Primary Hyperoxaluria Type 3 in Siblings with a HOGA1 Variant of Uncertain Significance: Divergent Clinical Presentations and the Role of Genetic Testing

Introduction: Primary hyperoxaluria (PH) comprises rare autosomal recessive disorders caused by enzymatic defects in hepatic glyoxylate metabolism, leading to oxalate overproduction. PH type 3, due to HOGA1 variants, is the rarest form, often linked to recurrent nephrolithiasis and typically preserved renal function. Unlike PH1, no specific treatment is available, and clinical progression is variable. Interpreting variants of uncertain significance (VUS) poses diagnostic challenges. Case Description: We report three siblings with a shared homozygous HOGA1 variant (chr10:99,358,651), classified as a VUS, and differing clinical features consistent with PH3. The index case, a 57-year-old man, had a history of hypertension, recurrent nephrolithiasis, and spontaneous stone passage. Imaging showed multiple bilateral renal calculi without nephrocalcinosis. Urine analysis revealed borderline elevated oxalate and hypocitraturia. Plasma oxalate was indicated but not performed. Despite conservative management, he progressed to advanced CKD with eGFR of 13 mL/min/1.73m2. His sisters, aged 60 and 68, also had recurrent stones, normal serum creatinine, and mildly reduced eGFRs compatible with age. Imaging confirmed nephrolithiasis without nephrocalcinosis. A deceased brother had a history of kidney stones and died on dialysis, suggesting undiagnosed PH. Genetic testing confirmed the same homozygous HOGA1 variant in all living siblings. Discussion: This series highlights the phenotypic heterogeneity of PH3 in a single family. While the sisters remain stable, the index case experienced significant renal decline, and a fourth sibling likely had undiagnosed disease. Though often mild, PH3 can lead to kidney failure if unrecognized. Management remains supportive, focusing on hydration, diet, and monitoring. The presence of a shared HOGA1 VUS across affected individuals underscores the importance of genetic testing in familial nephrolithiasis. Clinical context and family history are key to interpreting uncertain variants and guiding care.