Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA.
Department of Pediatrics B and Pediatric Nephrology unit, Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Pediatr Nephrol. 2019 Sep;34(9):1607-1613. doi: 10.1007/s00467-019-04256-0. Epub 2019 Apr 17.
Heterozygous PAX2 mutations cause renal coloboma syndrome (RCS) [OMIM no. 120330]. RCS is a renal syndromic disease encompassing retinal coloboma and sensorineural hearing loss. Recently, a causative role for PAX2 was reported in adult-onset nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS). However, the prevalence of PAX2 mutations among large cohort of children with steroid-resistant nephrotic syndrome (SRNS) and FSGS has not been systematically studied.
We employed whole-exome sequencing (WES) to identify the percentage of SRNS cases explained by monogenic mutations in known genes of SRNS/FSGS. As PAX2 mutations are not an established cause of childhood FSGS, we evaluated a cohort of 215 unrelated families with SRNS, in whom no underlying genetic etiology had been previously established.
Using WES, we identified 3 novel causative heterozygous PAX2 mutations in 3 out of the 215 unrelated index cases studied (1.3%). All three cases were detected in individuals from families with more than one affected and compatible with an autosomal dominant mode of inheritance (3/57 familial cases studied (5.2%)). The clinical diagnosis in three out of four pediatric index patients was done during routine medical evaluation.
Our findings demonstrate high frequency of PAX2 mutations in familial form of SRNS (5.2%) and further expand the phenotypic spectrum of PAX2 heterozygous mutations to include autosomal dominant childhood-onset FSGS. These results highlight the importance of including PAX2 in the list of genes known to cause FSGS in children.
杂合性 PAX2 突变导致肾结肠瘤综合征（RCS）[OMIM 编号：120330]。RCS 是一种肾综合征，包括视网膜脑回和感觉神经性听力损失。最近，PAX2 突变被报道与局灶节段性肾小球硬化（FSGS）引起的成人发病型肾病综合征有关。然而，在大样本的儿童激素耐药性肾病综合征（SRNS）和 FSGS 患者中，PAX2 突变的发生率尚未被系统研究过。
我们采用外显子组测序（WES）来鉴定已知的 SRNS/FSGS 基因中的单基因突变解释的 SRNS 病例的比例。由于 PAX2 突变不是儿童 FSGS 的既定原因，我们评估了 215 个无亲缘关系的 SRNS 家族的队列，这些家族以前没有确定的遗传病因。
通过 WES，我们在 215 个无亲缘关系的指数病例中发现了 3 个新的杂合性 PAX2 突变，占 3/215（1.3%）。这三个病例都出现在多个受影响的家族成员中，符合常染色体显性遗传模式（3/57 个研究的家族病例（5.2%））。在 4 名儿科指数患者中，有 3 名患者的临床诊断是在常规医疗评估中发现的。
我们的研究结果表明，PAX2 突变在家族性 SRNS 中频率较高（5.2%），并进一步扩大了 PAX2 杂合突变的表型谱，包括常染色体显性遗传的儿童期 FSGS。这些结果强调了将 PAX2 纳入已知导致儿童 FSGS 的基因列表的重要性。
