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Nephronophthisis (NPH) is a ciliopathy primarily affecting renal tubules and interstitial tissue, ultimately progressing to end-stage kidney disease (ESKD). The clinical spectrum of NPH is broad and can be classified according to the age at onset into infantile, juvenile, adolescent, and late-onset forms. Histopathologically, NPH is characterized by corticomedullary cysts, tubular atrophy, interstitial fibrosis, and cystic dilatation of distal tubules. The kidneys may appear normal in early stages but gradually shrink with disease progression. More than 20 causative genes have been identified, with NPHP1 being the most common. These genes encode proteins that localize predominantly to the ciliary transition zone and basal body, where they regulate ciliary structure and signaling. Loss of ciliary function disrupts epithelial polarity, intracellular trafficking, and signal transduction, leading to tubular injury and fibrosis. When extrarenal organs such as the retina, liver, or central nervous system are affected, the condition is defined as nephronophthisis-related ciliopathies (NPH-RC). This review summarizes the current understanding of NPH classification, clinical features, and molecular mechanisms. Here, we highlighted recent advances in genetic discoveries, pathogenic signaling pathways, and therapeutic strategies, including gene therapy and targeted molecular interventions.

Nephronophthisis (NPH), a rare but serious ciliopathy, is the predominant genetic cause of end-stage kidney disease (ESKD) in children and adolescents. Renal tubular dilatation and cyst formation are key pathological features of NPH. The mechanisms underlying renal cystogenesis remain poorly understood. This study employed sex-balanced Nphp1 deletion gene knockout (Nphp1KO) mice at 8, 12, and 24 weeks of age to investigate the spatiotemporal dynamics of renal tubules and cyst development, aiming to identify the origins of renal cysts. Quantitative evaluation of cyst progression revealed a significant increase in cyst number from 8 to 12 weeks of age, but no substantial change from 12 to 24 weeks. Additionally, cyst size remained stable throughout the study period. Serial section tracing and segment-specific tubular marker analysis confirmed that these cysts originated from the distal convoluted tubule (DCT), which displayed segmental dilation while preserving anatomical connections with adjacent, morphologically normal DCT. 3D reconstruction revealed that renal cysts appeared either as a single or in a bead-like arrangement. We demonstrated that human renal cyst epithelial cells from patients with NPH1 also originate primarily from the DCT. This study provides critical experimental evidence of the histopathological features of renal cysts in NPH1, advancing our understanding of the pathogenesis of NPHP-associated tubular dilation and cystogenesis.

BACKGROUND: A significant proportion of patients present with chronic kidney disease of unexplained cause (CKDx) despite standard-of-care diagnostic workup. Data from Australian, European and United States cohorts show that some are due to monogenic etiology. The diagnostic yield and clinical utility of genetic testing in Chinese patients remains unclear. METHODS: We prospectively recruited adult CKDx patients following up at Queen Mary Hospital nephrology unit from 1 Oct 2022 to 1 June 2024. After genetic counselling, patients underwent whole genome sequencing focused on kidney disease genes(637 genes). Variants classification was performed according to the American College of Medical Genetics guidelines. RESULTS: Among 131 CKDx patients, 92% self-identified as Chinese and 21% presented with kidney failure. Mean age at clinical presentation was 35 years. 36% had positive family history of CKD. We identified Pathogenic/Likely pathogenic variants in 13 patients, giving a diagnostic yield of 10%. 33% of variants identified were novel. Variants in type IV collagen genes(COL4A3, COL4A5, COL4A4) were the most frequent, followed by ALG9, CEP290 and IFT140. Alport-spectrum disorders were the leading genetic diagnoses, representing 77% of all genetically positive cases. A significantly higher proportion of patients with positive genetic findings had positive family history of CKD or CKDx, compared to those with negative genetic findings (CKD: 85% versus 31%, p<0.001; CKDx: 77% versus 19%, p<0.001). CONCLUSIONS: Monogenic etiology could be established in 10% of adult CKDx patients in Hong Kong. Alport-spectrum disorders were the leading genetic diagnoses, followed by atypical Autosomal Dominant Polycystic Kidney Disease and nephronophthisis. Genetic testing in CKDx population is clinically useful since a significant proportion could reach a diagnosis and permit disease specific management.

Nephronophthisis is a rare genetic disorder affecting the kidneys and is one of the leading causes of end-stage kidney disease in children. The Bombay blood group is an extremely rare blood type that poses serious clinical challenges, particularly when managing patients with chronic kidney diseases. This report described a 3-year-old female patient who presented with severe anemia and kidney impairment, which progressed to end-stage kidney disease. During blood grouping, she was unexpectedly identified as having the Bombay phenotype, complicating her anemia management. Genetic testing revealed two novel pathogenic variants: one in the NPHP2 gene, associated with nephronophthisis, and another in the FUT1 gene, which is responsible for the Bombay blood group. The child received treatment involving fluid restriction and diuretic infusions. However, she subsequently progressed to end-stage kidney disease with significant fluid overload and required peritoneal dialysis. Anemia management was achieved through intravenous iron and erythropoiesis-stimulating agents (erythropoietin), eliminating the need for blood transfusions. This case underscores the rare coexistence of nephronophthisis and the Bombay blood group alongside novel mutations, highlighting the critical need for early genetic diagnosis and intervention. It also emphasizes the complexities of managing patients with such rare blood types, which complicate potential transfusion options.

Nephronophthisis is an autosomal recessive ciliopathy and a major genetic cause of end-stage kidney disease in children and young adults. Although next-generation sequencing panels have improved diagnostic yield, some patients remain genetically unresolved, partly due to deep intronic variants that disrupt pre-mRNA splicing and are not captured by exon-focused approaches. We report a 13-year-old boy who presented with advanced kidney dysfunction, small renal cysts, and kidney histopathology consistent with nephronophthisis. Targeted gene panel sequencing failed to identify causative pathogenic variants beyond a missense variant of uncertain significance. Whole-genome sequencing subsequently revealed compound heterozygous variants in IFT172 (NM_015662.3): a missense variant (c.4696C > T, p.Arg1566Cys) and a deep intronic variant (c.4915-94A > G). In silico analysis predicted activation of cryptic splice sites leading to inclusion of an 86-bp pseudoexon, which was confirmed by a minigene splicing assay. These findings established a molecular diagnosis of IFT172-related nephronophthisis. To our knowledge, this is the first report demonstrating pseudoexon inclusion in IFT172, thereby expanding its mutational spectrum. Our case underscores the importance of evaluating deep intronic regions using whole-genome sequencing and functional validation in genetically unresolved nephronophthisis.