#2412 Monoallelic NEK8-related polycystic kidney disease in an Irish ADPKD cohort

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD), commonly caused by pathogenic variants in PKD1 and PKD2 genes, leads to enlarged cystic kidneys and typically present in adulthood where ∼70% of affected patients progress to kidney failure by their 7th decade of life. Recently, new genes have been reported that appear to explain some of the previously unresolved ADPKD-like cases. An example is the NEK8 gene, where monoallelic variants are reported to cause early-onset ADPKD with progressive phenotype. We are reporting 4 Irish families with monoallelic NEK8 variants. Method In-depth clinical and radiological evaluations were conducted on 250 families with polycystic kidney disease referred to the Irish Kidney Gene Project. All patients underwent genomic testing using gene-panel and exome Next Generation Sequencing (NGS), while multiple ligation probe amplification analysis of PKD1 or PKD2 was utilized in genetically unresolved families. The American College of Medical Genetics and Genomics guidelines were applied to assess variant pathogenicity. Results To date, 471 individuals representing 250 distinct families (F) have been studied, including 105 (42%) families with two or more individuals (326 individuals). 55.2% have reached end-stage kidney failure, with an average age of 49.1 ± 14.3 years. We identified pathogenic / likely pathogenic variants in 76% (190/250) of families, with variants in PKD1 accounting for 76.8% (146/190) and PKD2 accounting for 15.3% (29/190) of families, respectively. In familial cases with non-PKD1/PKD2 variants, we identified pathogenic variants in a small proportion of families with ADPKD-like phenotypes: IFT140 variants (n = 4), ALG5 (n = 2), 17q12 microdeletion (n = 2) and DNAJB11, ALG8, and ALG9 variants (n = 1 each). Upon thorough review of all genetically unresolved PKD families, 4 (6.7%) families were identified with monoallelic protein-kinase domain NEK8 variants [NM_178170.3]: p.R45W (in 2 families) and two other missense variants: p.N69D and p.R140L, none of which contained a second NEK8 variant despite extensive analysis. Autosomal dominant segregation was confirmed in two parent-child pairs, whereas the remaining two index patients reported no family history of kidney disease. The median age at the initial presentation was 12 years (IQR: 2.5–27.3), with a median follow-up period of 22.5 years at the last evaluation. The phenotype of all patients was consistent with polycystic kidney disease with the absence of liver and pancreatic cysts. All patients were diagnosed with hypertension at an average age of 15.3 ± 12.2 years. Cerebral aneurysms were detected in two patients (F1: at age 61 years and F4: at age 54 years), while F3 was reported to have childhood-onset frontal bossing, prominence cerebrospinal fluid, and large arachnoid cysts. Approximately 67% [4/6] patients progressed to end-stage kidney failure by the 3rd decade of life. Compared to families with PKD1/PKD2 variants, families with NEK8 variants were characterized by earlier average age at initial presentation (14.5 versus 29.9 years; p 0.01) and progression to end-stage kidney failure (15.5 versus 49.6 years; p < 0.0001). Table 1 summarizes the clinical and genetic characteristics of the reported families. Conclusion We provide further evidence that monoallelic NEK8 variants cause early presentation and progressive ADPKD-like phenotype. Sequencing for monoallelic NEK8 variants in patients with childhood and early-adulthood cystic kidney disease can inform renal prognosis, treatment planning, familial screening and reproductive choices.