Elisakova Veronika, Merta Miroslav, Reiterova Jana, Baxova Alica, Kotlas Jaroslav, Hirschfeldova Katerina, Obeidova Lena, Tesar Vladimir, Stekrova Jitka
Institute of Biology and Medical Genetics, First Faculty of Medicine Charles University and General University Hospital in Prague, Albertov 4, 128 00, Prague, Czech Republic.
Department of Nephrology, First Faculty of Medicine Charles University and General University Hospital in Prague, U Nemocnice 2, 128 00, Prague, Czech Republic.
BMC Nephrol. 2018 Jul 4;19(1):163. doi: 10.1186/s12882-018-0978-2.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder, leading to end stage renal failure and kidney transplantation in its most serious form. The severity of the disease's manifestation depends on the genetic determination of ADPKD. The huge variability of different phenotypes (even within a single family) is not only modulated by the two main ADPKD genes (PKD1 and PKD2) but also by modifier genes and the whole genetic background.
This is a report of an ADPKD family with co-inheritance of PKD1 and PKD2 pathogenic variants. The proband, with an extremely serious manifestation of ADPKD (the man was diagnosed in early childhood, and with end stage renal disease aged 23), underwent genetic analysis of PKD1 and PKD2, which revealed the presence of pathogenic mutations in both of these genes. The missense PKD2 mutation p.Arg420Gly came from the proband's father, with a mild ADPKD phenotype. The same mutation of the PKD2 gene and similar mild disease presentation were found in the proband's aunt (father's sister) and her son. The nonsense mutation p.Gln2196* within the PKD1 gene was probably inherited from the proband's mother, who died at the age of 45. It was only discovered post mortem, that the real cause of her death was kidney failure as a consequence of untreated ADPKD. Unfortunately, neither the DNA of the proband's mother nor the DNA of any other family members from this side of the pedigree were available for further examination. The proband underwent successful cadaveric kidney transplantation at the age of 24, and this replacement therapy lasted for the next 15 years.
Here, we present a first case of bilineal ADPKD inheritance in the Czech Republic. This report highlights the significant role of modifier genes in genetic determination of ADPKD, especially in connection with seriously deteriorated disease phenotypes. In our case, the modifying role is probably mediated by the PKD2 gene.
常染色体显性遗传性多囊肾病（ADPKD）是最常见的遗传性肾脏疾病，其最严重的形式会导致终末期肾衰竭和肾移植。该疾病表现的严重程度取决于ADPKD的基因决定因素。不同表型的巨大变异性（即使在单个家族中）不仅受两个主要的ADPKD基因（PKD1和PKD2）调控，还受修饰基因和整个遗传背景的影响。
本文报告了一个同时遗传有PKD1和PKD2致病变异的ADPKD家族。先证者ADPKD表现极其严重（该男性在幼儿期被诊断出，23岁时发展为终末期肾病），对其进行了PKD1和PKD2的基因分析，结果显示这两个基因均存在致病突变。错义PKD2突变p.Arg420Gly来自先证者的父亲，其ADPKD表型较轻。在先证者的姑姑（父亲的姐妹）及其儿子身上发现了相同的PKD2基因突变以及类似的轻度疾病表现。PKD1基因内的无义突变p.Gln2196*可能遗传自先证者的母亲，她45岁时去世。尸检时才发现，她的真正死因是未治疗的ADPKD导致的肾衰竭。不幸的是，无法获取先证者母亲的DNA或家系中这一侧任何其他家庭成员的DNA进行进一步检测。先证者在24岁时成功接受了尸体肾移植，这种替代治疗持续了接下来的15年。
在此，我们报告了捷克共和国首例双系ADPKD遗传病例。本报告强调了修饰基因在ADPKD基因决定中的重要作用，特别是与严重恶化的疾病表型相关。在我们的病例中，修饰作用可能由PKD2基因介导。
