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

TitleExome sequencing reveals a novel variant in causing intracranial aneurysm in a Chinese family.
Publication TypeJournal Article
Year of Publication2020
AuthorsDing, X, Zhao, S, Zhang, Q, Yan, Z, Wang, Y, Wu, Y, Li, X, Liu, J, Niu, Y, Zhang, Y, Zhang, M, Wang, H, Zhang, Y, Chen, W, Yang, X-Z, Liu, P, Posey, JE, Lupski, JR, Wu, Z, Yang, X, Wu, N, Wang, K
JournalJ Neurointerv Surg
Date Published2020 Feb
KeywordsAdult, Asian People, Computational Biology, Exome, Female, Genetic Variation, Humans, Intracranial Aneurysm, Male, Middle Aged, Pedigree, Phenotype, Repressor Proteins

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 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: c.2519T>C (p.Leu840Pro) may contribute to the pathogenetics of a subset of FIAs.

Alternate JournalJ Neurointerv Surg
PubMed ID31401562
PubMed Central IDPMC7014815
Grant ListK08 HG008986 / HG / NHGRI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States

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