He Zhechi, Wu Ke, Xie Wenqing, Chen Jianghua
Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Prenatal Diagnosis Center, Yiwu Maternity and Child Health Care Hospital, Yiwu, China.
Front Pediatr. 2022 Aug 25;10:930258. doi: 10.3389/fped.2022.930258. eCollection 2022.
Focal segmental glomerulosclerosis (FSGS) is a histopathological diagnosis of the sclerosis of glomeruli and the damage to renal podocytes. FSGS affects the filtration function of the kidneys and results in nephrotic syndrome (NS) in children and adults. FSGS is a clinically and genetically heterogeneous disorder. FSGS-1 [OMIM #603278] is one of the progressive hereditary renal diseases. It is caused by heterozygous variants of the () [OMIM*604638] gene on chromosome 19q13.2 in a dominant inheritance (AD) manner. With the recent development of whole-exome sequencing (WES), 22 (including our case) pathogenic or likely pathogenic variants have been identified in gene.
We reported a 17-year-old Chinese girl who was hospitalized with foamy urine, nausea and vomiting. Laboratory tests revealed increased levels of serum creatinine and urea nitrogen. Ultrasonography demonstrated bilaterally reduced size of kidneys. The primary diagnoses were NS and chronic kidney disease stage 5 (CKD5). The hemodialysis was initiated in 48 h after admission. After 4 months of treatment, the patient received an allogeneic kidney transplantation from her father. A novel heterozygous missense variant c.494C > T (p.A165V) in the gene was found by WES in the patient. This variant was confirmed by Sanger sequencing. The computational simulation of the stability of mutant protein (p.A165V) was decreased. Interatomic interactions of the p.A165V site were increased, and it might be associated with the increased ubiquitylation in the vicinity of the mutant site.
As per the guidelines of the American College of Medical Genetics and Genomics for interpreting sequence variants, the novel heterozygous missense variant was pathogenic (PS2 + PM1 + PM2 + PP3 + PP4). It should be noted that the early onset of severe proteinuria with a poor prognosis is an important and universal symptom for most genetic FSGS. If necessary, genetic screening is recommended.
局灶节段性肾小球硬化（FSGS）是一种肾小球硬化和肾足细胞损伤的组织病理学诊断。FSGS会影响肾脏的滤过功能，导致儿童和成人出现肾病综合征（NS）。FSGS是一种临床和遗传异质性疾病。FSGS-1[OMIM #603278]是一种进行性遗传性肾脏疾病。它由19号染色体q13.2上的（）[OMIM*604638]基因的杂合变异以显性遗传（AD）方式引起。随着全外显子测序（WES）的最新发展，已在该基因中鉴定出22个（包括我们的病例）致病或可能致病的变异。
我们报告了一名17岁的中国女孩，因泡沫尿、恶心和呕吐入院。实验室检查显示血清肌酐和尿素氮水平升高。超声检查显示双侧肾脏体积减小。初步诊断为NS和慢性肾脏病5期（CKD5）。入院后48小时开始进行血液透析。治疗4个月后，患者接受了来自其父亲的同种异体肾移植。通过WES在患者中发现了该基因中的一种新的杂合错义变异c.494C>T（p.A165V）。该变异通过桑格测序得到证实。突变蛋白（p.A165V）稳定性的计算模拟结果降低。p.A165V位点的原子间相互作用增加，这可能与突变位点附近泛素化增加有关。
根据美国医学遗传学与基因组学学会解释序列变异的指南，这种新的杂合错义变异是致病的（PS2 + PM1 + PM2 + PP3 + PP4）。需要注意的是，严重蛋白尿的早发且预后不良是大多数遗传性FSGS的一个重要且普遍的症状。如有必要，建议进行基因筛查。
