The genetics of polycystic kidney disease: a guide for patients and families

When I see a new patient with autosomal dominant polycystic kidney disease, the conversation often moves quickly from the diagnosis itself to the genetic implications for their family. These are some of the most important conversations I have with patients, and they are often the ones patients have not yet had with anyone else. This article covers what I tell patients and their families about the genetics of ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney condition. It affects around one in 1,000 people. For families with the condition, the genetic aspects shape decisions across generations: who will be affected, when to test, what to tell children, and what reproductive options are available. This guide walks through the genetics of ADPKD in detail, with practical guidance for patients and their families.

ADPKD is caused by mutations in one of two main genes. PKD1, on chromosome 16, accounts for around 78 per cent of cases. PKD2, on chromosome 4, accounts for around 15 per cent. A small remaining proportion of cases are caused by mutations in other rarer genes, including GANAB and DNAJB11, which were identified more recently. The two main forms behave somewhat differently. PKD1 mutations tend to produce earlier and more severe disease, with kidney failure typically occurring in the mid-fifties. PKD2 mutations tend to produce milder, later-onset disease, with kidney failure typically occurring around a decade later.

The term autosomal means the gene involved is not on a sex chromosome. Men and women are equally affected, and the inheritance pattern is the same regardless of which parent is affected. The term dominant means a single copy of the abnormal gene is enough to cause the condition. Each child of an affected parent has a 50 per cent chance of inheriting the mutated gene and developing the condition. The 50 per cent is per pregnancy, not across the family: a family with three children may have all three affected, none affected, or any combination in between.

Around 10 to 15 per cent of cases of ADPKD arise from new mutations, meaning the patient has no affected parent. The mutation has occurred either in the egg or sperm that formed the patient, or in the very early embryo. In these cases, the patient still has a 50 per cent risk of passing the mutation to each of their own children.

A recessive form, autosomal recessive polycystic kidney disease (ARPKD), exists but is much rarer. ARPKD typically presents in infancy or childhood, with a different pattern of kidney and liver involvement. Both parents are usually unaffected carriers. The inheritance and management of ARPKD are different from ADPKD, and this guide focuses on the dominant form.

The diagnosis of ADPKD in an adult can usually be made by ultrasound based on the number of cysts in each kidney, combined with family history. Standard diagnostic criteria are well established. In someone with a positive family history, the presence of three or more cysts (combined in both kidneys) is diagnostic at ages 15 to 39. The threshold rises to two or more cysts in each kidney for ages 40 to 59, and to four or more cysts in each kidney at age 60 or above. These thresholds reflect the fact that simple kidney cysts become more common with age in the general population, so a higher threshold is needed to distinguish ADPKD from age-related simple cysts.

In cases where the diagnosis is uncertain (for example, in young adults at risk of ADPKD whose ultrasound shows only one or two cysts), MRI is more sensitive than ultrasound and may resolve the question. Genetic testing is the definitive investigation in cases where imaging is inconclusive, where the family history is unclear, or where the result will inform major life decisions such as family planning.

Genetic testing for ADPKD has become more accessible over the last decade. The PKD1 and PKD2 genes can both be sequenced, and the great majority of patients with ADPKD have an identifiable mutation. The test is typically done on a blood sample and takes a few weeks to return. Cost has fallen substantially with improvements in sequencing technology.

Family screening of first-degree relatives is recommended once a diagnosis has been made in one family member. The usual approach is ultrasound from late teenage years onwards. Children of an affected parent are not usually screened in early childhood. There are two reasons for this. The first is that there is no specific treatment that needs to be started in childhood. The second is that a positive result in childhood could affect future life choices, including insurance and career planning. The decision to delay screening until adulthood respects the child’s right to make their own informed decisions about whether and when to be tested.

The decision about when to be screened, even in adulthood, is personal. Some young adults want to know as early as possible so they can plan ahead. Others prefer not to know unless symptoms arise. Both are valid choices. Specialist clinics that manage ADPKD can offer counselling to support the decision. Genetic counselling, in particular, can help with the emotional and practical implications of testing.

A negative ultrasound in early adulthood does not entirely exclude ADPKD. Patients with PKD2 mutations, in particular, may not show clear cyst formation on ultrasound until later in life. If the family history is clear and the ultrasound is normal in a young adult, repeat imaging in a few years or genetic testing can definitively resolve the question.

A positive result has several implications. For the individual, it means specialist follow-up, attention to blood pressure (which is often raised in early adulthood even before kidney function declines), and access to disease-modifying treatments such as tolvaptan if eligibility criteria are met. For family planning, it raises the question of how to manage reproductive choices.

Reproductive options for couples where one partner has ADPKD include natural conception with no specific intervention, prenatal diagnosis through chorionic villus sampling or amniocentesis during pregnancy, and pre-implantation genetic diagnosis (PGD) with in-vitro fertilisation. PGD involves IVF with selection of embryos that have not inherited the ADPKD gene. The process is technically demanding and involves multiple stages, but it allows couples to have a child who does not carry the gene. PGD for ADPKD is available in Ireland through specialist fertility clinics, although it is not always state-funded and the costs can be significant. The decision is highly personal and involves clinical, ethical, financial, and practical considerations.

What about telling children? This is one of the most difficult conversations many families with ADPKD face. There is no single right answer. Some families are open about the condition from the start, with information shared as children become old enough to understand. Others wait until adulthood. The decision usually depends on the family’s culture, the child’s age and maturity, and the parents’ own comfort with the topic. Genetic counsellors can support these conversations.

Insurance is a practical consideration. In Ireland, insurance companies cannot use the results of predictive genetic tests when assessing applications for life insurance or health insurance up to certain limits, under the Disability Act 2005 and subsequent agreements. This protection is important and means that getting tested does not automatically affect insurance options. However, the situation is more complex for very high-value policies, for specific products such as critical illness insurance, and for situations where genetic testing has been done after a policy was already in place. Specific advice from an insurance broker familiar with these issues is worthwhile before significant policy decisions.

For patients with ADPKD, the genetics matter most in two specific contexts: deciding when and how to inform children of their risk, and planning for any pregnancies. Specialist input from a genetic counsellor as well as a nephrologist can be valuable for both of these discussions. The aim is informed decisions made calmly, not rushed or under pressure.

For families considering whether to be tested, the principles are similar. Genetic testing should be approached after counselling, with realistic expectations about what the result will and will not tell you. A positive result establishes the diagnosis but does not predict the exact course of the disease. A negative result is reassuring but should be interpreted in the context of the family history and any imaging findings.

I see private patients at Blackrock Clinic, The Beacon Hospital, Bon Secours Dublin, the Hermitage Medical Centre, and St Vincent’s Private Hospital. If you would like a consultation about your kidney health, you or your GP can contact my secretary through drrorymcquillan.ie. Most patients are seen within two to three weeks of referral.