16 or 4

PKD chromosomes from PKD Foundation

PKD chromosomes from PKD Foundation









Genes are carried on chromosomes and the two that are important in PKD are chromosomes 16 and 4. I am not going to deal with the specifics of inheritance – this is best explained on the PKD Foundation web page. The relevant facts are that:

  • 85% people with PKD will have a mutation on chromosome 16
  • 15% people with PKD will have a mutation on chromosome 4


Does it matter?

Given that it is not routine to perform a genetic analysis on PKD patients in either UK or US we might be forgiven for thinking it is irrelevant. Many PKD patients are “reassured” by clinicians that the illness “runs true to form” or will “most likely not be worse than your parent had it”, based on the 1995 studies of parent-child pairs and natural history of PKD. (Gerberth et al, 1995)  So the issue of genetic testing is somewhat brushed under the carpet.
But there is a definite association between the severity of the disease and the gene involved and this has been known for 15 years (Hateboer et al, 1999)

    • PKD1 mutations tend to more serious disease, diagnosed at an earlier age and on average reaching end stage renal disease (ESRD) around 54-56 years.
    • PKD2 mutations are likely still to have some renal function beyond that, with 50% retaining renal function into their 70s


So wouldn’t it benefit us to know?

I am not here talking about testing at-risk asymptomatic individuals, rather about gaining knowledge that might help in predicting the expected course of the illness in someone who already knows the diagnosis.

The physicians reference, Wolters Kluwer Health  suggests genetic testing be reserved for cases where the diagnosis is unclear or for pre-pregnancy issues.

A gene sequencing company, based in Wisconsin,  offer testing for both PKD1 and PKD2, costing several thousands of pounds depending on which method is employed.

There are several problems, however, that limit the interpretations and therefore the usefulness of testing.

    • Genetic testing by direct mutation analysis is expensive and only gives a useful result in approximately 42-63% of cases.
    • Using linkage studies to identify a gene requires DNA from several affected members and so cannot be used with small families or when there is obscured family history. That is aside from any ethical considerations of requiring your relatives to be tested.
    • The PKD1 gene is very long and within the code several sections are duplicated. Some of these duplicated sections can also be found elsewhere on the chromosome 16, as pseudogenes – its as if you have a recipe with some of the ingredients listed twice and some even mentioned in the footnotes – how do you know which are the important parts and which are just copies? This complicates the molecular genetic testing, bringing a degree of uncertainly to the results.
    • Over 250 changes in the PKD1 gene have been described – the potential variation in phenotype (ie course of the illness) is therefore huge, so knowing the specific mutation may be no more accurate than knowing the age of the parent when they developed problems. (Paterson et al, 2004)
    • More than 75 mutations in PKD2 have been identified. The gene has 70,000 base pairs and in some mutations it is just a single pair that are altered, deleted or inserted. Finding this could be like looking for the proverbial needle in a haystack – costing time and money, once more for a result that cannot be stated with 100% accuracy.


What does the research say on the issue?

Given these difficulties with genetic testing, a recent study (Barua et al, 2009) looked at whether there was a simpler method of predicting outcome. After looking at 90 families in Toronto, 484 affected people, their findings were:

  1. the presence of at least one family member developing ESRD before the age of 55 was highly predictive of a PKD1 mutation
  2. the presence of at least one family member who continued with sufficient renal function at the age of 70 was highly predictive of a PKD2 mutation

    Their conclusion was

“paying close attention to the family history of renal disease severity may provide a simple means of predicting the mutated gene”

The positive predictive values for both were 100% and the sensitivities 72% and 74%. The study limitations might be that they only looked at 90 families and all from a limited geographical area. Their age criteria have been adjusted for these to the more stringent age cut-off values given in the conclusion. They also note that there is still a large interfamilial variability for the age at which ESRD occurred.


Back in 2003 a large study on PKD2 concluded that for known PKD2 patients there was no correlation between the actual mutation and phenotype. (Magistroni, 2003)


PKD1 on short arm of chromosome 16; PKD2 on long arm of chromosome 4.

