Kidney Week

Abstract: PUB296

Uncovering the Hidden Genetic Causes of Kidney Diseases: A Whole-Genome Sequencing (WGS) Study

Session Information

• Publication Only

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Giovanella, Silvia, Universita degli Studi di Modena e Reggio Emilia, Modena, Italy

Silvia Giovanella, MS

• Terracciano, Alessandra, Bambin Gesù Children Hospital, Rome, Italy

Alessandra Terracciano, PhD

• Emma, Francesco, Bambin Gesù Children Hospital, Rome, Italy

Francesco Emma, MD

• Ferrulli, Angela, University of Bari, Department of Biosciences, Biotechnologies and Environment, Bari, Italy

Angela Ferrulli, MS

• Testa, Francesca, Azienda Ospedaliero-Universitaria di Modena, Modena, Emilia-Romagna, Italy

Francesca Testa, MD

• Ferri, Maria, Universita degli Studi di Modena e Reggio Emilia, Modena, Italy

Maria Ferri, MD

• Donati, Gabriele, Universita degli Studi di Modena e Reggio Emilia, Modena, Italy

Gabriele Donati, MD, PhD

• Rossini, Michele, University Hospital Bari, Bari, Italy

Michele Rossini

• Valenti, Giovanna, University of Bari, Department of Biosciences, Biotechnologies and Environment, Bari, Italy

Giovanna Valenti, PhD

• Pisani, Antonio, Azienda Ospedaliera Universitaria Federico II, Napoli, Campania, Italy

Antonio Pisani, MD, PhD

• Massella, Laura, Bambin Gesù Children Hospital, Rome, Italy

Laura Massella, MD

• Magistroni, Riccardo, Universita degli Studi di Modena e Reggio Emilia, Modena, Italy

Riccardo Magistroni, MD

Background

Employing a genomic approach holds promise in elucidating the etiology of CKD. Our prior study (‘DECIDE’) demonstrated a yield of 36% in a select population (n=692) undergoing gene panel, with an additional 12% diagnostic rate upon further investigation. This study showed that a large proportion of our patients lacked a final diagnosis despite a high suspicion of genetic disease. This spurred the creation of an Italian consortium comprising 4 clinical centers specialized in genetic kidney diseases. We propose to assess the diagnostic yield of Whole Genome Sequencing (WGS) in unresolved cases.

Methods

The consortium will conduct WGS analysis on 300 patients (100 index cases in trios) with suspected genetic kidney disease who tested negative in initial genetic analyses. Collaboration with AIRP (Italian Patients' Association for Kidney Diseases) will ensure that our protocols align with patient expectations. During recruitment, clinical data will be centralized in RedCAP, with emphasis on family history, age of onset, and lacking diagnosis despite thorough diagnostic evaluation, to prioritize patients with a high suspicion of a genetic condition. The genomic analysis will utilize Illumina's NovaSeq 6000 sequencing platforms. Variants will be classified following ACMG guidelines. The clinical impact of new genomic diagnoses will be assessed by determining whether they will guide tailored therapies, prevent futile treatments, and facilitate cascade testing.
In a subset of patients with cystic manifestations, identified variants will undergo evaluation through functional studies focusing on renal concentrating ability alterations.

Results

Our goal is to identify new pathogenic variants that may have been missed by previous analyses. Integration of genetic results with functional assessment could allow evaluation of the potential of personalized medicine in rare cystic conditions other than ADPKD.

Conclusion

A genetic diagnosis may hold direct clinical implications. By leveraging WGS and advanced bioinformatics, we aim to unearth novel insights contributing to our comprehension of the mechanisms underlying renal diseases.

Funded by the European Union - Next Generation EU - PNRR M6C2 - Investment 2.1 Valorization and
Enhancement of NHS Biomedical Research.

Funding

• Government Support – Non-U.S.