In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 3 ( 2022-3-17), p. e0265359-
Abstract:
Intracranial aneurysms (IAs) cause subarachnoid hemorrhage, which has high rates of mortality and morbidity when ruptured. Recently, the role of rare variants in the genetic background of complex diseases has been increasingly recognized. The aim of this study was to identify rare variants for susceptibility to IA. Methods Whole-exome sequencing was performed on seven members of a Japanese pedigree with highly aggregated IA. Candidate genes harboring co-segregating rare variants with IA were re-sequenced and tested for association with IA using additional 500 probands and 323 non-IA controls. Functional analysis of rare variants detected in the pedigree was also conducted. Results We identified two gene variants shared among all four affected participants in the pedigree. One was the splicing donor c.1515+1G 〉 A variant in NPNT (Nephronectin), which was confirmed to cause aberrant splicing by a minigene assay. The other was the missense p.P83T variant in CBY2 (Chibby family member 2). Overexpression of p.P83T CBY2 fused with red fluorescent protein tended to aggregate in the cytoplasm. Although Nephronectin has been previously reported to be involved in endothelial angiogenic functions, CBY2 is a novel molecule in terms of vascular pathophysiology. We confirmed that CBY2 was expressed in cerebrovascular smooth muscle cells in an isoform2-specific manner. Targeted CBY2 re-sequencing in additional case-control samples identified three deleterious rare variants (p.R46H, p.P83T, and p.L183R) in seven probands, showing a significant enrichment in the overall probands (8/501) compared to the controls (0/323) ( p = 0.026, Fisher’s extract test). Conclusions NPNT and CBY2 were identified as novel susceptibility genes for IA. The highly heterogeneous and polygenic architecture of IA susceptibility can be uncovered by accumulating extensive analyses that focus on each pedigree with a high incidence of IA.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0265359
DOI:
10.1371/journal.pone.0265359.g001
DOI:
10.1371/journal.pone.0265359.g002
DOI:
10.1371/journal.pone.0265359.g003
DOI:
10.1371/journal.pone.0265359.g004
DOI:
10.1371/journal.pone.0265359.g005
DOI:
10.1371/journal.pone.0265359.t001
DOI:
10.1371/journal.pone.0265359.t002
DOI:
10.1371/journal.pone.0265359.s001
DOI:
10.1371/journal.pone.0265359.s002
DOI:
10.1371/journal.pone.0265359.s003
DOI:
10.1371/journal.pone.0265359.r001
DOI:
10.1371/journal.pone.0265359.r002
DOI:
10.1371/journal.pone.0265359.r003
DOI:
10.1371/journal.pone.0265359.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2267670-3
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