Pediatric Nephrology Unit, Department of Child Healthy, Royal Hospital, Muscat, Oman.
Translational and Clinical Research Institute, Faculty of Medical Science, Newcastle University, Newcastle upon Tyne, UK.
Mol Genet Genomic Med. 2023 Sep;11(9):e2201. doi: 10.1002/mgg3.2201. Epub 2023 May 19.
Nephrotic syndrome (NS) is one of the most common kidney disorders seen by pediatric nephrologists and is defined by the presence of heavy proteinuria (>3.5 g/24 h), hypoalbuminemia (<3.5 g/dL), edema, and hyperlipidemia. Most children with NS are steroid-responsive and have a good prognosis following treatment with prednisolone. However, 10%-20% of them have steroid-resistant nephrotic syndrome (SRNS) and fail to respond to treatment. A significant proportion of these children progress to kidney failure.
This retrospective study aimed to determine the underlying genetic causes of SRNS among Omani children below 13 years old, over a 15-year period and included 77 children from 50 different families. We used targeted Sanger sequencing combined with next-generation sequencing approaches to perform molecular diagnostics.
We found a high rate of underlying genetic causes of SRNS in 61 (79.2%) children with pathogenic variants in the associated genes. Most of these genetically solved SRNS patients were born to consanguineous parents and variants were in the homozygous state. Pathogenic variants in NPHS2 were the most common cause of SRNS in our study seen in 37 (48.05%) cases. Pathogenic variants in NPHS1 were also seen in 16 cases, especially in infants with congenital nephrotic syndrome (CNS). Other genetic causes identified included pathogenic variants in LAMB2, PLCE1, MYO1E, and NUP93.
NPHS2 and NPHS1 genetic variants were the most common inherited causes of SRNS in Omani children. However, patients with variants in several other SRNS causative genes were also identified. We recommend screening for all genes responsible for SRNS in all children who present with this phenotype, which will assist in clinical management decisions and genetic counseling for the affected families.
肾病综合征 (NS) 是儿科肾脏病医生最常见的肾脏疾病之一，其特征是大量蛋白尿 (>3.5 g/24 h)、低白蛋白血症 (<3.5 g/dL)、水肿和高脂血症。大多数患有 NS 的儿童对皮质类固醇有反应，经泼尼松龙治疗后预后良好。然而，其中 10%-20%患有皮质类固醇耐药性肾病综合征 (SRNS)，对治疗无反应。这些儿童中有很大一部分进展为肾衰竭。
本回顾性研究旨在确定 15 年间，13 岁以下阿曼儿童 SRNS 的潜在遗传原因，共纳入 50 个不同家庭的 77 名儿童。我们使用靶向 Sanger 测序结合下一代测序方法进行分子诊断。
我们发现 61 名 (79.2%) 患有 SRNS 的儿童存在潜在的遗传原因，这些儿童的相关基因存在致病性变异。这些通过基因检测确诊的 SRNS 患者大多出生于近亲家庭，且变异呈纯合状态。在本研究中，NPHS2 的致病性变异是导致 SRNS 的最常见原因，见于 37 例 (48.05%) 病例。NPHS1 的致病性变异也见于 16 例，尤其是患有先天性肾病综合征 (CNS) 的婴儿。其他确定的遗传原因包括 LAMB2、PLCE1、MYO1E 和 NUP93 的致病性变异。
NPHS2 和 NPHS1 基因变异是阿曼儿童 SRNS 的最常见遗传原因。然而，也发现了其他几个 SRNS 致病基因的变异。我们建议对所有表现出这种表型的儿童筛查所有导致 SRNS 的基因，这将有助于临床管理决策和受影响家庭的遗传咨询。
