To Do or Not to Do - Genetic Testing for Autosomal Dominant Polycystic Kidney Disease in Children and Adolescents

Abstract

Despite increasing evidence of the clinical utility of genetic testing in adults with Autosomal Dominant Polycystic Kidney disease (ADPKD), its benefits in asymptomatic children, including adolescents, remain controversial. While there may be medical benefits in an early accurate molecular diagnosis for targeted disease monitoring and intervention, these benefits need to be carefully balanced against the potential legal, ethical, psychological, and socioeconomic harms for a developing child and adolescent. Comprehensive genetic counselling is essential to facilitate family-centered decision-making.

Rapid advancement in clinical genetics enables timely diagnosis that has changed the management landscape of individuals with monogenic kidney diseases. Genetic testing can facilitate disease diagnosis, inform prognosis, impact treatment options and benefit family relatives via cascade testing. In patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), genetic testing can help establish diagnosis in patients with atypical clinical presentation, equivocal imaging findings or negative family history; in case of children, they may not yet satisfy diagnostic criteria.¹ The score of PROPKD (Predicting Renal Outcome in Polycystic Kidney Disease) integrates genetic and clinical information to predict likelihood of kidney failure before age 60 and help stratifying patients’ risk and guiding initiation of disease-modifying treatment. Genetic results can also influence the choice of living kidney donor as relatives carrying the same familial variant should not act as kidney donor,² as well as affecting parental reproductive decisions when conducted pre-conception or prenatally (the pros, cons and ethical challenges of which would be worth another in-depth discussion). However, genetic testing in asymptomatic children and adolescents for adult-onset disease such as ADPKD remains controversial.

The study by Gimpel C et al illustrates some of the challenges.³ The largest multi-national registry of children and adolescents with ADPKD, ADPedKD, comprising 1060 individuals, as well as samples from European Rare Kidney Disease Registry (ERKReg) and United Kingdom National Registry of Rare Kidney Diseases Registry (RaDaR), comprising 825 and 269 children and adolescents respectively, were used. Diagnoses of ADPKD were based on family history, imaging findings and/or molecular genetic testing. Nearly half (48%) of the ADPedKD cohort were diagnosed following asymptomatic family screening. In the ERKReg cohort (n = 825), 62% of children and adolescents were diagnosed pre-symptomatically. Mean age at diagnosis in ADPedKD cohort was 5.7 years (±5.2 years), and only 0.7% of these children and adolescents were diagnosed after age 16 (consent age in the UK). Mean age at diagnosis in ERKReg and RaDaR cohorts were 9.3 years (±6.2 years) and 10.5 years (±6.7 years), respectively. These diagnoses may refer to a positive genetic testing or imaging, though proportion of diagnoses made by each method were not differentiated in the study. Reporting these proportions would facilitate further interpretation of the presented data. On one hand, diagnosing ADPKD in the pediatric population is difficult due to insensitivity of ultrasound. On the other, a known familial variant allows for high sensitivity of genetic testing, approaching 100%.⁴ Here, we focus on the potential medical benefits and risks of genetic testing in symptomatic and asymptomatic children and adolescents.

The cohorts examined do not provide reasons behind each family’s decision to undergo genetic testing for their asymptomatic minors. Based on prior qualitative studies, the authors postulated that parental stress facing minor’s uncertain transmission status and their desire to be proactive in disease management were key drivers for early screening.³ Knowing the diagnosis early may have several benefits (Table 1). First, it allows for disease monitoring. High blood pressure (BP) is more prevalent in children and adolescents with ADPKD (~20%–40%) compared to the general pediatric population (<5%).¹ Faster kidney growth and kidney function decline have been observed in pediatric patients with ADPKD who are hypertensive. Patients identified pre-symptomatically can benefit from early detection of hypertension and proteinuria via regular monitoring and rigorous BP control with renin angiotensin aldosterone system inhibitors which slows disease progression. Second, early diagnosis enables vigilance and avoidance of potentially nephrotoxic agents. In addition, early diagnosis may encourage healthy lifestyle from childhood through role modelling in the family and help parents to be better prepared for future challenges.

Table 1.

