Next-generation sequencing errors due to genetic variation in WRAP53 encoding TCAB1 on chromosome 17

IF 3.7 2区医学 Q2 GENETICS & HEREDITY Human Mutation Pub Date : 2022-09-18 DOI:10.1002/humu.24469

Sharon A. Savage, Kristine Jones, Kedest Teshome, Adriana Lori, Lisa J. McReynolds, Marena R. Niewisch

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Abstract

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.

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17号染色体上编码TCAB1的WRAP53遗传变异导致的下一代测序错误

下一代测序(NGS)是一种有价值的工具，但在单核苷酸(均聚物)重复测序方面存在局限性。编码端粒Cajal体蛋白1 (TCAB1)的WRAP53致病性种系变异是已知的先天性角化不良的原因。我们在WRAP53, c.1562dup, p.Ala522Glyfs*8 (rs755116516 G>-/GG/GGG)中发现了一个显著的NGS错误，未通过Sanger测序验证。这种错误的发生是因为rs755116516 G>-/GG/GGG (Chr17:7,606,714)是多态性的，该位点的变异挑战了NGS在均聚物序列中准确调用正确核苷酸数量的能力。更复杂的是，chr17:7,606,721 (rs769202794)是多等位基因G>A, C, T，而且chr17:7,606,722也是多等位基因(rs7640C>A/G/T和rs373064567C>delC)。除了对潜在的临床可操作变异的专家解释外，它还建议在临床行动之前，通过Sanger测序验证具有均聚物的基因组区域的所有变异。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human Mutation 医学-遗传学

CiteScore

8.40

自引率

5.10%

发文量

190

审稿时长

2 months

期刊介绍： Human Mutation is a peer-reviewed journal that offers publication of original Research Articles, Methods, Mutation Updates, Reviews, Database Articles, Rapid Communications, and Letters on broad aspects of mutation research in humans. Reports of novel DNA variations and their phenotypic consequences, reports of SNPs demonstrated as valuable for genomic analysis, descriptions of new molecular detection methods, and novel approaches to clinical diagnosis are welcomed. Novel reports of gene organization at the genomic level, reported in the context of mutation investigation, may be considered. The journal provides a unique forum for the exchange of ideas, methods, and applications of interest to molecular, human, and medical geneticists in academic, industrial, and clinical research settings worldwide.