Larrue Romain, Chamley Paul, Bardyn Thomas, Lionet Arnaud, Gnemmi Viviane, Cauffiez Christelle, Glowacki François, Pottier Nicolas, Broly Franck
Service de Toxicologie et Génopathies, CHU Lille, F-59000 Lille, France.
Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020- UMR-S 1277, F-59000 Lille, France.
NPJ Genom Med. 2020 Sep 21;5:38. doi: 10.1038/s41525-020-00147-8. eCollection 2020.
Next-generation sequencing has revolutionized the molecular diagnosis of individuals affected by genetic kidney diseases. Indeed, rapid genetic testing in individuals with suspected inherited nephropathy has not only important implications for diagnosis and prognosis but also for genetic counseling. Nephronophthisis (NPHP) and related syndromes, a leading cause of end-stage renal failure, are autosomal recessive disorders characterized by the variable presentation and considerable locus heterogeneity with more than 90 genes described as single-gene causes. In this case report, we demonstrate the utility of whole-genome sequencing (WGS) for the molecular diagnosis of NPHP by identifying two putative disease-causing intronic mutations in the gene, including one deep intronic variant. We further show that both intronic variants, by affecting splicing, result in a truncated nephrocystin-3 protein. This study provides a framework for applying WGS as a first-line diagnostic tool for highly heterogeneous disease such as NPHP and further suggests that deep intronic variations are an important underestimated cause of monogenic disorders.
下一代测序技术彻底改变了对受遗传性肾脏疾病影响个体的分子诊断。事实上，对疑似遗传性肾病个体进行快速基因检测不仅对诊断和预后有重要意义，对遗传咨询也很重要。肾单位肾痨（NPHP）及相关综合征是终末期肾衰竭的主要原因，是常染色体隐性疾病，其特征为表现多样且基因座异质性高，有超过90个基因被描述为单基因病因。在本病例报告中，我们通过鉴定该基因中两个推定的致病内含子突变，包括一个深层内含子变异，证明了全基因组测序（WGS）在NPHP分子诊断中的效用。我们进一步表明，这两个内含子变异通过影响剪接，导致肾囊肿蛋白-3蛋白截短。本研究为将WGS作为NPHP等高度异质性疾病的一线诊断工具提供了框架，并进一步表明深层内含子变异是单基因疾病一个重要的、被低估的病因。
