P0051NOVEL AND KNOWN MUTATIONS IDENTIFIED BY CLINICAL EXOME SEQUENCING FOR THE DIAGNOSIS OF POLYCYSTIC KIDNEY DISEASE

• Published in: Nephrology, dialysis, transplantation dialysis, transplantation, 2020-06, Vol.35 (Supplement_3)
• Main Authors: Vaisitti, Tiziana, Sorbini, Monica, Callegari, Martina, Kalantari, Silvia, Bracciamà, Valeria, Arruga, Francesca, Vanzino, Silvia Bruna, Pelle, Alessandra, Giachino, Daniela, Cocchi, Enrico, Baldovino, Simone, Rollino, Cristiana, Fenoglio, Roberta, Tamagnone, Michela, Gherzi, Maurizio, Soragna, Giorgio, Vitale, Corrado, Berta, Valentina, Calabrese, Giovanni, Leonardi, Gianluca, Biancone, Luigi, Strampelli, Emanuela, Maroni, Serena, Santi, Sonia, Funaro, Loredana, Borzumati, Maurizio, Bertinetto, Patrizia, Viglino, Giusto, Gianoglio, Bruno, Peruzzi, Licia, Roccatello, Dario, Amoroso, Antonio, Deaglio, Silvia
• Format: Article
• Language: English
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfaa142.P0051

Abstract Background and Aims Autosomal dominant PKD determines formation of multiple cysts predominantly in the kidneys and usually becomes symptomatic during adulthood and can lead to renal failure. In contrast, in autosomal recessive PKD cysts occur in both the kidneys and the liver and usually presents an earlier onset. Obtaining genetic diagnosis is important to confirm clinical diagnosis and is required before treating with vasopressin 2 receptor blockers, which are the only drugs known to slow down the disease. Furthermore, in the case of kidney transplant from a living family member it is essential to exclude the presence of the mutation in the donor. We used clinical exome sequencing to provide genetic diagnosis to a cohort of patients with a clinical suspicion of PKD. Method 175 patients were referred to the Immunogenetics and Transplant Biology Service of the Turin University Hospital through a network of nephrology centers operating in the Piedmont region. Some patients were referred following genetic counseling. All patients signed an informed consent and the referring physicians provided relevant clinical data. DNA from eligible patients was extracted, checked for integrity, quantified and used for library preparation. A clinical exome sequencing (CES) kit by Illumina was used, allowing the analysis of 6,700 clinically relevant genes. Results Out of the 175 recruited patients eligible for CES, 38 (21.7%) had a clinical suspicion or diagnosis of PKD, with 50% of them presenting family history. The majority of the cohort was represented by male subjects (60.5%) and included both children (34.2%) and adults. The analytical approach was based on initial analysis of genes responsible for PKD (PKD1, PKD2 and PKHD1). If no mutation could be identified, analysis was then extended to a panel of 99 genes responsible for ciliopathies. This approach led to the identification of causative variants in 33/38 (86.8%) of the PKD cohort, while no variant could be identified in 5/38 patients. In 5/33 (15.2%) patients, mutations were inconclusive as found in heterozygosity in genes known to have an autosomal recessive mode of inheritance, while 27/33 (81.8%) were in line with the initial clinical suspicion/diagnosis. Of these, the majority was represented by missense mutations (12), followed by frameshift and nonsense mutations (6 each) and 3 splicing variants. As expected, the majority of mutations were found in PKD1 17/27 (63%), PKD2 3/27 (11.1%) and PKHD1 2/27