Deciphering the complexity: a case of kidney failure with co-inheritance of COL4A5 and APOE variants
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Background Alport syndrome represents the most prevalent inherited glomerular disease in chronic kidney disease patients. With the increased utilization of exome-based sequencing in clinical practice, pathogenic variants in Alport syndrome genes- COL4A3/COL4A4/COL4A5 have been detected in patients with more diverse clinical presentations including a proteinuria-predominant phenotype as well as kidney failure of unknown etiology. Complexity also rises when COL4A3/COL4A4/COL4A5 variants are co-inherited with pathogenic variants in other genetic kidney diseases. Case presentation We reported a 31-year-old male presented with kidney failure, prominent proteinuria, familial hematuria and hyperlipidemia. Whole exome sequencing detected two pathogenic variants: hemizygous COL4A5 (p.Gly702Asp) and heterozygous APOE Kyoto (p.Arg43Cys), which prompted the need for a kidney biopsy to confirm the co-occurrence of Alport syndrome and lipoprotein glomerulopathy (LPG). Biopsy findings revealed Alport syndrome histological finding with no LPG-related lesions observed. Cascade screening revealed APOE Kyoto variant in the patient’s father and elder-sister, neither of whom had proteinuria, indicating incomplete penetrance of APOE Kyoto variant in this pedigree. Conclusion This case underscores the utility of kidney biopsy as complementary to the "exome-first" approach for atypical Alport syndrome cases with complex genetic mechanism and also shed light on the incomplete penetrance of APOE Kyoto variant which is not uncommon in Chinese carriers.
