Whole-exome sequencing reveals known and novel variants in a cohort of intracranial vertebral-basilar artery dissection (IVAD)

• Published in: Journal of human genetics 2018-11, Vol.63 (11), p.1119-1128
• Main Authors: Wang, Kun, Zhao, Sen, Zhang, Qianqian, Yuan, Jian, Liu, Jiaqi, Ding, Xinghuan, Song, Xiaofei, Lin, Jiachen, Du, Renqian, Zhou, Yangzhong, Sugimoto, Michihiko, Chen, Weisheng, Yuan, Bo, Liu, Jian, Yan, Zihui, Liu, Bowen, Zhang, Yisen, Li, Xiaoxin, Niu, Yuchen, Long, Bo, Shen, Yiping, Zhang, Shuyang, Abe, Kuniya, Su, Jianzhong, Wu, Zhihong, Wu, Nan, Liu, Pengfei, Yang, Xinjian
• Format: Article
• Language: English
• Subjects: Adult; Aneurysm, Dissecting - genetics; Basic Helix-Loop-Helix Transcription Factors - genetics; Bone surgery; Cohort Studies; Collagen Type III - genetics; Dissection; Etiology; Exome; Female; Fibrillin-1 - genetics; Genetic diversity; Genetic factors; Genetics; Genomics; High-Throughput Nucleotide Sequencing; Hospitals; Humans; Intracranial Aneurysm - genetics; Laboratories; Male; Maternal & child health; Medical imaging; Medical schools; Middle Aged; Molecular Motor Proteins - genetics; Mutation; Myosin Heavy Chains - genetics; Neoplasm Proteins - genetics; Patients; Phenotypes; Scoliosis; Veins & arteries; Vertebrae
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1038/s10038-018-0496-x

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.