#4413 MOLECULAR SPECTRUM OF GENETIC ANOMALIES IN PEDIATRIC PATIENTS WITH EARLY ONSET OF RENAL CYSTIC DISEASE
Authors: Bracciamà Valeria , Bucchino Laura , Carli Diana , Solito Arianna , Faini Angelo Corso , Kalantari Silvia , del Prever Giulia Margherita Brach , Amoroso Antonio , Vaisitti Tiziana , Peruzzi Licia , Deaglio Silvia 
Published: June 2023

Abstract

Background and Aims
Renal cystic disease (RCD) includes a spectrum of disorders with heterogenous clinical presentation. Among RCD are autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), ciliopathies, HNF1B-nephropathy, and congenital anomalies of the kidneys and of the urinary tract (CAKUT). Diagnosis is based on clinical criteria, yet, given the extreme genetic heterogeneity and phenotypic overlap among different conditions, confirmation by genetic testing is paramount for correct clinical management and recurrence risk assessment. Although genotype-phenotype correlations are scanty, recently, coexisting variants in the same gene or in multiple cystogenes have been associated with earlier and more severe renal phenotype. The aim of this study is to describe the clinical and molecular characteristics of pediatric patients with early onset of RCD and provide genotype-phenotype correlations.

Method
A retrospective study was conducted collecting patients with a prenatal or early-childhood ultrasound finding of renal hyper-echogenicity or cysts. All patients were followed at the Pediatric Nephrology Unit of the Città della Salute e della Scienza University Hospital of Torino, Italy. Genetic analyses were mostly performed at the Immunogenetic and Transplant Biology Unit and included clinical exome sequencing (CES), array-CGH, MLPA and single gene testing.

Results
65 patients we recruited, 42 males (64.6%) and 23 females (35.4%), mean age 8 ± 5.9 years (range 0-18). The most frequent clinical suspicion was ADPKD (n = 40, 61.5%), followed by CAKUT (n = 9, 13.8%), ARPKD (n = 8, 12.3%), ciliopathy and tuberous sclerosis complex (TSC) (n = 3, 4.6% for each condition), and medullary cystic disease (n = 2, 3.1%).
Overall, causative variants (C4/C5) were identified in 39 patients (60.0%), 18 (27.7%) were carriers of variants of uncertain significance (C3) and 8 (12.3%) were inconclusive. Among the 40 patients with a clinical suspicion of ADPKD, 23 received a conclusive genetic diagnosis with 20 (87%) variants in PKD1, 2 (8.7%) in PKD2, one in HNF1B and 14 carried C3 variants. All patients with a clinical suspicion of ARPKD received molecular confirmation and, notably, in one case we observed biallelic variants in PKD1. Among the 21 patients with PKD1 variants, 6 (28.6%) had multiple PKD1 variants and 2 (9.5%) carried an additional PKHD1 variant. TSC diagnosis was confirmed in all 3 cases and two of them (66.7%) carried a contiguous gene TSC2-PKD1 deletion. Two out of 3 (66.7%) patients with a clinical suspicion of ciliopathy carried biallelic variants in BBS10, in one case associated with an additional variant in PKD2. Four (44.4%) CAKUT cases were solved with 3 causative variants in HNF1B (75%) and one in PAX2 (25%), 2 cases (22.2%) carried C3 variants and 3 (33.3%) were inconclusive. Causative variants were de novo in 10 cases (25.6%).

Conclusion
Our data confirms that genetic evaluation is a powerful tool for the diagnosis of RCD, as witnessed by a detection rate of 60%. Although the clinical suspicion was confirmed in the majority of cases, one suspected ARPKD case carried two PKD1 variants and one suspected ADPKD case carried a whole HNF1B gene deletion, highlighting the need for extensive genetic analysis. Moreover, nine patients had multiple variants potentially contributing with additive effect to a more severe renal phenotype: 6 patients had two variants in PKD1, 2 patients with a PKD1 variant had an additional variant in PKHD1 and one patient had biallelic BBS10 variants plus a nonsense PKD2 variant. In this context, genetic analysis by CES permits simultaneous evaluation of all RCD associated genes, uncovering both multiple variants and clinical phenocopies. In conclusion, the CES driven genetic characterization of pediatric patients with renal cysts allows to avoid misdiagnosis, minimize diagnostic invasive investigations, set up correct follow-up, and define recurrence risk, with a time- and cost- efficient approach.