Abstract
PurposeTo understand the role of the angiopoietin-like 6 gene (ANGPTL6) in intracranial aneurysms (IAs), we investigated its role in a large cohort of familial IAs.MethodsIndividuals with family history of IA were recruited to the Genetic and Observational Subarachnoid Haemorrhage (GOSH) study. The ANGPTL6 gene was sequenced using Sanger sequencing. Identified genetic variants were compared to a control population.ResultsWe found 6 rare ANGPTL6 genetic variants in 9/275 individuals with a family history of IA (3.3%) (5 missense mutations and 1 nonsense mutation leading to a premature stop codon), none present in controls. One of these had been previously reported: c.392A>T (p.Glu131Val) on exon 2; another was very close: c.332G>A (p.Arg111His). Two further genetic variants lie within the fibrinogen-like domain of the ANGPTL6 gene, which may influence function or level of the ANGPTL6 protein. The last 2 missense mutations lie within the coiled-coil domain of the ANGPTL6 protein. All genetic variants were well conserved across species.ConclusionANGPTL6 genetic variants are an important cause of IA. Defective or lack of ANGPTL6 protein is therefore an important factor in blood vessel proliferation leading to IA; dysfunction of this protein is likely to cause abnormal proliferation or weakness of vessel walls. With these data, not only do we emphasize the importance of screening familial IA cases for ANGPTL6 and other genes involved in IA, but also highlight the ANGPTL6 pathway as a potential therapeutic target.Classification of EvidenceThis is a Class III study showing some specificity of presence of the ANGPTL6 gene variant as a marker of familial intracranial aneurysms in a small subset of individuals with familial aneurysms.
Highlights
We found 6 rare angiopoietin-like 6 gene (ANGPTL6) genetic variants in 9/275 individuals with a family history of intracranial aneurysms (IAs) (3.3%) (5 missense mutations and 1 nonsense mutation leading to a premature stop codon), none present in controls
Two further genetic variants lie within the fibrinogen-like domain of the ANGPTL6 gene, which may influence function or level of the ANGPTL6 protein
ANGPTL6 genetic variants are an important cause of IA
Summary
We aimed to externally validate the previous findings, to search for additional rare variants, and to evaluate the rate of rare variants in a large cohort of individuals with family history of IA. Because the primary aim of this study was to replicate the association between IA and identifier variants in ANGPTL6, and genetic data from affected/unaffected relatives were not collected with the exception of a mother and daughter pair, segregation analysis was not performed. Our study has limitations: we did not sequence affected or unaffected family members as DNA for family members was not available and our aim was to externally validate the previous results of 4 rare coding variants within the ANGPTL6 gene; information and DNA for relatives were generally not collected as part of the GOSH study
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