RT Journal Article
SR Electronic
T1 Genome sequencing reveals the role of rare genomic variants in Chinese patients with symptomatic intracranial atherosclerotic disease
JF Stroke and Vascular Neurology
JO Stroke Vasc Neurol
FD BMJ Publishing Group Ltd
SP 182
OP 189
DO 10.1136/svn-2021-001157
VO 7
IS 3
A1 Mengmeng Shi
A1 Xinyi Leng
A1 Ying Li
A1 Zihan Chen
A1 Ye Cao
A1 Tiffany Chung
A1 Bonaventure YM Ip
A1 Vincent HL Ip
A1 Yannie OY Soo
A1 Florence SY Fan
A1 Sze Ho Ma
A1 Karen Ma
A1 Anne Y Y Chan
A1 Lisa WC Au
A1 Howan Leung
A1 Alexander Y Lau
A1 Vincent CT Mok
A1 Kwong Wai Choy
A1 Zirui Dong
A1 Thomas W Leung
YR 2022
UL http://svn.bmj.com/content/7/3/182.abstract
AB Objectives The predisposition of intracranial atherosclerotic disease (ICAD) to East Asians over Caucasians infers a genetic basis which, however, remains largely unknown. Higher prevalence of vascular risk factors (VRFs) in Chinese over Caucasian patients who had a stroke, and shared risk factors of ICAD with other stroke subtypes indicate genes related to VRFs and/or other stroke subtypes may also contribute to ICAD.Methods Unrelated symptomatic patients with ICAD were recruited for genome sequencing (GS, 60-fold). Rare and potentially deleterious single-nucleotide variants (SNVs) and small insertions/deletions (InDels) were detected in genome-wide and correlated to genes related to VRFs and/or other stroke subtypes. Rare aneuploidies, copy number variants (CNVs) and chromosomal structural rearrangements were also investigated. Lastly, candidate genes were used for pathway and gene ontology enrichment analysis.Results Among 92 patients (mean age at stroke onset 61.0±9.3 years), GS identified likely ICAD-associated rare genomic variants in 54.3% (50/92) of patients. Forty-eight patients (52.2%, 48/92) had 59 rare SNVs/InDels reported or predicted to be deleterious in genes related to VRFs and/or other stroke subtypes. None of the 59 rare variants were identified in local subjects without ICAD (n=126). 31 SNVs/InDels were related to conventional VRFs, and 28 were discovered in genes related to other stroke subtypes. Our study also showed that rare CNVs (n=7) and structural rearrangement (a balanced translocation) were potentially related to ICAD in 8.7% (8/92) of patients. Lastly, candidate genes were significantly enriched in pathways related to lipoprotein metabolism and cellular lipid catabolic process.Conclusions Our GS study suggests a role of rare genomic variants with various variant types contributing to the development of ICAD in Chinese patients.Data are available upon reasonable request. Anonymised data can be available for qualified investigators upon request to the corresponding authors.