Abstract：
As nephrology practice is evolving toward precision medicine, and genetic tests are becoming widely available, basic genetic literacy is increasingly required for clinical nephrologists. Yet, decisions based on results of genetic tests are seldom straightforward. We report a 37-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) who was referred for medically assisted reproduction with monogenic preimplantation genetic testing (PGT-M). The PKD1 and PKD2 genes were screened for pathogenic variants. Sequencing analysis revealed the presence of three novel missense single nucleotide variants, two in the PKD1 gene - c.349T>G, p.(Leu117Val) and c.1736C>T, p.(Pro579Leu); and the third in the PKD2 gene - c.1124A>G, p.(Asn375Ser). Bioinformatic predictions of the functional effects of those three missense variants were inconsistent across different software tools. The family segregation analysis, which was mandatory to identify the relevant variant(s) for PGT-M, strongly supported that the disease-causing variant was PKD1 c.349T>G p.(Leu117Val), while the other two were nonpathogenic or, at most, phenotypic modulators. Proving the pathogenicity of novel variants is often complex but is critical to guide genetic counseling and screening, particularly when discussing reproductive alternatives for primary prevention in the progeny of at-risk couples. The family reported herein illustrates those challenges in the setting of ADPKD, and the invaluable importance of a detailed family history and segregation analysis for proper clinical annotation of novel variants. Basic genetic knowledge and proper clinical annotation of novel allelic variants in genes associated with hereditary kidney disorders are increasingly necessary for the contemporary practice of clinical nephrology.
摘要：
随着肾脏病学实践向精准医学发展，基因测试正在变得广泛可用，临床肾病学家越来越需要基本的遗传素养。然而，基于基因测试结果的决定很少是直截了当的。我们报告了一名37岁的常染色体显性遗传多囊肾病（ADPKD）女性，她被转诊为单基因植入前遗传检测（PGT-M）的医学辅助生殖。筛选PKD1和PKD2基因的致病变异。测序分析显示存在三个新的错义单核苷酸变体，两个在PKD1基因-c.349T>G，p.(Leu117Val)和c.1736C>T，p。（Pro579Leu）；PKD2基因中的第三个-c.114A>G，p.（Asn375Ser）。对这三个错义变体的功能影响的生物信息学预测在不同的软件工具中不一致。家庭隔离分析,这是强制性的，以确定PGT-M的相关变体，强烈支持致病变异为PKD1c.349T>Gp。(Leu117Val)，而另外两个是非致病性的，最多,表型调节剂。证明新变体的致病性通常很复杂，但对指导遗传咨询和筛查至关重要，特别是在讨论高危夫妇后代的一级预防生殖替代方案时。本文报道的家族说明了ADPKD背景下的这些挑战，以及详细的家族史和隔离分析对于新变体的正确临床注释的宝贵重要性。与遗传性肾脏疾病相关的基因中的新等位基因变体的基本遗传知识和适当的临床注释对于当代临床肾病学实践越来越必要。
