Inversion of the Frequencies of Autosomal Recessive and X-Linked Dominant Forms of Alport Syndrome in the Tunisian Population

Abstract

Abstract Background: Alport syndrome is defined by the co-occurrence of hematuria, renal failure, and a family history of renal failure or hematuria. Pathogenic variants in COL4A3, COL4A4, and COL4A5 cause this phenotype. These genes code for the α3, α4, and α5 chains of collagen IV found in the kidneys, eyes, and cochlea. This explains the frequent association of extra-renal signs, such as bilateral sensorineural deafness and ocular abnormalities. Different modes of transmission have been reported. X-linked transmission is attributed to the pathogenic variants of COL4A5, while homozygous pathogenic variants of COL4A3 or COL4A4 lead to autosomal recessive inheritance. The digenic form occurs when a pathological variation in both COL4A3 and COL4A4coexist. Additionally, autosomal dominant inheritance can occur due to heterozygous pathogenic variants in COL4A3or COL4A4. In this study, we investigated 45 patients with Alport syndrome from 11 Tunisian families to establish their clinical and genetic characteristics. Methods: Clinical data were collected retrospectively, and molecular analysis of COL4A3, A4,andA5 was performed. Among the 45 patients, whole-exome sequencing was performed on 11 individuals, with one patient selected from each family. All candidate pathogenic variations were validated by Sanger sequencing. Cascade screening in the family of each proband allowed us to expand the number of individuals tested to 53 to verify the presence of the pathogenic variant found in their family. Results: We identified 9 likely pathogenic variations among 11 index cases. Six were novel variations and three were known ones. Of these, five out of nine were in the COL4A3 gene, while four out of nine were found in the COL4A5 gene. Frame-shift, nonsense, missense, and alternative splicing variants were detected in our cohort. Most of these variants affected the Gly-XY codon.Thirty out of the 45 clinically identified siblings were tested and confirmed for Alport syndrome. Cascade screening then identified 3 additional affected individuals, along with 10 unaffected siblings and 10 unaffected parents.The mode of inheritance of Alport syndrome was autosomal recessive in 6 familiesand X-linked in 4 families. Conclusions: This study represents the first Tunisian screening of the mutational spectrum of Alport syndrome. It contributes new pathogenic variants to the literature and demonstrates that autosomal recessive inheritance of Alport syndrome is more frequent in the Tunisian population than the X-linked dominant form as reported in the literature.