Article révisé par les pairs
Résumé : Autosomal Dominant Tubulointerstitial Kidney Disease-Uromodulin (ADTKD-UMOD) is classically due to missense variants displaying a dominant negative effect. Here we describe a family with high clinical suspicion of ADTKD-UMOD for which no molecular diagnosis was obtained through standard techniques including extensive panel sequencing. Whole genome and long read sequencing in multiple affected family members uncovered a large deletion (1313 bp) encompassing part of exon 3, the entire intron 3 and exon 4, and part of intron 4, conserved regions of UMOD where most known pathogenic variants are found. The pathogenic effect of the variant was validated through multimodal analysis of the urinary protein composition. Instead of loss-of-function, our data suggest that it may result in an altered protein. This is the first large deletion demonstrated by functional assessment as responsible for ADTKD-UMOD, and importantly it was undetected by conventional variant calling on short read exome sequencing. Our result suggest that copy number variant may also be responsible for ADTKD-UMOD. We propose that when ADTKD is suspected but not explained by massive parallel sequencing and MUC-1 analysis, additional sequencing techniques might unravel other types of genetic alteration, notably copy number variants, and thereby address unsolved ADTKD cases.

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