Background Genetic risk factors play an important role in the pathogenesis of familial intracranial aneurysms (FIAs); however, the molecular mechanisms remain largely unknown.
Objective To investigate potential FIA-causing genetic variants by rare variant interrogation and a family-based genomics approach in a large family with an extensive multigenerational pedigree with FIAs.
Method Exome sequencing (ES) was performed in a dominant likely family with intracranial aneurysms (IAs). Variants were analyzed by an in-house developed pipeline and prioritized using various filtering strategies, including population frequency, variant type, and predicted variant pathogenicity. Sanger sequencing was also performed to evaluate the segregation of the variants with the phenotype.
Results Based on the ES data obtained from five individuals from a family with 7/21 living members affected with IAs, a total of 14 variants were prioritized as candidate variants. Familial segregation analysis revealed that NFX1 c.2519T>C (p.Leu840Pro) segregated in accordance with Mendelian expectations with the phenotype within the family—that is, present in all IA-affected cases and absent from all unaffected members of the second generation. This missense variant is absent from public databases (1000genome, ExAC, gnomAD, ESP5400), and has damaging predictions by bioinformatics tools (Gerp ++ score = 5.88, CADD score = 16.43, MutationTaster score = 1, LRT score = 0). In addition, 840Leu in NFX1 is robustly conserved in mammals and maps in a region before the RING-type zinc finger domain.
Conclusion NFX1 c.2519T>C (p.Leu840Pro) may contribute to the pathogenetics of a subset of FIAs.
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XD and SZ contributed equally.
Contributors Study concept and design: KW, XY, NW, ZW, JRL. Acquisition of data and technique support: XD, SZ, QZ, ZY. Analysis and interpretation of data: YaW, YoW, XL, JL, YN, YigZ, MZ, HW, YinZ. Drafting or revising the manuscript: XD, SZ, WC, X-ZY, PL, JEP. Final approval of the version to be published: KW, XY, NW. Agreement to be accountable for all aspects of the work: XD.
Funding This work was supported by grants No. 2016YFC1300800 from the National Key Research and Development Plan of China, Nos. 81801156, 81801158, 81471167, and 81671139 from the National Natural Science Foundation of China, and No. 2018-4-1077 from the Special Research Project for Capital Health Development (all to XY); and grants Nos. 81822030 and 81501852 from the National Natural Science Foundation of China; 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine, No. 7172175 from Beijing Natural Science Foundation and No. 2016-I2M-3-003 from the CAMS Initiative for Innovative Medicine (all to NW). JRL was supported by the US National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS R01 NS058529 and R35 NS105078), National Human Genome Research Institute/National Heart, Lung, and Blood Institute to the Baylor Hopkins Center o Mendelian Genomics (NHGRI/NHLBI UM1 HG006542). JEP was supported by the National Human Genome Research Institute (NHGR K08 HG008986). The funding sources had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Competing interests No, there are no competing interests for any author.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All the data are available upon request to the corresponding author.
Patient consent for publication Obtained.
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