Steroid resistant nephrotic syndrome (SRNS) represents a significant renal disease burden in childhood and adolescence. In contrast to steroid sensitive nephrotic syndrome (SSNS), renal outcomes are significantly poorer in SRNS. Over the past decade, extensive genetic heterogeneity has become evident while disease-causing variants are still only identified in 30% of cases in previously reported studies with proportion and type of variants identified differing depending on the age of onset and ethnical background of probands. A genetic diagnosis however can have implications regarding clinical management, including kidney transplantation, extrarenal disease manifestations, and, in some cases, even causal therapy. Genetic diagnostics therefore play an important role for the clinical care of SRNS affected individuals.

Here, we performed NPHS2 Sanger sequencing and subsequent exome sequencing in 30 consanguineous Iranian families with a child affected by SRNS with a mean age of onset of 16 months. We identified disease-causing variants and one variant of uncertain significance in 22 families (73%), including variants in NPHS1 (30%), followed by NPHS2 (20%), WT1 (7%) as well as in NUP205, COQ6, ARHGDIA, SGPL1, and NPHP1 in single cases. Eight of these variants have not previously been reported as disease-causing, including four NPHS1 variants and one variant in NPHS2, ARHGDIA, SGPL1, and NPHP1 each.

In line with previous studies in non-Iranian subjects, we most frequently identified disease-causing variants in NPHS1 and NPHS2. While Sanger sequencing of NPHS2 can be considered as first diagnostic step in non-congenital cases, the genetic heterogeneity underlying SRNS renders next-generation sequencing based diagnostics as the most efficient genetic screening method. In accordance with the mainly autosomal recessive inheritance pattern, diagnostic yield can be significantly higher in consanguineous than in outbred populations.

类固醇抵抗性肾病综合征 (SRNS) 代表了儿童和青春期的重大肾脏疾病负担。与类固醇敏感性肾病综合征 (SSNS) 相比，SRNS 的肾脏预后明显较差。在过去十年中，广泛的遗传异质性已经变得明显，而在先前报道的研究中，致病变异仍然仅在 30% 的病例中被发现，所发现的变异的比例和类型因先证者的发病年龄和种族背景而异。然而，基因诊断可能对临床管理产生影响，包括肾移植、肾外疾病表现，在某些情况下甚至是因果治疗。因此，基因诊断在 SRNS 患者的临床护理中发挥着重要作用。

在这里，我们表演了NPHS2在 30 个近亲伊朗家庭中进行 Sanger 测序和随后的外显子组测序，这些家庭有一个平均发病年龄为 16 个月的 SRNS 影响的孩子。我们在 22 个家族 (73%) 中发现了致病变异和一种意义不确定的变异，包括NPHS1(30%)，其次是NPHS2(20%),WT1(7%) 以及在NUP205、COQ6、ARHGDIA、SGPL1， 和NPHP1在单个情况下。其中八种变体以前没有被报道为致病，包括四种NPHS1变体和一个变体NPHS2、ARHGDIA、SGPL1， 和NPHP1每个。

与之前对非伊朗受试者的研究一致，我们最常在NPHS1和NPHS2. 而 Sanger 测序NPHS2可以被认为是非先天性病例的第一个诊断步骤，SRNS 的遗传异质性使得基于下一代测序的诊断成为最有效的遗传筛查方法。根据主要的常染色体隐性遗传模式，近亲的诊断率明显高于远交种群。