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

IF 4.3 3区材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC

ACS Applied Electronic Materials 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。

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来源期刊

ACS Applied Electronic Materials Multiple-

CiteScore

7.20

自引率

4.30%

发文量

567