TY - JOUR T1 - Exome sequencing reveals a novel variant in <em>NFX1</em> causing intracranial aneurysm in a Chinese family JF - Journal of NeuroInterventional Surgery JO - J NeuroIntervent Surg SP - 221 LP - 226 DO - 10.1136/neurintsurg-2019-014900 VL - 12 IS - 2 AU - Xinghuan Ding AU - Sen Zhao AU - Qianqian Zhang AU - Zihui Yan AU - Yang Wang AU - Yong Wu AU - Xiaoxin Li AU - Jian Liu AU - Yuchen Niu AU - Yisen Zhang AU - Mingqi Zhang AU - Huizi Wang AU - Ying Zhang AU - Weisheng Chen AU - Xin-Zhuang Yang AU - Pengfei Liu AU - Jennifer E Posey AU - James R Lupski AU - Zhihong Wu AU - Xinjian Yang AU - Nan Wu AU - Kun Wang Y1 - 2020/02/01 UR - http://jnis.bmj.com/content/12/2/221.abstract N2 - 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&gt;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&gt;C (p.Leu840Pro) may contribute to the pathogenetics of a subset of FIAs. ER -