家族性颈内动脉夹层患者的下一代测序分析

Next generation sequencing analysis of patients with familial cervical artery dissection.

作者信息

Grond-Ginsbach Caspar, Brandt Tobias, Kloss Manja, Aksay Suna Su, Lyrer Philipp, Traenka Christopher, Erhart Philipp, Martin Juan Jose, Altintas Ayse, Siva Aksel, de Freitas Gabriel R, Thie Andreas, Machetanz Jochen, Baumgartner Ralf W, Dichgans Martin, Engelter Stefan T

机构信息

Department of Neurology, University of Heidelberg, Heidelberg, Germany.

Clinics for Neurologic Rehabilitation, Kliniken Schmieder, Heidelberg, Germany.

出版信息

Eur Stroke J. 2017 Jun;2(2):137-143. doi: 10.1177/2396987317693402. Epub 2017 Feb 9.

DOI:10.1177/2396987317693402

PMID:31008308

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6453217/

Abstract

BACKGROUND

The cause of cervical artery dissection is not well understood. We test the hypothesis that mutations in genes associated with known arterial connective tissue disorders are enriched in patients with familial cervical artery dissection.

PATIENTS AND METHODS

Patient duos from nine pedigrees with familial cervical artery dissection were analyzed by whole exome sequencing. Single nucleotide variants in a panel of 11 candidate genes (ACTA2, MYH11, FBN1, TGFBR1, TGFBR2, TGFB2, COL3A1, COL4A1, SMAD3, MYLK and SLC2A10) were prioritized according to functionality (stop-loss, nonsense, and missense variants with polyphen-2 score ≥0.95). Variants classified as "benign" or "likely benign" in the ClinVar database were excluded from further analysis. For comparison, non-benign stop-loss, nonsense and missense variants with polyphen-2 score ≥0.95 in the same panel of candidate genes were identified in the European non-Finnish population of the ExAC database ( = 33,370).

RESULTS

Non-benign Single nucleotide variants in both affected patients were identified in four of the nine cervical artery dissection families (COL3A1; Gly324Ser, FBN1: Arg2554Trp, COL4A1: Pro116Leu, and TGFBR2: Ala292Thr) yielding an allele frequency of 22.2% (4/18). In the comparison group, 1782 variants were present in 33,370 subjects from the ExAC database (allele frequency: 1782/66,740 = 2.7%; = 0.0008; odds ratio = 14.2; 95% confidence interval = 3.8-52.9).

CONCLUSION

Cervical artery dissection families showed enrichment for non-benign variants in genes associated with arterial connective tissue disorders. The observation that findings differed across families indicates genetic heterogeneity of familial cervical artery dissection.

摘要

背景

颈内动脉夹层的病因尚不完全清楚。我们检验了一个假设，即已知动脉结缔组织疾病相关基因的突变在家族性颈内动脉夹层患者中更为富集。

患者与方法

对来自9个家族性颈内动脉夹层家系的患者对进行全外显子组测序分析。根据功能（截短型、无义突变以及多聚嘧啶结合蛋白2评分≥0.95的错义突变）对11个候选基因（ACTA2、MYH11、FBN1、TGFBR1、TGFBR2、TGFB2、COL3A1、COL4A1、SMAD3、MYLK和SLC2A10）中的单核苷酸变异进行优先级排序。ClinVar数据库中分类为“良性”或“可能良性”的变异被排除在进一步分析之外。作为对照，在ExAC数据库的欧洲非芬兰人群（n = 33370）中鉴定出同一组候选基因中多聚嘧啶结合蛋白2评分≥0.95的非良性截短型、无义突变和错义突变。

结果

在9个颈内动脉夹层家族中的4个家族（COL3A1；Gly324Ser、FBN1：Arg2554Trp、COL4A1：Pro116Leu和TGFBR2：Ala292Thr）的两名患病患者中均鉴定出非良性单核苷酸变异，等位基因频率为22.2%（4/18）。在对照组中，ExAC数据库的33370名受试者中存在1782个变异（等位基因频率：1782/66740 = 2.7%；P = 0.0008；优势比 = 14.2；95%置信区间 = 3.8 - 52.9）。