Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Cohort Study

• DOI: 10.1053/j.ajkd.2021.02.326
• Publication Date: 2021-04-07T08:08:00Z
• Authors: Mónica Furlano; Victor Martínez; Marc Pybus; Yolanda Arce; Jaume Crespí; María del Prado V...; Gemma Bullich; Andrea Domingo; Nadia Ayasreh; Silvia Benito; Laura Lorente; Patricia Ruíz; Vanesa López Gonz...; Rosa Arlandis; Elisa Cabello; Ferran Torres; Lluis Guirado; Elisabet Ars; Roser Torra
• Keywords: Adult; Collagen Type IV; Male; Genotype-phenotype correlation; Adolescent; COL4A3; Nephritis, Hereditary; Autoantigens; Cohort Studies; Young Adult; 03 medical and health sciences; Autosomal-dominant Alport syndrome; 0302 clinical medicine; Genetic; COL4A4; Humans; Hereditary kidney disease; Thin basement membrane disease; Genetic Testing; Renal Insufficiency; Familial benign hematuria; Aged; Retrospective Studies; Aged, 80 and over; Familial hematuria; Genetic Variation; Hearing loss; Middle Aged; 3. Good health; Inherited kidney disease; Female; Alport syndrome

Alport syndrome is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in the gene COL4A3, COL4A4, or COL4A5. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS).Retrospective cohort study.82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected.A pathogenic DNA variant in COL4A3 was identified in 107 patients (35 families), whereas 133 harbored a pathogenic variant in COL4A4 (43 families). Digenic/complex inheritance was observed in 12 patients. Overall, the median kidney survival was 67 (95% CI, 58-73) years, without significant differences across sex (P=0.8), causative genes (P=0.6), or type of variant (P=0.9). Microhematuria was the most common kidney manifestation (92.1%), and extrarenal features were rare. Findings on kidney biopsies ranged from normal to focal segmental glomerulosclerosis. The slope of estimated glomerular filtration rate change was-1.46 (-1.66 to-1.26) mL/min/1.73m2 per year for the overall group, with no significant differences between ADAS genes (P=0.2).The relatively small size of this series from a single country, potentially limiting generalizability.Patients with ADAS have a wide spectrum of clinical presentations, ranging from asymptomatic to kidney failure, a pattern not clearly related to the causative gene or type of variant. The diversity of ADAS phenotypes contributes to its underdiagnosis in clinical practice.