title: Whole-exome identifies RXRG and TH germline variants in familial isolated prolactinoma.
abstract: 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.
authors.affiliation: Department of Surgery, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Flavia M
authors.initials: FM
authors.lastname: Melo
authors.affiliation: Department of Surgery, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Patrícia P
authors.initials: PP
authors.lastname: Couto
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, USA.
authors.forename: Allen E
authors.initials: AE
authors.lastname: Bale
authors.affiliation: Department of Basic Sciences, Universidade Federal de Juiz de Fora, Governador Valadares, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Bastos-Rodrigues
authors.affiliation: Department of Surgery, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Flavia M
authors.initials: FM
authors.lastname: Passos
authors.affiliation: Laboratory of Clinical Genomics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Raony G C
authors.initials: RG
authors.lastname: Lisboa
authors.affiliation: Dept. of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Jessica M Y
authors.initials: JM
authors.lastname: Ng
authors.affiliation: Children's Mercy Hospital Research Institute, Kansas City, MO, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Curran
authors.affiliation: Department of Endocrinology, Hospital Felício Rocho, Belo Horizonte, Brazil.
authors.forename: Eduardo P
authors.initials: EP
authors.lastname: Dias
authors.affiliation: The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.affiliation: Department of Surgery, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Electronic address: Ldemarco@ufmg.br.
authors.forename: Luiz
authors.initials: L
authors.lastname: De Marco
mesh_terms: D000236:Adenoma / Q000235:genetics*; D000328:Adult; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics; D008297:Male; D010375:Pedigree; D015175:Prolactinoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics; D011981:Receptors, Prolactin / Q000737:chemistry / Q000235:genetics; D047491:Retinoid X Receptor gamma / Q000737:chemistry / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000737:chemistry / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; D047491:Retinoid X Receptor gamma; C103265:aryl hydrocarbon receptor-interacting protein; D014446:Tyrosine 3-Monooxygenase
keywords: FIPA; Familial isolated prolactinoma; PRL; whole exome