OR04-02 KANK1 Deficiencies Underlie A Subset of Male Congenital Genitourinary Anomalies

Abstract

Abstract Disclosure: D.J. Lamb: Advisory Board Member; Self; Roman Health, American Board of Bioanalysts, American Association of Bioanalysts, Northeastern Region. Consulting Fee; Self; Roman Health. Stock Owner; Self; Fellow Health. M.A. O'Neill: None. Development of the genitourinary (GU) system involves several complex processes directed both by genetic and hormonal signals essential for proper sexual differentiation. Studying genetic and genomic variants can provide insight into genes which drive GU development. Using array comparative genomic hybridization (aCGH), 9p24 was identified as a putative hotspot for copy number variants (CNVs) in patients with non-syndromic GU anomalies. Analysis of genes in the minimal overlap region of these CNVs revealed KANK1 as a candidate for GU development. KANK1, an anchor protein, which has been studied in kidney cancer and cerebral palsy, is an important regulator of cytoskeletal formation through the polymerization of f-actin. Using DECIPHER, ICSA, ClinVar, and published datasets a total of 43 CNVs (30 duplications, 13 deletions) encompassing KANK1, variants were identified in patients with GU anomalies including both upper tract and lower tract anomalies. The incidence of KANK1 CNVs was further established by screening non-syndromic patients with GU anomalies from Texas Children’s Hospital by Taqman CNV qPCR and 2.2% of patients screened have KANK1 CNVs. Since the majority of KANK1 CNVs identified encompassed of more than one gene, KANK1 was further analyzed as a causative gene for GU anomalies through an analysis of exome sequencing variants in the University of Washington Center for Mendelian Genomics (Geno2MP). Through Geno2MP, 46 KANK1 missense variants were identified in patients with GU anomalies including hypospadias, cryptorchidism, and nephrotic syndrome. Of these variants, 31 were predicted to be deleterious or probably deleterious by Polyphen2. A mouse model of Kank1 loss was generated by CRISPR/Cas9 deletion to further analyze Kank1’s role in GU development and function. Kank1 deficient males were found to have decreased penile length, abnormal development of the urethral opening, and renal dysfunction. These phenotypes are consistent with those found in patients with Kank1 CNVs and SNPS supporting the hypothesis that KANK1 regulates GU development and function. Presentation: Thursday, June 15, 2023