Heterozygous Urinary Abnormality-Causing Variants of COL4A3 and COL4A4 Affect Severity of Autosomal Recessive Alport Syndrome

Background Autosomal recessive Alport syndrome (ARAS) is an inherited renal disorder caused by homozygous and compound heterozygous mutations inCOL4A3orCOL4A4, but the prognostic predictors for this disorder are not yet fully understood. Recently, the magnitude of the clinical spectrum of theCOL4A3andCOL4A4heterozygous state has attracted attention. This spectrum includes asymptomatic carriers of ARAS, benign familial hematuria, thin basement membrane disease, and autosomal dominant Alport syndrome. Methods We retrospectively analyzed 49 patients with ARAS from 41 families with a median age of 19 years to examine the clinical features and prognostic factors of ARAS, including the associated genotypes. Results The median age of patients with ARAS at ESKD onset was 27 years. There was no significant association between the presence or absence of hearing loss or truncating mutations and renal prognosis. However, there was a statistically significant correlation between renal prognosis and heterozygous variants that cause urinary abnormalities. Where the urinary abnormality-causing variant was absent or present in only one allele, the median age of ESKD onset was 45 years, whereas the same variant present on both alleles was associated with an age of onset of 15 years (P < 0.001). Conclusions This study was the first to demonstrate the clinical importance in ARAS of focusing on variants inCOL4A3orCOL4A4that cause urinary abnormalities in both the homozygous or heterozygous state. Although heterozygous mutation carriers ofCOL4A3andCOL4A4comprise a broad clinical spectrum, clinical information regarding each variant is important for predicting ARAS prognosis.