Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients
Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients
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DOI：
10.1038/s41436-019-0435-z
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发表时间：
2019-08-01
影响因子：
8.8
通讯作者：
Rosenberger, Georg
中科院分区：
文献类型：
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作者：
Renner, Sina;Schueler, Helke;Rosenberger, Georg
目的：遗传因素在血管累及结缔组织疾病（CTD）中起着重要的病因学作用，基因诊断对于基因定制，个性化患者管理变得越来越重要。方法：采用新一代测序和外显子组测序对199例临床相关队列的32个疾病相关基因进行分析。我们根据其致病性的可能性对序列变异进行分类和细化。结果：我们在15例患者（7.5%）中鉴定出1个致病变异（PV；在FBN1或SMAD3中），在19例患者（9.6%）中鉴定出1个可能致病变异（LPV；在COL3A1、FBN1、FBN2、LOX、MYH11、SMAD3、TGFBR1或TGFBR2中），共获得17.1%的诊断率。13个PV/LPV是新的。PV/ lpv阴性患者中47例（23.6%）出现>= 1不确定意义变异（VUS）。25例患者伴有变异。对报告/计算的变异分类进行深入评估，导致19.8%的变异被重新分类。结论：变异分类和细化是形成疾病基因突变谱的必要条件，从而提高临床敏感性。严格的多基因分析是鉴别临床相关CTDs遗传原因的有力工具。尽管如此，PV/LPV/ vus阴性患者的相对较高比例强调了未知疾病位点和/或少基因/多基因遗传的存在。
Purpose: Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management.Methods: We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity.Results: We identified 1 pathogenic variant (PV; in FBN1 or SMAD3) in 15 patients (7.5%) and >= 1 likely pathogenic variant (LPV; in COL3A1, FBN1, FBN2, LOX, MYH11, SMAD3, TGFBR1, or TGFBR2) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed >= 1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants.Conclusion: Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.