BACKGROUND Understanding the genetic basis of human diseases has become integral to drug development and precision medicine. Recent advancements have enabled the identification of molecular pathways driving diseases, leading to targeted treatment strategies. The increasing investment in rare diseases by the biotech industry underscores the importance of genetic evidence in drug discovery and approval processes. Here we studied a monogenic Mendelian kidney disease, TRPC6-associated podocytopathy (TRPC6-AP), to present its natural history, genetic spectrum, and clinicopathological associations in a large cohort of patients with causal variants in TRPC6, in order to help define the specific features of disease and further facilitate drug development and clinical trials design. METHODS the study involved 64 individuals from 39 families with TRPC6 causal missense variants. Clinical data, including age of onset, laboratory results, response to treatment, kidney biopsy findings, and genetic information, were collected from multiple centers nationally and internationally. Exome or targeted sequencing was performed and variant classification was based on strict criteria. Structural and functional analyses of TRPC6 variants were conducted to understand their impact on protein function. In depth re-analysis of light and electron microscopy specimens for 9 available kidney biopsies was conducted to identify pathological features and correlates of TRPC6-AP. RESULTS Large-scale sequencing data did not support causality for TRPC6 protein-truncating variants. We identified 21 unique TRPC6 missense variants, clustering in three distinct regions of the protein, and with different effects on TRPC6 3D protein structure. Kidney biopsy analysis revealed FSGS patterns of injury in most cases, along with distinctive podocyte features including diffuse foot process effacement and swollen cell bodies. The majority of patients presented in adolescence or early adulthood but with ample variation (average 22, SD ± 14 years), with frequent progression to kidney failure but with variability in time between presentation and ESKD. CONCLUSIONS This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP.

中文翻译：

---

TRPC6 相关足细胞病的自然史和临床病理学关联。


背景 了解人类疾病的遗传基础已成为药物开发和精准医学不可或缺的一部分。最近的进展使识别驱动疾病的分子途径成为可能，从而产生了靶向治疗策略。生物技术行业对罕见病的投资不断增加，这凸显了遗传证据在药物发现和审批过程中的重要性。在这里，我们研究了一种单基因孟德尔肾病，TRPC6 相关足细胞病 （TRPC6-AP），以呈现其在 TRPC6 中具有因果变异的大量患者的自然病程、遗传谱和临床病理关联，以帮助定义疾病的具体特征并进一步促进药物开发和临床试验设计。方法 该研究涉及来自 39 个具有 TRPC6 因果错义变异的 64 个家系的 64 个体。临床数据，包括发病年龄、实验室结果、对治疗的反应、肾活检结果和遗传信息，是从国内和国际的多个中心收集的。进行外显子组或靶向测序，变异分类基于严格的标准。对 TRPC6 变体进行结构和功能分析，以了解它们对蛋白质功能的影响。对 9 例可用肾活检的光学和电子显微镜标本进行深入再分析，以确定 TRPC6-AP 的病理特征和相关性。结果 大规模测序数据不支持 TRPC6 蛋白截短变异的因果关系。我们鉴定了 21 个独特的 TRPC6 错义变体，聚集在蛋白质的三个不同区域，对 TRPC6 3D 蛋白结构具有不同的影响。 肾活检分析显示，大多数病例存在 FSGS 损伤模式，以及独特的足细胞特征，包括弥漫性足突消失和细胞体肿胀。大多数患者在青春期或成年早期就诊，但差异很大（平均 22 岁，SD ± 14 岁），经常进展为肾衰竭，但表现和 ESKD 之间的时间存在差异。结论 本研究提供了对 TRPC6-AP 的遗传谱、临床病理关联和自然史的见解。