Kidney Week

Abstract: FR-OR16

Genetic Landscape in Population-Based ADPKD Cohort: Beyond PKD Type 1 and PKD Type 2

Session Information

• Cystic Kidney Diseases: Basic and Translational Research
  October 25, 2024 | Location: Room 23, Convention Center
  Abstract Time: 05:30 PM - 05:40 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Zagorec, Nikola, Centre Hospitalier Regional et Universitaire de Brest, Brest, Bretagne, France

Nikola Zagorec, MD

• Audrezet, Marie-Pierre, Centre Hospitalier Regional et Universitaire de Brest, Brest, Bretagne, France

Marie-Pierre Audrezet, PhD

• Halimi, Jean-Michel, Groupement Hospitalier de Territoire Touraine-Val de Loire, Tours, Centre-Val de Loire, France

Jean-Michel Halimi

• Bridoux, Frank, Centre Hospitalier Universitaire de Poitiers, Poitiers, France

Frank Bridoux, MD, PhD

• Augusto, Jean Francois, Centre Hospitalier Universitaire d'Angers, Angers, Pays de la Loire, France

Jean Francois Augusto, MD, PhD

• Dantal, Jacques, Centre Hospitalier Universitaire de Nantes, Nantes, Pays de la Loire, France

Jacques Dantal, MD

• Le Meur, Yannick, Centre Hospitalier Regional et Universitaire de Brest, Brest, Bretagne, France

Yannick Le Meur

• Cornec-Le Gall, Emilie, Centre Hospitalier Regional et Universitaire de Brest, Brest, Bretagne, France

Emilie Cornec-Le Gall, MD, PhD

Group or Team Name

• European Renal Association.

Background

A substantial proportion of individuals with ADPKD-like phenotype carry pathogenic variants in other cystic genes or genes phenocopying ADPKD or are genetically unresolved (GUR). Deciphering this variability is a reseach priorities highlighted in the KDIGO guidelines.

Methods

Genkyst is a population based ADPKD cohort including all patients with (a)typical ADPKD in 28 centers. A panel of 27 known or candidate genes was employed, whole exome sequencing (WES) was performed in a subset of the GUR cases.

Results

Genetic analysis was performed in 3432 individuals (48.4% males), included at the median age of 54.5y [16-95]. Likely pathogenic or pathogenic variants (LP/P) were identified in 87.1%. While PKD1 and PKD2 LP/P variants were identified in 66.7 and 17.7% of participants, 2.9% had atypical forms of ADPKD caused by variants in 15 different genes, the most common being DNAJB11 (n=15), IFT140 (n=14), ALG8 (n=13), HNF1B (n=12) and GANAB (n=8)(Figure). WES was performed in 151 GUR cases, revealing some important ADPKD-differentials like heterozygous COL4A4, OFD1 or biallelic TULP3, with significant clinical implications. Of interest, monoallelic loss-of-function variants were detected within 13 different ciliopathy genes (15 patients); causality is being investigated. A total of 435 individuals (416 families) remain GUR, with WES ongoing in 258. Compared to PKD1-PKD2 patients, GUR individuals were more often males (65vs46%), significantly older (65.1vs53 y), more often diagnosed incidentally (40vs24%) with less common PKD familial history (24vs74%), and less kidney failure (16vs42%)(all P<0.01).

Conclusion

ADPKD is genetically heterogeneous, with in our cohort 8 ADPKD-associated genes and 9 phenocopies. Further genetic heterogenity is likely, with candidate genes identified by WES being currently characterized.

Funding

• Government Support – Non-U.S.