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

• Published in: Cancer genetics Vol. 209; no. 6; pp. 251 - 257
• Main Authors: Melo, Flavia M, Couto, Patrícia P, Bale, Allen E, Bastos-Rodrigues, Luciana, Passos, Flavia M, Lisboa, Raony G.C, Ng, Jessica M.Y, Curran, Tom, Dias, Eduardo P, Friedman, Eitan, De Marco, Luiz
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2016
• Subjects: Adenoma - genetics; Adult; Computer Simulation; DNA Mutational Analysis; Exome; Familial isolated prolactinoma; Female; FIPA; Genetic Predisposition to Disease; Germ-Line Mutation; Growth Hormone-Secreting Pituitary Adenoma - genetics; Hematology, Oncology and Palliative Medicine; Humans; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - genetics; Male; Medical Education; Pedigree; PRL; Prolactinoma - genetics; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - genetics; Receptors, Prolactin - chemistry; Receptors, Prolactin - genetics; Retinoid X Receptor gamma - chemistry; Retinoid X Receptor gamma - genetics; Tyrosine 3-Monooxygenase - chemistry; Tyrosine 3-Monooxygenase - genetics; whole exome; Familial isolated prolactinoma; whole exome; PRL; FIPA
• ISSN: 2210-7762; 2210-7770
• DOI: 10.1016/j.cancergen.2016.05.065

Familial isolated pituitary adenoma (FIPA) is a rare genetic disorder. In a subset of FIPA families AIP germline mutations have been reported, but in most FIPA cases the exact genetic defect remains unknown. The present study aimed to determine the genetic basis of FIPA in a Brazilian family. Three siblings presented with isolated prolactin genes. Further mutation screening was performed using whole-exome sequencing and all likely causative mutations were validated by Sanger sequencing. In silico analysis and secreting pituitary adenoma diagnosed through clinical, biochemical and imaging testing. Sanger sequencing was used to genotype candidate prolactinoma-mutated 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 of three affected siblings revealed novel, predicted damaging, heterozygous variants in three different genes: RXRG , REXO4 and TH . In conclusion, the RXRG and TH possibly pathogenic variants may be associated with isolated prolactinoma in the studied family. The possible contribution of these genes to additional FIPA families should be explored.