A Partial UMOD Deletion Results in Altered Uromodulin Synthesis and Autosomal-Dominant Tubulointerstitial Kidney Disease-Uromodulin

Autosomal dominant tubulointerstitial kidney disease-uromodulin (ADTKD-<i>UMOD</i>) is classically due to missense variants in <i>UMOD</i> that display a dominant-negative effect. Here, we describe a family with high clinical suspicion for ADTKD-<i>UMOD</i> 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 (1,313 bp) encompassing part of exon 3, the entire intron 3 and exon 4, and part of intron 4, conserved regions of <i>UMOD</i> in which 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 this deletion may result in an altered protein. This is the first large deletion demonstrated by functional assessment as responsible for ADTKD-<i>UMOD</i>, and importantly, it was undetected by conventional variant calling on short-read exome sequencing. Our results suggest that copy number variants may also be responsible for ADTKD-<i>UMOD</i>. We propose that when ADTKD is suspected but not explained by massive parallel sequencing and <i>MUC1</i> analysis, additional sequencing techniques might unravel other types of genetic alteration, notably copy number variants, and thereby address unsolved ADTKD cases.