Development of a new expanded next‐generation sequencing panel for genetic diseases involved in dyslipidemia,Clinical Genetics

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Development of a new expanded next‐generation sequencing panel for genetic diseases involved in dyslipidemia
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-08-16 , DOI: 10.1111/cge.13832
Oriane Marmontel _{1,

2} , Pierre Antoine Rollat-Farnier ₃ , Anne-Sophie Wozny ₄ , Sybil Charrière _{2,

5} , Xavier Vanhoye ₁ , Thomas Simonet ₃ , Nicolas Chatron ₆ , Delphine Collin-Chavagnac ₄ , Séverine Nony ₁ , Sabrina Dumont ₁ , Muriel Mahl ₄ , Chantal Jacobs ₁ , Alexandre Janin ₁ , Cyrielle Caussy _{2,

7} , Pierre Poinsot ₈ , Igor Tauveron ₉ , Claire Bardel ₃ , Gilles Millat ₁ , Noël Peretti _{2,

8} , Philippe Moulin _{2,

5} , Christophe Marçais ₄ , Mathilde Di Filippo _{1,

2}

Affiliation

The aim of this study was to provide an efficient tool: reliable, able to increase the molecular diagnosis performance, to facilitate the detection of copy number variants (CNV), to assess genetic risk scores (wGRS) and to offer the opportunity to explore candidate genes. Custom SeqCap EZ libraries, NextSeq500 sequencing and a homemade pipeline enable the analysis of 311 dyslipidemia‐related genes. In the training group (48 DNA from patients with a well‐established molecular diagnosis), this next‐generation sequencing (NGS) workflow showed an analytical sensitivity >99% (n = 532 variants) without any false negative including a partial deletion of one exon. In the prospective group, from 25 DNA from patients without prior molecular analyses, 18 rare variants were identified in the first intention panel genes, allowing the diagnosis of monogenic dyslipidemia in 11 patients. In six other patients, the analysis of minor genes and wGRS determination provided a hypothesis to explain the dyslipidemia. Remaining data from the whole NGS workflow identified four patients with potentially deleterious variants. This NGS process gives a major opportunity to accede to an enhanced understanding of the genetic of dyslipidemia by simultaneous assessment of multiple genetic determinants.

中文翻译：

针对与血脂异常相关的遗传疾病开发新的扩展的下一代测序面板

本研究的目的是提供一种有效的工具：可靠、能够提高分子诊断性能、促进拷贝数变异 (CNV) 的检测、评估遗传风险评分 (wGRS) 并提供探索候选基因的机会基因。自定义 SeqCap EZ 文库、NextSeq500 测序和自制管道能够分析 311 个血脂异常相关基因。在训练组（来自具有完善分子诊断的患者的 48 个 DNA）中，这种新一代测序 (NGS) 工作流程显示分析灵敏度 >99%（n = 532 个变异），没有任何假阴性，包括一个部分缺失外显子。在前瞻性组中，从未经事先分子分析的患者的 25 个 DNA 中，在第一意图面板基因中鉴定出 18 个罕见变异，允许诊断 11 名患者的单基因血脂异常。在其他六名患者中，次要基因分析和 wGRS 测定提供了解释血脂异常的假设。来自整个 NGS 工作流程的剩余数据确定了四名具有潜在有害变异的患者。该 NGS 过程提供了一个重要机会，可以通过同时评估多个遗传决定因素来进一步了解血脂异常的遗传。

更新日期：2020-08-16

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