PDF(Pubmed)
Abstract：
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, and it is typically caused by PKD1 and PKD2 heterozygous variants. Nonetheless, the extensive phenotypic variability observed among affected individuals, even within the same family, suggests a more complex pattern of inheritance. We describe an ADPKD family in which the proband presented with an earlier and more severe renal phenotype (clinical diagnosis at the age of 14 and end-stage renal disease aged 24), compared to the other affected family members. Next-generation sequencing (NGS)-based analysis of polycystic kidney disease (PKD)-associated genes in the proband revealed the presence of a pathogenic PKD2 variant and a likely pathogenic variant in PKD1, according to the American College of Medical Genetics and Genomics (ACMG) criteria. The PKD2 nonsense p.Arg872Ter variant was segregated from the proband\'s father, with a mild phenotype. A similar mild disease presentation was found in the proband\'s aunts and uncle (the father\'s siblings). The frameshift p.Asp3832ProfsTer128 novel variant within PKD1 carried by the proband in addition to the pathogenic PKD2 variant was not found in either parent. This report highlights that the co-inheritance of two or more PKD genes or alleles may explain the extensive phenotypic variability among affected family members, thus emphasizing the importance of NGS-based techniques in the definition of the prognostic course.
摘要：
常染色体显性遗传性多囊肾病（ADPKD）是最常见的遗传性肾病，它通常是由PKD1和PKD2杂合变体引起的。尽管如此，在受影响的个体中观察到的广泛的表型变异性，即使在同一个家庭里，暗示了一个更复杂的继承模式。我们描述了一个ADPKD家族，其中先证者具有更早和更严重的肾脏表型（14岁时的临床诊断和24岁的终末期肾病），与其他受影响的家庭成员相比。根据美国医学遗传学和基因组学学院（ACMG）标准，先证者中多囊肾病（PKD）相关基因的基于下一代测序（NGS）的分析显示，PKD1中存在致病性PKD2变体和可能的致病性变体。PKD2无意义p.Arg872Ter变体与先证者的父亲分开，具有轻度表型。在先证者的姑姑和叔叔（父亲的兄弟姐妹）中发现了类似的轻度疾病表现。除致病性PKD2变体外，在任一亲本中均未发现先证者携带的PKD1内的移码p.Asp3832ProfsTer128新变体。该报告强调，两个或多个PKD基因或等位基因的共同遗传可能解释了受影响的家族成员之间广泛的表型变异性。因此强调了基于NGS的技术在定义预后过程中的重要性。
