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

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.