PD15-01 KANK1 GENETIC AND GENOMIC ANOMALIES AFFECT GENITOURINARY (GU) DEVELOPMENT IN HUMANS

Abstract

You have accessJournal of UrologyPediatric Urology I (PD15)1 Sep 2021PD15-01 KANK1 GENETIC AND GENOMIC ANOMALIES AFFECT GENITOURINARY (GU) DEVELOPMENT IN HUMANS Marisol O'Neill, and Dolores Lamb Marisol O'NeillMarisol O'Neill More articles by this author , and Dolores LambDolores Lamb More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001997.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: 9p24.3 is a chromosome hotspot for human GU anomalies with micro-deletions or -duplications associated with ambiguous genitalia and gonadal dysgenesis. One gene in 9p24.3, DMRT1, is needed for normal testicular fetal development. Using array comparative genomic hybridization (aCGH) together with retrospective literature/database analysis, locus mapping identified 60 patients with 9p24.3 CNVs of 37 duplications and 23 microdeletions. 50 of these patients had disorders of sexual differentiation, 7 had congenital anomalies of the kidney and urinary tract (CAKUT). We identified a second gene candidate in the minimal overlap region of 9p24.3 5' to DMRT1 that encompasses KN Motif and Ankyrin Repeat Domain Containing Protein 1 (KANK1). We used human and mouse models to test the hypothesis that genetic and genomic defects of KANK1 also resulted in anomalies of the external genitalia and CAKUT. METHODS: A mouse model of haploinsufficiency was generated using CRISPR-Cas9 to delete Kank1 and mice phenotyped. Penile and renal anomalies were defined by micro-CT analysis. Patients with upper and lower tract genitourinary birth defects underwent phenotypic analysis, genetic and genomic analysis by aCGH and whole exome sequencing. RESULTS: A mouse model of Kank1 haploinsufficiency exhibited renal dysfunction, penile anomalies and subfertility. KANK1 genetic variants were identified by Whole Exome Sequencing (WES) in patients with GU anomalies-2 had novel variants; one individual with an absent cervix, vaginal atresia and two novel variants resulting in nonsynonymous changes of two consecutive amino acids (p.C1187F and p.N118Y) both predicted to be deleterious. 14 individuals were identified with 10 rare variants, five of which (rs61737971, rs148744436, rs143675911, rs74458120, rs370051574) were present in individuals with CAKUT, renal insufficiency, focal segmental glomerulosclerosis, abnormal reproductive track development, hypospadias, bladder exstrophy- glomerular fibrosis, renal dysfunction, penile anomalies were also present in the Kank1 haploinsufficient mouse models. CONCLUSIONS: This study identifies a novel mechanism that underlies some GU birth defects which are usually surgically repaired with the etiology defined as idiopathic. This study identified renal dysfunction and a potentially severe kidney phenotype, as well as developmental anomalies of the penis caused by KANK1 haploinsufficiency in humans & mouse models. Source of Funding: T32 DK007763 (MO was a trainee) & R01DK078121 from NIDDK & Frederick J. and Theresa Dow Wallace Fund of the NY Community Trust (awarded to DJL) © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e272-e272 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Marisol O'Neill More articles by this author Dolores Lamb More articles by this author Expand All Advertisement Loading ...