PKD1 on short arm of chromosome 16; PKD2 on long arm of chromosome 4.












Is there any more recent research on this issue?

In 2012/13 a study in Brittany (Cornec LeGall, 2013) analysed mutations in 700 families and reached two very significant conclusions:

  1. ESRD in PKD1 occurs on average 21.6 years earlier (58.1 years) than in PKD2 (79.9years)
  2. Truncating mutations of PKD1 were associated with much earlier onset of ESRD, a difference of 12 years when compared with non-truncating mutations.

(Briefly, a truncating mutation is one that results in a code that stops the polycystin from being made, also called a nonsense mutation)

This aspect was investigated further by a Mayo Clinic team (Harris & Hopp, 2013) who conclude that the actual mutation is a key determinant of the phenotype, or presentation and outcome for the patient.

On the flip side of truncating mutations indicating a worse outlook is the important finding that approximately 30% of PKD1 patients with non-truncating mutations had not reached ESRD by the age of 80 years. The current prognosis that PKD1 mutations result in a more severe phenotype with earlier ESRD needs to be reconsidered.


Are there occasions when it is definitely helpful to know?

Identifying a donor: where there is a potential living related donor with equivocal imaging results then knowing the mutation in both patient and donor might be helpful. With a hoped for increase in living donors then molecular diagnostics may become more mainstream.

Diagnosis of atypical patients: If there is no family history and unusual features definitive genetic testing might provide important prognostic and management information and prevent misdiagnosis.

Pre-gestational diagnosis: in families with a particularly severe disease pattern or with early onset the potential parents may need to know before committing to a family. Once a mutation has been identified within a family then it is relatively easy to search for that mutation in at-risk relatives.

Research: patient selection in clinical trials

Management: Deciding on future treatments – risks might outweigh benefits if there is in fact a low chance of the patient reaching ESRD

What might be the negative impact of genetic analysis?

Aside for the difficulties in the process of analysis, drawing conclusions from the results of analysis remain in the domain of the uncertain. As yet little research has been undertaken on potential gene modifiers, or on the environmental effect on gene expression so providing a statement of genetic analysis is by no means equivalent to a making a prognosis.

The emotional aspect of “knowing” is a complex minefield – all well and good to be told you have a mutation that is usually linked with longer life, but what if your results show the opposite?

The Bottom Line

Currently if a positive diagnosis can be obtained by imaging then molecular genetic testing is not recommended. It is a strange situation however because more research will lead to further characterisation of mutations and then the greater use this can be in clinical situations, but if not routinely analysed then a great deal of potential information is in effect wasted.

For myself, I am fascinated and admit that I would like to know which gene and which mutation I carry. But, aside from the expense, I hesitate from volunteering myself for testing because I am not sure if I could accept the answers with any degree of objectivity.


Further Reading:

Molecular Diagnostics for autosomal dominant polycystic kidney disease    A 2010 summary of the understanding of genetic analysis with respect to ADPKD

Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1 and PKD2 targeted next-generation sequencing    A 2014 update on new technology


Barua, Moumita, et al. (2009) “Family history of renal disease severity predicts the mutated gene in ADPKD.” JASN 20.8: 1833-1838.

Cornec-Le Gall et al. (2013) JASN 24(6):1006-1013,

Geberth S, Ritz E, Zeier M, Stier E.(1995) Anticipation of age at renal death in autosomal dominant polycystic kidney disease (ADPKD) Nephrol Dial Transplant. 1995;10:1603–6.

Harris P, Hopp K (2013) : “The mutation, a key determinant of phenotype in ADPKD” JASN vol 24:5 June 2013

Hateboer N, v Dijk MA, Bogdanova N, Coto E, Saggar-Malik AK, San Millan JL, Torra R, Breuning M, Ravine D. (1999) : “Comparison of phenotypes of polycystic kidney disease types 1 and 2.” European PKD1-PKD2 Study Group. Lancet. 1999;353:103–7

Magistroni R, et al (2003) “Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease” JASN 2003;14:1164–74.


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