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Background <p>Alport syndrome (AS) is the most common inherited glomerular disease among patients with chronic kidney disease. With exome sequencing now widely used in clinical practice, pathogenic variants in Alport-related genes (<i>COL4A3/COL4A4/COL4A5</i>) are increasingly identified in patients with diverse phenotypes, including proteinuria‑predominant disease and kidney failure of unknown etiology. Diagnostic complexity further increases when <i>COL4A3/COL4A4/COL4A5</i> variants are co‑inherited with pathogenic variants associated with other genetic kidney disorders.</p> Case presentation <p>We reported a 31‑year‑old male presenting with kidney failure, significant proteinuria, familial hematuria and hyperlipidemia. Whole‑exome sequencing (WES) identified two pathogenic variants: a hemizygous <i>COL4A5</i> variant (c.2105G &gt; A; p.Gly702Asp) and a heterozygous <i>APOE</i> Kyoto variant (c.127C &gt; T; p.Arg43Cys). Given the potential dual diagnosis of AS and lipoprotein glomerulopathy (LPG), a kidney biopsy was performed. Histologic examination revealed uneven thickness of the glomerular basement membrane consistent with the diagnosis of AS, but no LPG-related lesions were observed, indicating incomplete penetrance of <i>APOE</i> Kyoto variant. Cascade family screening detected <i>APOE</i> Kyoto variant in the patient’s father and elder sister, both of whom lacked proteinuria until follow-up period.</p> Conclusion <p>This case highlights the complementary role of kidney biopsy alongside WES in AS with complex genetic mechanisms. It also illustrates the incomplete penetrance of <i>APOE</i> Kyoto, common among Chinese carriers.</p>

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Deciphering the complexity: a case of kidney failure with co-inheritance of COL4A5 and APOE variants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月29日

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  • Xiaoyan Zhang,
  • Shi Jin,
  • Xuantong Dai,
  • Chenlin Yao,
  • Ziyi Zhao,
  • Fujun Lin,
  • Yiqin Shi

摘要

Background

Alport syndrome (AS) is the most common inherited glomerular disease among patients with chronic kidney disease. With exome sequencing now widely used in clinical practice, pathogenic variants in Alport-related genes (COL4A3/COL4A4/COL4A5) are increasingly identified in patients with diverse phenotypes, including proteinuria‑predominant disease and kidney failure of unknown etiology. Diagnostic complexity further increases when COL4A3/COL4A4/COL4A5 variants are co‑inherited with pathogenic variants associated with other genetic kidney disorders.

Case presentation

We reported a 31‑year‑old male presenting with kidney failure, significant proteinuria, familial hematuria and hyperlipidemia. Whole‑exome sequencing (WES) identified two pathogenic variants: a hemizygous COL4A5 variant (c.2105G > A; p.Gly702Asp) and a heterozygous APOE Kyoto variant (c.127C > T; p.Arg43Cys). Given the potential dual diagnosis of AS and lipoprotein glomerulopathy (LPG), a kidney biopsy was performed. Histologic examination revealed uneven thickness of the glomerular basement membrane consistent with the diagnosis of AS, but no LPG-related lesions were observed, indicating incomplete penetrance of APOE Kyoto variant. Cascade family screening detected APOE Kyoto variant in the patient’s father and elder sister, both of whom lacked proteinuria until follow-up period.

Conclusion

This case highlights the complementary role of kidney biopsy alongside WES in AS with complex genetic mechanisms. It also illustrates the incomplete penetrance of APOE Kyoto, common among Chinese carriers.