collagen–encoding genes were also reported in patients with a histologic diagnosis of FSGS. Pathogenic COL4A3/COL4A4/COL4A5 variants were recently identified in familial cases of IgAN, but the contribution of these variants to sporadic IgAN is still unclear. Methods We compared 161 patients with sporadic IgAN with tGBM lesions (IgAN-tGBM) to matched patients with IgAN without tGBM lesions and matched patients with thin basement membrane nephropathy (TBMN). Variants of COL4A3/COL4A4/COL4A5 genes were screened and evaluated after whole-exome sequencing. GBM thickness was measured, and levels of circulating galactose-deficient IgA1 (Gd-IgA1) were assessed by ELISA. Results The patients with IgAN-tGBM manifested milder disease than did patients with IgAN without tGBM but had more severe features than the patients with TBMN. Exome sequence analysis of the 122 patients with IgAN-tGBM identified 37 diagnostic variants of the COL4A3/COL4A4/COL4A5 genes among 38 patients (31.1%). Furthermore, patients with IgAN-tGBM who had diagnostic variants had higher proportions of GBM thickness <250 nm and milder glomerular injury, whereas patients with IgAN-tGBM who did not have diagnostic variants showed more characteristic features of IgAN, including higher intensity of glomerular IgA deposits and elevated Gd-IgA1 levels. These findings suggest different mechanisms in patients with versus without diagnostic variants of these collagen genes. Conclusions COL4A3/COL4A4/COL4A5 variant detection is essential in evaluating patients with sporadic IgAN with tGBM lesions....

中文翻译：

---

COL4A3、COL4A4 和 COL4A5 基因的遗传变异导致散发性 IgA 肾病患者肾小球基底膜病变变薄


组织学诊断为 FSGS 的患者中也有报道胶原蛋白编码基因。最近在 IgAN 家族病例中发现了致病性 COL4A3/COL4A4/COL4A5 变异，但这些变异对散发性 IgAN 的贡献仍不清楚。方法 我们将 161 例伴有 tGBM 病变的散发性 IgAN 患者 (IgAN-tGBM) 与匹配的无 tGBM 病变的 IgAN 患者以及匹配的薄基底膜肾病 (TBMN) 患者进行了比较。全外显子组测序后筛选并评估了 COL4A3/COL4A4/COL4A5 基因的变异体。测量 GBM 厚度，并通过 ELISA 评估循环半乳糖缺陷型 IgA1 (Gd-IgA1) 水平。结果 IgAN-tGBM 患者比不伴 tGBM 的 IgAN 患者病情较轻，但比 TBMN 患者病情更严重。对 122 名 IgAN-tGBM 患者的外显子组序列分析在 38 名患者 (31.1%) 中发现了 COL4A3/COL4A4/COL4A5 基因的 37 个诊断变异。此外，具有诊断变异的 IgAN-tGBM 患者具有较高比例的 GBM 厚度 <250 nm 和较轻的肾小球损伤，而没有诊断变异的 IgAN-tGBM 患者则表现出更多的 IgAN 特征，包括较高的肾小球 IgA 强度沉积物和 Gd-IgA1 水平升高。这些发现表明，具有这些胶原蛋白基因诊断变异的患者与不具有诊断变异的患者存在不同的机制。结论 COL4A3/COL4A4/COL4A5 变异检测对于评估伴有 tGBM 病变的散发性 IgAN 患者至关重要。