibly pathogenic variants may be associated with isolated prolactinoma in the studied family and the possible contribution of these genes to additional FIPA families should be explored.