Laboratory of Human Molecular Genetics, Center for Molecular Biology and Genetic Engineering (CBMEG), State University of Campinas, UNICAMP, Caixa Postal 6010, 13083-875, Campinas, SP, Brazil.
Integrated Center of Pediatric Nephrology (CIN), Department of Pediatrics, School of Medical Sciences (FCM), State University of Campinas, UNICAMP, Campinas, Brazil.
Mol Genet Genomics. 2020 Jan;295(1):135-142. doi: 10.1007/s00438-019-01609-0. Epub 2019 Sep 13.
High-throughput techniques such as whole-exome sequencing (WES) show promise for the identification of candidate genes that underlie Mendelian diseases such as nephrotic syndrome (NS). These techniques have enabled the identification of a proportion of the approximately 54 genes associated with NS. However, the main pitfall of using WES in clinical and research practice is the identification of multiple variants, which hampers interpretation during downstream analysis. One useful strategy is to evaluate the co-inheritance of rare variants in affected family members. Here, we performed WES of a patient with steroid-resistant NS (SRNS) and intermittent microhematuria. Currently, 15 years after kidney transplantation, this patient presents normal kidney function. The patient was found to be homozygous for a rare MYO1E stop-gain variant, and was heterozygous for rare variants in NS-associated genes, COL4A4, KANK1, LAMB2, ANLN, E2F3, and APOL1. We evaluated the presence or absence of these variants in both parents and 11 siblings, three of whom exhibited a milder phenotype of the kidney disease. Analysis of variant segregation in the family, indicated the MYO1E stop-gain variant as the putative causal variant underlying the kidney disease in the patient and two of her affected sisters. Two secondary variants in COL4A4-identified in some other affected family members-require further functional studies to determine whether they play a role in the development of microhematuria in affected family members. Our data illustrate the difficulties in distinguishing the causal pathogenic variants from incidental findings after WES-based variant analysis, especially in heterogenous genetic conditions, such as NS.
高通量技术，如全外显子组测序（WES），为鉴定导致孟德尔疾病（如肾病综合征）的候选基因提供了希望。这些技术已经能够鉴定出与 NS 相关的约 54 个基因中的一部分。然而，在临床和研究实践中使用 WES 的主要陷阱是鉴定出多个变体，这在下游分析中妨碍了解释。一种有用的策略是评估受影响家庭成员中罕见变异的共遗传。在这里，我们对一名患有类固醇耐药性肾病综合征（SRNS）和间歇性镜下血尿的患者进行了 WES。目前，在肾移植后 15 年，该患者的肾功能正常。该患者被发现为一种罕见的 MYO1E 终止变异的纯合子，并且为与 NS 相关基因 COL4A4、KANK1、LAMB2、ANLN、E2F3 和 APOL1 中的罕见变异的杂合子。我们评估了这些变异在父母和 11 个兄弟姐妹中的存在或不存在，其中 3 人表现出肾脏疾病的轻度表型。对家族中变异分离的分析表明，MYO1E 终止变异是该患者及其两名受影响姐妹肾脏疾病的潜在致病变异。在一些其他受影响的家族成员中鉴定出的 COL4A4 中的两个次要变异需要进一步的功能研究，以确定它们是否在受影响的家族成员中微血尿的发展中起作用。我们的数据说明了在 WES 变异分析后，从偶然发现中区分致病变异的困难，特别是在遗传异质性条件下，如 NS。
