#1507 Genetics in suspected cases of hereditary kidney diseases
Authors: Saiz Víctor Joaquín Escudero , Xipell Marc , Guillen-Olmos Elena , Piñeiro Gaston , Rodas Lida , Cucchiari David , Diekmann Fritz , Poch Esteban , Porras Luis Fernando Quintana , Badenas Celia , Pelicano Miquel Blasco , Isabel Álvarez María 
Published: May 2024

Abstract

Background and Aims
Hereditary kidney diseases are the fifth cause of chronic kidney disease (CKD). They are responsible for around 10% of adults with kidney replacement therapy. Genetic testing in suspected cases allows us to make a definitive diagnosis, prognosis, therapeutic options and family counselling.

Method
We present a descriptive study from Hospital Clínic Barcelona (Spain) of all genetic tests performed in suspected cases of hereditary kidney diseases between 2019 and 2023 by using whole exome sequencing. Diseases are classified into these groups: cyst kidney diseases, Alport syndrome spectrum (ASS), complement-related kidney diseases, tubulointerstitial kidney disease (TID), CKD of unknow etiology (CKDUE), podocytopathies, and miscellaneous. All analyses were made with blood samples.

Results
As of December 31st, genetic test has been made in 198 patients, of which 172 have definitive results (82/172 women). Genetic tests increase over time with 10 (2019), 15 (2020), 36 (2021), 56 (2022) and 81 (2023). The most frequent suspected genetic kidney diseases were cyst-related (n = 57) followed by CKDUE (n = 43), complement-related kidney disease (n = 27), ASS (n = 20), podocytopathies (n = 16) and TID (n = 6).
Globally, 104 genetic alterations were detected; 40,7% (70/172) were pathogenic or likely pathogenic (P/LP) variants; and 19,8% (34/172) were variants of uncertain significance (VUS). The highest test performance was observed in the cyst-related group with 70,2% (40/57) followed by ASS with 45% (9/20) and TID with 33,1% (2/6) while the lowest performance groups were CKDUE and complement-related diseases with 25,6% (11/43) and 11,1% (3/27) respectively.
The most frequent P/LP variants identified per group were PKD1 (28/40) and PKD2 (12/40) in cyst-related; COL4A4 (5/9) in ASS; CFH, COQ8B and C3 (1/3 each one) in complement-related; UMOD and MUC (1/2 each one) in TID; COL4A4 (2/11) in CKDUE; and TRPC6:1, LMXB1, COL4A3, COL4A5 and COQB8 (1/5 each one) in podocytopathies. The highest genetic heterogeneity was found in CKDUE with 28 genetic variants detected (11 P/LP and 17 VUS).

Conclusion
Although the comparison between the different groups of diseases is complex, because of the different genetic study indication in each one, as well as their prevalence and the performance of the test, in our cohort the most suspected hereditary kidney diseases in which a genetic test was performed was cyst-related diseases, with the highest P/LP variants found and the highest test performance. However, it is worth noting that more than half of the patients had non-related cystic disease, thus increasing the knowledge and detection of less common genetic kidney diseases. CKDUE is the second group with more P/LP variants and with the highest heterogeneity. It is essential that national health systems provide access to genetic tests to complete the study of CKD of unknow etiology.