VNtyper enables accurate alignment-free genotyping of coding VNTR using short-read sequencing data in autosomal dominant tubulointerstitial kidney disease.
Saei H,Morinière V,Heidet L,Gribouval O,Lebbah S,Tores F,Mautret-Godefroy M,Knebelmann B,Burtey S,Vuiblet V,Antignac C,Nitschké P,Dorval G
Source :
iScience
2023 Jun 17
Pmid / DOI:
37456840
Abstract
The human genome comprises approximately 3% of tandem repeats with variable length (VNTR), a few of which have been linked to human rare diseases. Autosomal dominant tubulointerstitial kidney disease- (ADTKD-) is caused by specific frameshift variants in the coding VNTR of the gene. Calling variants from VNTR using short-read sequencing (SRS) is challenging due to poor read mappability. We developed a computational pipeline, VNtyper, for reliable detection of VNTR pathogenic variants and demonstrated its clinical utility in two distinct cohorts: (1) a historical cohort including 108 families with ADTKD and (2) a replication naive cohort comprising 2,910 patients previously tested on a panel of genes involved in monogenic renal diseases. In the historical cohort all cases known to carry pathogenic variants were re-identified, and a new 25bp-frameshift insertion in an additional mislaid family was detected. In the replication cohort, we discovered and validated 30 new patients.KEYWORDSGenetics, Genomics, Genotyping, Techniques in genetics© 2023 The Authors.