[New Genetic Variants Involved in the Pathogenesis of Autosomal Dominant Alport Syndrome: A Familial Case Report]

Alport syndrome is a hereditary disorder characterized by hematuria, proteinuria and progressive renal failure, frequently associated with extrarenal manifestations. The pathogenic variants of the COL4A5 gene are associated with X-linked Alport syndrome while those of the COL4A3 and COL4A4 genes are associated with the autosomal recessive (AR) or dominant (AD) form. The disease is characterized by considerable phenotypic variability linked to the different genes involved and the different mutations present, so the symptoms manifest themselves in different frequencies depending on the case. The existence of an autosomal dominant form of Alport syndrome has been identified in recent years thanks to next generation gene sequencing (NGS) techniques which have made it possible to highlight unknown genetic variants of Alport syndrome. The family studied by us presents concomitant heterozygous alterations of the COL4A3 genes (c.1029+5G>A with MAF 0 and c.3211-7A>G with MAF 1:100000), heterozygous alterations of the MTHFR gene (both C677T and A1298C) and homozygous alteration of the PAI-1 gene. While the variant c.3211-7A>G, as shown by genetic databases (ClinVar), appears to be benign, the intronic variant c.1029+5G>A (caused by exon skipping) can be classified as pathogenic due to its characteristics and the fact that it co-segregates with the phenotype within the family. The histological data, in one of the sisters, highlighted the presence of a discrete global glomerular sclerosis and the ultrastructural investigation a thinning of the glomerular basement membrane. New mutational variants of the COL4A3 gene may play a role as risk variants for the development of chronic kidney disease.