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Exome sequencing reveals a novel variant in NFX1 causing intracranial aneurysm in a Chinese family

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机构： [1]Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China [2]Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China [3]Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China [4]Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China [5]Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, China [6]Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China [7]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [8]Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA [9]Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA [10]Texas Children’s Hospital, Houston, Texas, USA

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关键词： Aneurysm Genetic Hemorrhage

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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. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

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出版当年[2018]版：

大类 | 3 区医学

小类 | 2 区外科 3 区神经成像

最新[2023]版：

大类 | 1 区

医学

小类 | 1 区神经成像 1 区外科

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第一作者机构： [1]Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China

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通讯机构： [1]Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China [2]Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China [3]Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China [4]Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China [*1]Department of Interventional Neuroradiology Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University Beijing China [*2]Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences Beijing China [*3]Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China

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Exome sequencing reveals a novel variant in NFX1 causing intracranial aneurysm in a Chinese family

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