Bilineal inheritance of pathogenic PKD1 and PKD2 variants in a Czech family with autosomal dominant polycystic kidney disease – a case report

Abstract

BackgroundAutosomal 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.Case presentationThis 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.ConclusionsHere, 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.

Gene Panel Analysis in a Large Cohort of Patients With Autosomal Dominant Polycystic Kidney Disease Allows the Identification of 80 Potentially Causative Novel Variants and the Characterization of a Complex Genetic Architecture in a Subset of Families

“…Bilineal inheritance of PKD1 and PKD2 variants is an extremely rare finding and, as expected, disease associated with the presence of two distinct mutations appeared to be more severe than the disease associated with either mutation alone (Pei et al, 2001;Elisakova et al, 2018).…”

Polycystic Kidney Disease Caused by Bilineal Inheritance of Truncating PKD1 as Well as PKD2 Mutations

“…Thus far, only the combination of 1 truncating and 1 missense mutation or 2 missense mutations has been described. 4 , 5 , 7 , S6−S11 These reports confirmed that in ADPKD patients, the level of functional polycystin-1 or polycystin-2 affects the age of presentation and the disease progression. In addition, it became clear that bilineal inheritance of a PKD1 and a PKD2 mutation caused more severe disease than either one of them, pin-pointing them as important disease modifiers.…”

“…Similarly, more progressive disease was described in a patient with bilineal inheritance of a truncating PKD1 p.(Gln2196∗) and a PKD2 missense mutation p.(Arg420Gly). 5 Compound heterozygotes for 2 PKD1 mutations have been described more frequently, including either one truncating with 1 missense mutation or 2 missense mutations in trans . Overall the phenotypes vary from more or less typical to early onset in utero .…”

Rare genetic causes of complex kidney and urological diseases

“…Digenic inheritance can also lead to intrafamilial variability. Thus, co-inheritance of PKD1 and PKD2 variants can yield severe, early-onset ADPKD, whereas family members who harbour only one of the two variants typically present with milder disease 161,162 . Similarly, in families with PKD1and PKD2associated ADPKD, individuals who have mutations in genes associated with other hereditary nephropathies, such as HNF1B 163 and COL4A1 (REF.…”