Autosomal Dominant Alport Syndrome in a Patient with Familial Thin Basement Membrane Nephropathy: Expanding the Phenotypic Spectrum of COL4A4 Mutations

Introduction: Autosomal dominant Alport syndrome (ADAS) is a rare genetic disorder characterized by mutations in type IV collagen genes, particularly COL4A3 and COL4A4. It shares a genetic continuum with thin basement membrane nephropathy (TBMN), a typically benign condition. The clinical features of ADAS genotype are variable, ranging from isolated microscopic hematuria to proteinuria to some individuals who progress to end-stage kidney disease. Extrarenal findings e.g., sensorineural hearing loss are rare. The phenotypic overlap and variable expression make diagnosis particularly challenging. Case Description: A 50-year-old hispanic female with a family history of thin-membrane disease in two sisters was referred by her PCP for proteinuria. She reported bilateral lower extremity edema but was otherwise asymptomatic. Exam showed bilateral lower extremity edema. Labs revealed a creatinine 1.4mg/dl, microscopic hematuria, eGFR of 49, proteinuria of 315mg/24hr. Genetic testing confirmed COL4A4 gene with an autosomal dominant inheritance consistent with autosomal dominant Alport Syndrome. She was started on lisinopril. Discussion: Although kidney biopsy may reveal thin GBM as the only abnormality, incubation of kidney tissue with antibodies against the alpha chains of type IV collagen reveals abnormalities of GBM staining in majority of the patients with ADAS but shows normal GBM staining in TBMN. Molecular testing for COL4A3, COL4A4, COL4A5 variants by next-generation sequencing is a valuable addition to the diagnostic menu for familial hematuria. This case underscores the phenotypic spectrum of COL4A4 mutations, ranging from benign Thin Basement Membrane Nephropathy to progressive Autosomal Dominant Alport Syndrome. It emphasizes the critical role of genetic testing in differentiating these conditions and guiding family screening. Early identification allows for closer monitoring and potential interventions to delay disease progression.