Benefits and risks of genetic testing for ADPKD in minors

Benefits	Risks
Provide an accurate molecular diagnosis, particularly in those with atypical clinical presentation	Increase psychological burden of the minors and their families (e.g., anxiety), may potentially affect minor’s psychological development and self-esteem
Be proactive in disease management, including monitoring, early intervention (e.g., rigorous BP control with renin angiotensin system inhibitors can slow down disease progression) and prevention (e.g., avoid potentially nephrotoxic agent exposure)	Impact on family dynamics (e.g., parental guilt, survivor guilt)
Give motivation for early lifestyle modification	Give false reassurance of one is not at risk of developing the disease with a negative screening result
Empower parents to better prepare for future challenges and alleviate anxiety due to uncertainty	Loss of legal opportunities such as difficulty in obtaining disability insurance and life insurance

Genetic testing is also beneficial in children and adolescents with atypical presentation of ADPKD (e.g., multiple unilateral cysts, extra-renal cysts or concomitant diabetes) and a negative family history, where differentiation from other causes of cystic kidney disease is important.¹ Rarely, ADPKD may present in early childhood or even antenatally that mimic Autosomal Recessive Polycystic Kidney Disease. Genetic testing in these cases is important for clear diagnosis, prognostication, identifying extra-renal manifestation, and informing reproductive choices.

Still, the medical benefits of screening asymptomatic children and adolescents for a disease that typically presents in adulthood, with no specific therapy to slow down progression in childhood, remain unclear (Table 1). The psychological, ethical, legal, and socioeconomic implications of a positive genetic testing result must be considered.⁵ Pre-symptomatic diagnosis may predispose the child and their families to years of anxiety, a feeling that even some describe as ‘resembling time-bomb ticking.’⁶ This impending sense of doom may be worse if one witnessed adverse health outcomes of other affected family members. Growing up with the impression that one is different from their peers may further impact adversely on a child’s psychosocial development, especially adolescents who are in the critical process of identity development.⁷ The psychological burden may extend to other family members, interfering with family dynamics. Prior to testing, parents and their adolescent children may disagree on whether to be tested and with whom to share the results. Parents may feel guilty for ‘passing on’ a faulty gene, and siblings who tested negative for the familial variant may have survivor’s guilt.^7,8 Loss of legal opportunities due to genetic diagnosis is possible, depending on the ever-evolving laws of each country. In the US, children identified as having a genetic risk for a condition due to positive family history may face difficulties obtaining disability and life insurances. This challenge is greater if they are confirmed as carriers of the familial variant. In the UK, new regulatory frameworks are called upon to address fairness, accessibility and price of insurance for patients with genetic information.⁹ Conversely, a negative genetic testing result for ADPKD may provide false impression that one has no risk instead of the population-level risk of developing the disease. One may also be falsely reassured by negative ultrasound screening. This highlights the need to carefully explain results to patients and their family in appropriate language, including their scope, implications, and preventative environmental and lifestyle measures that could be adopted to reduce the risk. Competent children and adolescents should be engaged in the decision-making process, giving due weight to the age and maturity of the child as required by local laws and internationally, for State signatories of the Convention on the Rights of the Child.

Local healthcare systems, economic factors and legal frameworks may also affect clinicians’ and families’ decisions on screening of pre-symptomatic children. In the current study, lower rates of genetic testing were observed in regions with lower health expenditure, possibly due to the cost of genetic testing. However, there are exceptions such as the US, where genetic testing may not be covered by health insurance. The legal standards for testing asymptomatic or pre-symptomatic children and adolescents vary worldwide. In some countries, such predictive genetic testing is prohibited by law unless there is clear benefit. In others, disclosure of predictive genetic testing results to private insurance companies is not mandatory.⁹

The KDIGO 2025 Clinical Practice Guideline for the Evaluation, Management, and Treatment of ADPKD emphasized the importance of providing comprehensive counselling that encompasses the potential diagnostic options (genetic testing or abdominal ultrasound), alternative approach of periodic screening for hypertension and proteinuria, and their respective benefits and harms in children and adolescents who are at risk for ADPKD.¹ A family-centered approach is recommended, including parents or legal guardians, mature child and a multi-disciplinary team consisting of a pediatric nephrologist and a genetic counsellor/geneticist with expertise in ADPKD for shared decision-making.

Genetic technology enables increasingly accurate genetic testing within hours. The key question is whether one should employ the technology to actively screen for ADPKD in children and adolescents who are at risk but asymptomatic. Comprehensive counselling of the aforementioned considerations is needed to achieve a shared decision-making for the best interest of the child. Future longitudinal studies engaging parents with ADPKD and their at-risk children to assess health outcomes and psychosocial wellbeing, with or without genetic testing, as well as cost-effective analyses comparing different screening approaches, are needed to better delineate benefits and risks of genetically diagnosing ADPKD in asymptomatic children. Finally, results of clinical trials in pediatric ADPKD patients are eagerly anticipated as effective interventions would change the screening landscape in asymptomatic children.