Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
Nephrology Unit, Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.
Pediatr Nephrol. 2023 Nov;38(11):3663-3670. doi: 10.1007/s00467-023-06042-5. Epub 2023 Jun 19.
Enhanced availability of high-throughput sequencing (at progressively reducing costs) has revolutionized the identification of monogenic SRNS. However, in resource-poor settings, it may not be possible to perform next-generation sequencing (NGS) in all children wherein monogenic SRNS is suspected. Besides, the optimal strategy of genetic evaluation (in patients with SRNS) in routine clinical practice in resource-limited settings is unknown.
Patients with newly diagnosed SRNS were recruited from our center and followed up prospectively. We analyzed the factor(s) independently predicting the occurrence of disease-causing variants in these patients.
In our study, 36 children/adolescents with SRNS were included (initial steroid resistance in 53%). On targeted NGS, pathogenic/likely pathogenic variants were identified in 31% (n = 11). These included homozygous or compound heterozygous variants in the following genes: ALOX12B, COL4A3, CRB2, NPHS1, NPHS2, PLCE1, and heterozygous variant in WT1 gene. Overall, 14 variants were identified of which 5 (36%) were novel. Age of < 1 or < 2 years and presence of family history of nephrotic syndrome independently predicted the occurrence of monogenic SRNS on multivariate analysis.
While NGS-based genetic testing in SRNS is increasingly being incorporated in routine clinical practice the world over, the scenario is far from optimal in resource-limited settings. Our study highlights that resources for genetic testing in SRNS should be prioritized for patients with early age at disease onset and presence of family history. Larger studies composed of diverse multi-ethnic cohorts of patients with SRNS are required to further delineate the optimal strategy of genetic evaluation in resource-poor settings. A higher resolution version of the Graphical abstract is available as Supplementary information.
高通量测序（成本不断降低）的广泛应用彻底改变了单基因 SRNS 的鉴定方式。然而，在资源匮乏的地区，对所有疑似单基因 SRNS 的患儿进行下一代测序（NGS）可能并不现实。此外，在资源有限的情况下，常规临床实践中 SRNS 患者的基因评估最佳策略尚不清楚。
我们从中心招募了新诊断为 SRNS 的患者，并进行前瞻性随访。我们分析了这些患者发生致病变异的独立预测因素。
在我们的研究中，纳入了 36 名患有 SRNS 的儿童/青少年（53%初始激素耐药）。在靶向 NGS 检测中，发现了 31%（n=11）的致病性/可能致病性变异。这些变异包括 ALOX12B、COL4A3、CRB2、NPHS1、NPHS2、PLCE1 基因的纯合或复合杂合变异，以及 WT1 基因的杂合变异。总共发现了 14 个变异，其中 5 个（36%）为新变异。多变量分析显示，年龄<1 岁或<2 岁以及肾病综合征家族史是单基因 SRNS 发生的独立预测因素。
虽然基于 NGS 的遗传检测在全世界范围内逐渐被纳入常规临床实践，但在资源有限的地区，情况远非理想。我们的研究表明，应优先为发病年龄早和有家族史的 SRNS 患者提供遗传检测资源。需要进行更大规模、由不同种族 SRNS 患者组成的多中心队列研究，以进一步确定资源匮乏地区的基因评估最佳策略。一个更高分辨率的图表摘要版本可以在补充信息中找到。
