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  • Title: A wave of deep intronic mutations in X-linked Alport syndrome.
    Author: Boisson M, Arrondel C, Cagnard N, Morinière V, Arkoub ZA, Saei H, Heidet L, Kachmar J, Hummel A, Knebelmann B, Bonnet-Dupeyron MN, Isidor B, Izzedine H, Legrand E, Couarch P, Gribouval O, Bole-Feysot C, Parisot M, Nitschké P, Antignac C, Dorval G.
    Journal: Kidney Int; 2023 Aug; 104(2):367-377. PubMed ID: 37230224.
    Abstract:
    X-linked Alport syndrome (XLAS) is an inherited kidney disease caused exclusively by pathogenic variants in the COL4A5 gene. In 10-20% of cases, DNA sequencing of COL4A5 exons or flanking regions cannot identify molecular causes. Here, our objective was to use a transcriptomic approach to identify causative events in a group of 19 patients with XLAS without identified mutation by Alport gene panel sequencing. Bulk RNAseq and/or targeted RNAseq using a capture panel of kidney genes was performed. Alternative splicing events were compared to those of 15 controls by a developed bioinformatic score. When using targeted RNAseq, COL4A5 coverage was found to be 23-fold higher than with bulk RNASeq and revealed 30 significant alternative splicing events in 17 of the 19 patients. After computational scoring, a pathogenic transcript was found in all patients. A causative variant affecting COL4A5 splicing and absent in the general population was identified in all cases. Altogether, we developed a simple and robust method for identification of aberrant transcripts due to pathogenic deep-intronic COL4A5 variants. Thus, these variants, potentially targetable by specific antisense oligonucleotide therapies, were found in a high percentage of patients with XLAS in whom pathogenic variants were missed by conventional DNA sequencing.
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