Autosomal dominant Alport syndrome: molecular analysis of theCOL4A4 gene and clinical outcome

Alport syndrome is a clinically and genetically heterogeneous nephropathy characterized by irregular thinning, thickening, and splitting of the glomerular basement membrane often associated with hearing loss and ocular symptoms. While the X-linked and the autosomal recessive forms are well known, the autosomal dominant form is not well acknowledged. We have investigated 37 patients with a clinical and molecular diagnosis of autosomal ATS belonging to 8 different families. The mean age of patients was 38.7 years ranging from 6 to 76 years. Only 9 out of 37 (24.3%) patients reached the ESRD, at the mean age of 51.2 years. Four patients (13.8%) had hearing loss and none ocular changes. DHPLC analysis revealed 8 novel private COL4A4 gene mutations: 3 frameshift, 3 missense and 2 splice-site mutations. These data indicate autosomal dominant Alport syndrome as a disease with a low risk of ocular and hearing anomalies but with a significant risk to develop renal insufficiency although at an older age than autosomal recessive and X-linked forms. These clinical features make difficult differential diagnosis with the benign familial hematuria due to heterozygous mutations of COL4A4. On the other hand, we are unable to demonstrate a genotype-phenotype correlation with the type and the site of the COL4A4 mutations. A correct diagnosis and prognosis is based on a comprehensive clinical investigation in as many family members as possible.