%0 Journal Article
%T Next-generation sequencing errors due to genetic variation in WRAP53 encoding TCAB1 on chromosome 17.
%A Savage SA
%A Jones K
%A Teshome K
%A Lori A
%A McReynolds LJ
%A Niewisch MR
%J Hum Mutat
%V 43
%N 12
%D 12 2022
%M 36116037
%F 4.7
%R 10.1002/humu.24469
%X Next-generation sequencing (NGS) is a valuable tool, but has limitations in sequencing through repetitive runs of single nucleotides (homopolymers). Pathogenic germline variants in WRAP53 encoding telomere Cajal body protein 1 (TCAB1) are a known cause of dyskeratosis congenita. We identified a significant NGS error in WRAP53, c.1562dup, p.Ala522Glyfs*8 (rs755116516 G>-/GG/GGG) that did not validate by Sanger sequencing. This error occurs because rs755116516 G>-/GG/GGG (Chr17:7,606,714) is polymorphic, and variants at this site challenge the ability of NGS to accurately call the correct number of nucleotides in a homopolymer run. This was further complicated by the fact that chr17:7,606,721 (rs769202794) is multiallelic G>A, C, T, and that chr17:7,606,722 is also multiallelic (rs7640C>A/G/T and rs373064567C>delC). In addition to the expert interpretation of potentially clinically actionable variants, it recommended that all variants in regions of the genome with homopolymers be validated by Sanger sequencing before clinical action.