#1936 Investigating genetic and environmental modifiers of autosomal dominant polycystic kidney disease through a distinct PKD2-founder variant (p.Arg803*)
Authors: Brigl Carolin , Münster Julia , Arjune Sita , Demoulin Nathalie , Gansevoort Ronald , Torra Roser , Sans Laia , Pamplona Irene Agraz , Sayer John , Gall Emilie Cornec-Le , Hwang Daw-Yang , Halbritter Jan 
Published: May 2024

Background and Aims

Autosomal dominant polycystic kidney disease (ADPKD) is among the most common hereditary diseases that lead to kidney failure [1]. Apart from progressive, cystic enlargement of the kidneys, classic ADPKD is inevitably associated with polycystic liver disease (PLD) and arterial hypertension [2] due to mutated PKD1 (78%) or PKD2 (15%) [3]. Despite knowledge of the diagnostic PKD1 or PKD2 variant, there is great intrafamilial variability in terms of disease progression and organ involvement. Therefore, there is an unmet medical need to establish better genotype-phenotype correlations.

In 2022, Taiwanese colleagues identified a PKD2 founder variant (NM_000297.4 (PKD2): c.2407C&gt;T (p.Arg803*)) which accounts for 17.8% of all ADPKD cases in Taiwan [4]. As we also detected patients with PKD2-Arg803* in our European center, we hypothesize that p.Arg803* constitutes a recurrent mutation. The established Taiwanese cohort provides the unique opportunity to build up a sister cohort of patients with this specific mutation. This novel approach can aid in identifying genetic and environmental modifiers of ADPKD, which in turn is essential in elucidating the pathogenesis, as well as the adequate classification, prognosis and treatment of ADPKD patients.

Method

For patient recruitment, the search was carried out simultaneously in a multi-pronged approach. First, the European Rare Kidney Disease Network (ERKNet), relevant registries and biobanks were searched to identify patients. In addition, authors of ClinVar entries and published literature with specific mentions of the variant were contacted. Lastly, clinical and genetic ADPKD specialists were reached out to directly.

Deep phenotyping was performed by a specific clinical questionnaire that was sent to the respective treating physicians via Microsoft Forms. This included baseline information about patients as well as clinical parameters. Specifically, a detailed analysis of kidney, liver, CNS and further manifestations of ADPKD was performed. In addition to the main mutation, additional findings in relevant ADPKD genes were documented. Environmental factors such as smoking, estrogen use, diets and exercise were also been explicitly recorded.

Results

Through systematic search, 545 institutions or clinicians were contacted in 47 countries. Thus far, about 170 patients with PKD2-p.Arg803* have been identified in 25 centers from 15 countries outside of Taiwan. The process of deep phenotyping is ongoing (completed on 20 patients as of 01/2024). A preliminary analysis of this smaller cohort showed a mean age of 62 (range: 38–90) years and a sex distribution (F:M) of 11: 9. The median total kidney volume was 1437 ml (IQR 2525.5) mL and three patients had reached kidney failure at age 70, 72 and 69. Eighteen out of the 20 patients had three or more liver cysts with a median total liver volume of 1849 (IQR 822.5) mL.

Conclusion

We are continuing to expand the cohort, aiming to reach full datasets in about 80 international patients for joint analysis with the Taiwanese founder cohort. Detailed statistical analysis of the joint cohort will allow us to better characterize modifiers on the genetic and environmental level. We hope our project can contribute to further understanding disease variability in ADPKD.