#2446 Collagen IV diseases—genetic testing yield of a single-center cohort

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Abstract Background and Aims Type IV collagen is a key structural component of the glomerular basement membrane (GBM). Variants in COL4A3, COL4A4, and COL4A5 genes disrupt GBM integrity, leading to genetic kidney diseases (KD) such as Alport syndrome and thin basement membrane nephropathy. These variants impair collagen assembly, leading to hematuria, proteinuria, and progressive kidney dysfunction. Recently, an expanded spectrum of clinical phenotypes has been attributed to type IV collagen variants, namely proteinuria, focal and segmental glomerulosclerosis and cystic KD. Advances in molecular genetics are improving understanding of the genetic and phenotypic spectrum of type IV collagen-related nephropathies. Method Genetic and phenotypic characterization of the COL4 renal disease cohort of patients in the adult Nephrogenetics’ Clinic of a tertiary-level care hospital, between 2014 and 2024. Genetic testing was performed through next generation sequencing gene panels based on whole exome sequencing. Results Of the 332 screened patients, 41 patients (27 families) presented variants in the type IV collagen gene. Variants were reported in COL4A3 (n = 14), COL4A5 (n = 14), COL4A4 (n = 11), COL4A1 (n = 3) and COL4A6 (n = 1). Two patients had more than one identified mutation. According to American College of Medical Genetics and Genomics criteria, variants were classified as follows: 7 pathogenic (P); 23 likely pathogenic (LP); 11 variants of uncertain significance (VUS) and 2 as likely benign. A total of 30 patients had P/LP variants: 10 in COL4A5 (heterozygous), 1 COL4A5 heterozygous deletion, 11 in COL4A3 (10 heterozygous, 1 homozygous), 8 in COL4A4 (heterozygous). The majority of patients were female (n = 24), and mean age at diagnosis was 48.7 ± 15.8 years. Most (n = 27) had positive family history for CKD. The most common renal presentations included chronic kidney disease (n = 23) and hematuria and/or proteinuria in the remaining patients. Six patients had kidney cysts. Hypoacusia was reported in 6 patients, and one had reduced visual acuity. Of note, we highlight co-existing variants in other genes, in addition to P/LP COL4 variants: heterozygous CFHR3/CFHR1 deletion (2 patients); NADSYN1 LP variant (1 patient), CC2D2A LP variant (1 patient), MYH9 VUS (1 patient), KIAA0586 LP variant (1 patient). Conclusion Genetic testing for mutations in type IV collagen is crucial for early diagnosis, accurate classification, and prognostic assessment of hereditary kidney diseases. Genetic diagnosis also enables personalized Nephrology care in the era of precision medicine, namely for actionable genes as COL4.

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