Intracranial vertebral–basilar artery dissection (IVAD) is an arterial disorder leading to life-threatening consequences. Genetic factors are known to be causative to certain syndromic forms of IVAD. However, systematic study of the molecular basis of sporadic and isolated IVAD is lacking. To identify genetic variants contributing to the etiology of IVAD, we enrolled a cohort of 44 unrelated cases with a clinical diagnosis of isolated IVAD and performed whole-exome sequencing (WES) for all the participants; a trio exome sequencing approach was used when samples from both parents were available. Four previously reported disease-causing heterozygous variants (three in COL3A1 and one in FBN1) and seven novel heterozygous variants in IVAD-related genes were identified. In addition, six variants in novel IVAD genes including two de novo heterozygous nonsynonymous variants (each in VPS52 and CDK18), two stop-gain variants (each in MYH9 and LYL1), and two heterozygous biallelic variants in TNXB were considered to be possibly contributing to the phenotype, with unknown significance according to the existing knowledge. A significantly higher mutational rate of IVAD candidate genes was observed in patients versus our in-house controls (P = 0.002) (DISCO study, http://www.discostudy.org/, n = 2248). Our study provided a mutational landscape for patients with isolated IVAD.
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James R Lupski (Baylor College of Medicine) and Jennifer Posey (Baylor College of Medicine) assisted with organizing the study and revision of the manuscript. We thank the families who participated in this research. We also thank GeneSeeq Inc. for the technical support of whole-exome sequencing.
NW, XY, and PL conceived the project and designed the study. KW, QZ, XD, Jian Liu, XL, YZ, WC, and YN collected the cohorts. Sen Zhao, NW, PL, KW, QZ, MS, KA, JY, Jiachen Lin, and Bowen Liu analyzed the data. XS, YZ, YS, and ZY conducted the bioinformatic analysis. RD, Jiaqi Liu, BL, and BY helped with data interpretation and revised the manuscript. ZW, JS, and Shuyang Zhang helped in organizing the study and revising the manuscript. Sen Zhao, NW, KW, and PL wrote the manuscript.
Funding for this study was provided by grant no. 2016YFC1300800 from the National Key Research and Development Plan of China, nos. 81471167, 81671139, 81220108007, and no. 2014-1-1071 from the Special Research Project for Capital Health Development (all to Dr. Xinjian Yang), grant no. 81501852 from the National Natural Science Foundation of China; 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine, no. 7172175 from the Beijing Natural Science Foundation, no. Z161100004916123 from the Beijing nova program, no. xxjc201717 from the Beijing nova program interdisciplinary collaborative project, no. 2016ZX310177 from the Central Level Public Interest Program for Scientific Research Institute, no. 3332016006 from the PUMC Youth Fund & the Fundamental Research Funds for the Central Universities, no. 2016-I2M-3-003 from the CAMS Initiative for Innovative Medicine, no. JQ201506 from the Distinguished Youth foundation of Peking Union Medical College Hospital (all to Dr. Nan Wu), and nos. 2016-I2M-2-006 and 2017-I2M-2-001 from the CAMS Initiative for Innovative Medicine (to Dr. Zhihong Wu).
This study was approved by the ethics committee of Beijing Tiantan Hospital. Informed consent was obtained from each patient or their parents.
Conflict of interest
The authors declare that they have no conflict of interest.
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Journal of the American College of Cardiology (2019)
European Stroke Journal (2019)