#5124 GENETIC GLOMERULAR DISEASES IN THE ADULT PATIENT: A WORK IN PROGRESS – SINGLE CENTRE COHORT

Abstract

Abstract Background and Aims Recent advances in genetic molecular techniques have allowed the expansion of knowledge in glomerular diseases of genetic cause, including the identification of genes involved in focal and segmental glomerular sclerosis (FSGS). The prevalence of adult-onset genetic FSGS varies widely depending on the population studied. In central Europe, NPHS2 and COL4A3, COL4A4 e COL4A5 genes are postulated to be the most frequent genes implicated in genetic causes of adult FSGS. This study aims to characterize patients submitted to genetic study of glomerular diseases in the Nephrogenetics Clinic of our centre. Method We conducted a single-centre retrospective analysis of the patients submitted to genetic study of glomerular diseases in the Nephrogenetics Clinic of our centre from 2016 to 2022. Adult patients with a glomerular disease phenotype suggestive of a genetic cause were studied, using a predetermined phenotype-targeted panel of genes, through massive parallel sequencing. The number of genes included in this panel has increased (from 21 genes in 2016 to 49 genes since 2018); given this change, patients with a negative result on the first approach repeated screening with the broader panel. Additionally, patients presenting with advanced chronic kidney disease (CKD) without an identifiable phenotype, studied with a larger panel for CKD causing genes, are reported. In patients with a negative result but highly suggestive presentation, whole exome sequencing (WES) was considered, after multidisciplinary discussion with a Geneticist's evaluation. Patients with variants of unknown significance (VUS) were referred to a Genetics’ consultation for genetic counselling and segregation studies. Results Of the 80 patients studied (comprising 74 families), 52.5% were female (n=42) and 79% (n=63) of Caucasian ascent. Mean age was 45.4 ± 16.0 years. Nine patients were studied with the larger gene panel for CKD. 85% (n=68) had CKD (all stages) at presentation, with proteinuria (ranging from sub-nephrotic to nephrotic range) and 15% had asymptomatic urinary changes. 50% (n=40) of patients had positive family history, and 31% (n=25) had a syndromic presentation and/or extra renal manifestations. 27.5% (n=22) had a renal biopsy, and the most prevalent result was FSGS (11%; n=9). Genetic variants were identified in 70% (n=56) of the patients; but pathogenicity is not fully established in all: genotype-phenotype correlations, including inheritance pattern and histological correlation, and segregation studies (when indicated and possible) are ongoing. In 5 patients results are pending. Pathogenic / likely pathogenic variants were identified in at least 47.5% (n=38) patients. The most frequently implicated genes were: COL4A3, COL4A4 e COL4A5 (n=21), high risk APOL1 (n=8); NPSH2 (n=5), IFN2 (n=6, 3 pathogenic, 1 variant of unknown significance (VUS), 2 under segregation studies) and MYH9 (n=3). COL4A3, COL4A4 e COL4A5 mutations occur with Alport syndrome, but also with histologically documented FSGS, sub-nephrotic and nephrotic proteinuria, nephrotic syndrome and asymptomatic urinary changes. In our cohort, NPHS2 p.R229Q was identified in 5 patients (6%), but only with pathogenic significance in 3 patients, and APOL1 high risk haplotype was co-identified with COL4 variants in 3 patients. Conclusion The genetic study of a cohort of patients suspected of genetic FSGS allowed the identification of genetic variants in the genes of interest in a high percentage of cases. The most frequently implicated genes were COL4A3, COL4A4 e COL4A5, NPHS2, INF2 and APOL1 high risk haplotype. The high percentage of gene variants identified in our cohort is probably due to the selection of a population with a high likelihood of genetic FSGS. Further studies will clarify the causal and/or modifier effect of some genes, namely COL4A3, COL4A4 e COL4A5. The future use of WES in cases of high likelihood of genetic cause will probably allow the identification on novel candidate genes and increase the clinical benefits of a genetic diagnosis of FSGS.