MP65-12 MURINE RBFOX-2 HAPLOINSUFFICIENCY PARALLELS CONGENITAL ANOMALIES IN HUMAN PATIENTS WITH RBFOX-2 COPY NUMBER VARIANTS

Abstract

You have accessJournal of UrologyPediatrics: Hypospadias and Penile Surgery (MP65)1 Apr 2020MP65-12 MURINE RBFOX-2 HAPLOINSUFFICIENCY PARALLELS CONGENITAL ANOMALIES IN HUMAN PATIENTS WITH RBFOX-2 COPY NUMBER VARIANTS Jeffrey White, Marisol O'Neill, Kunj Sheth, and Dolores Lamb* Jeffrey WhiteJeffrey White More articles by this author , Marisol O'NeillMarisol O'Neill More articles by this author , Kunj ShethKunj Sheth More articles by this author , and Dolores Lamb*Dolores Lamb* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000940.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Copy number variants (CNVs) are micro-deletions or micro-duplications of a chromosome. When these occur in a dosage-sensitive gene, birth defects can develop. Hypospadias is a common, externally identifiable genitourinary birth defect. We hypothesized that, through a top-down approach utilizing CNVs from patients with hypospadias, novel genes in penile development can be discovered. METHODS: By searching CNV databases for hypospadias, candidate genes were identified. Four hypospadic patients had CNVs in the RNA binding FOX 2 (RBFOX-2) gene. TaqMan CNV assays identified the incidence of RBFOX-2 CNVs. By crossing Gdf9-Cre mice with conditional Rbfox-2-Flox mice, Rbfox-2Δ/+ mice (single copy deletion of Rbfox-2) were analyzed using microCT. Gene expression analyses were performed with in vitro and in vivo models. RESULTS: Seventeen patients with RBFOX-2 CNVs were identified in DECIPHER: 4 had hypospadias, 8 had intellectual disabilities, 7 had CNS anomalies, 7 had cardiac defects, and 3 had facial deformities. Though RBFOX-2 CNVs are not common in population-level database (Database of Genomic Variants, 0.11%, n=42,511, p=0.3), samples from patients with GU birth defects identified 11 (2.4%, n=450) with CNVs for RBFOX-2: 21% with hypospadias, 21% cryptorchidism, 29% vesicoureteral reflux and 29% ureteropelvic junction obstruction. When compared with controls (0.0%, n=64), an enrichment of RBFOX-2 CNVs was discovered in GU birth defect patients (p<0.01). A murine model of Rbfox-2 haploinsufficiency was analyzed at E14.5, E16.5 and E18.5. MicroCT was performed to assay for phenotypes. Head defects (hydrocephalus, branchial arch defects and facial asymmetry), chest anomalies (asymmetric cardiac hypertrophy and septal anomalies), abdominal phenotypes (bile duct anomalies and omphalocele), spinal anomalies (neural tube defects), kidney phenotypes (hydroureteronephrosis), and genital tubercle (GT) anomalies (hypospadias) were discovered. Through in vitro and in vivo studies, RBFOX-2 was discovered to have a role in FGFR2 splicing in penile development. CONCLUSIONS: RBFOX-2 gene dosage changes are enriched in patients with GU birth defects but several other organ systems may also be affected. Murine models of Rbfox-2 haploinsufficiency parallel anomalies of humans with RBFOX-2 CNVs. Our data suggest that RBFOX-2 regulates mesenchyme-to-epithelial transitions in the penis and may play a role in basic developmental programs which regulate many organ systems. Source of Funding: This project was supported by the Urology Care Foundation Research Scholar Award funded by the Society of Pediatric Urology and the Sushil Lacy, MD Foundation as well as NIH R01DK078121 © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e978-e978 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jeffrey White More articles by this author Marisol O'Neill More articles by this author Kunj Sheth More articles by this author Dolores Lamb* More articles by this author Expand All Advertisement PDF downloadLoading ...