#4215 MONOALLELIC IFT140-RELATED POLYCYSTIC KIDNEY DISEASE IN AN ITALIAN ADPKD COHORT

Abstract Background and Aims Autosomal-dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder characterized by progressive bilateral renal cysts development and extrarenal phenotype, i.e. liver and/or pancreatic cysts, intracranial aneurism, hernias, mitral valve prolapse and diverticulosis. More than 90% of patients harbour heterozygous pathogenic variant in PKD1 or PKD2 genes, rarely in other cystogenes (e.g. GANAB, DNAJB11, ALG8, ALG9). Recently Senum et al. demonstrated that monoallelic loss of function (LoF) IFT140 variants are an important cause of ADPKD-like disease distinguished by large renal cysts, few liver cysts and mostly mild renal failure. The aim of our study was to define prevalence and phenotype of IFT140-ADPKD in an Italian ADPKD cohort. Methods The study included ADPKD patients, evaluated in 2021 and 2022, at Outpatient Clinic of Genetic Kidney Diseases of Brescia, Italy, that underwent in-depth clinical, laboratory, and instrumental assessments. ADPKD was clinically diagnosed according to Pei modified criteria, in patients with age-specific ultrasound criteria and family history consistent with autosomal dominant inheritance. From January 2022, NGS genetic testing protocol for ADPKD has been updated with IFT140 gene, thus the ADPKD gene panel included: ALG8, ALG9, ANKS6, DNAJB11, GANAB, IFT140, LRP5, PARN, PKD1, PKD2, PRKCSH, SEC61A1, SEC63. The new protocol has been offered to patients evaluated since January 2022 and to all genetically unresolved patients evaluated in 2021. All patients performed also multiple ligation probe amplification (MPLA) analysis of PKD1 or PKD2. Results In 2021 and 2022 ADPKD genes testing has been performed in 129 patients. Pathogenic variants in PKD1 or PKD2 genes were detected in 110/129 patients (85%); among the negative cases (19/129, 15%), 3 patients (P1,P2,P3) resulted heterozygous carrier of LoF variants in IFT140 gene: p.Arg307*, p.Lys1275Argfs*23 and p.Arg834* respectively. Overall 2,3% of ADPKD patients harboured IFT140 pathogenic variant; considering unresolved cases only, the prevalence was 15.7% (3/19). Segregation analysis identified the LoF variant in 3 daughters of P1 and in a son of P2. The 3 probands were diagnosed with renal disease in adulthood from fourth to sixth decade. In P1 eGFR (CKD-EPI formula) slowly declined from 104 ml/min/1.73 at onset (43 year-old) to 74.6 ml/min/1.73 at age 55. In P2 eGFR at first evaluation was 38 ml/min/1.73 (68 year-old); at last follow-up 32.9 ml/min/1.73 (73 year-old). In P3 eGFR declined from 51.7 ml/min/1.73 (55 year-old) to 42 ml/min/1.73 at age 67. Renal imaging in P1 at and P2 disclosed increased total kidney volume (TKV 1042 and 5520 cc respectively), large cysts and absence of cystic liver disease. P3 had slightly increased kidneys (TKV 447cc) with large renal cysts and few liver cysts. Hypertension was present in 4 patients, all with adult-onset (46-60 years). Two patients had an early diagnosis of kidney stones (age 24 and 18). No macroscopic hematuria or cyst infections were reported. In accordance with an ADPKD-like disease form, P1 presented inguinal hernia. Imaging data are summarized in Figure 1. Conclusion In this Italian cohort, heterozygous LoF variants in IFT140 gene is confirmed to be the third most common genetic cause of ADPKD-spectrum disease, the prevalence being 2,3%. The major features are late onset hypertension, increased kidney volume due to large cysts and slow progressive renal failure. IFT140 gene must be included in diagnostic protocol of ADPKD patients to better define renal prognosis, therapy and familial screening.