#4410 NOVEL DOMINANT ALG5 VARIANT IN TWO UNRELATED FAMILIES WITH LATE-ONSET ADPKD AND ATYPICAL TUBULOINTERSTITIAL CHANGES

Abstract

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder renowned for its clinical and genetic heterogeneity. Recently, variants in the ALG5 gene have been described as a cause of atypical ADPKD and interstitial fibrosis through the disruption of polycystin 1 maturation and trafficking via underglycosylation. In this report, we investigated genetic cause of the disease in two unrelated Irish families displaying late-onset ADPKD phenotype with atypical tubulointerstitial changes. Method Routine clinical and radiological evaluations were carried out. Available kidney biopsy specimens were reassessed. Genetic testing was performed on probands and all relatives with cystic kidneys. First, a custom-targeted gene panel of 227 genes associated with kidney disease was used, but the causal variant was not identified. Then reading frame-changing variants in variable number tandem repeats region of MUC1 were excluded by single-molecule real-time sequencing. Whole exome sequencing revealed a variant in the ALG5 gene, which is not included in the initial custom gene panel. By targeted Sanger sequencing, segregation of the variant with the disease phenotype was confirmed in both investigated families. Multiple bioinformatic tools were employed to predict the effect on protein structure and functions. Results The clinical diagnosis was consistent in most of the 20 affected individuals with non-enlarged cystic kidneys and few or no liver cysts. All but 1 individual underwent radiological assessment; 7 had kidney and liver cysts, 7 had only kidney cysts, and 5 had no kidney cysts at ages 68.6±14.4, 55.1±15.8, 46.8±15.6 years, respectively. Polycystic liver phenotype (>20 cysts) was present in two individuals. Biopsy-proven extensive kidney interstitial fibrosis and cystic tubular dilation were evident in four affected individuals with available kidney samples. Of the 20 genetically-defined individuals, 4 had end-stage kidney failure at a mean age of 70.25±3.1 years. Ten individuals were CKD stage 3 or greater, while 6 were CKD stage 4 or lower at ages 43.2±12.6 and 63.1±7.5 years (P value 0.004). A novel heterozygous missense variant in the ALG5 gene (NM_013338.5, c.235C>T, p.Arg79Trp) was identified in affected members from investigated families. Genetic screening of 20 affected and 10 unaffected individuals from both pedigrees revealed segregation of the variant with the disease phenotype. The novel ALG5 variant was classified as likely pathogenic as it was absent in the Genome Aggregation Database (gnomAD), is located in a conserved region and is predicted to be deleterious on protein stability. Conclusion This study expands the clinical and genetic spectrum of the identified range of ADPKD, considering the pathogenic ALG5 variants. Establishing a precise diagnosis of atypical cystic and interstitial kidney disease is crucial, with essential implications including follow-up, genetic counselling, prognostication, and therapeutic interventions.