Hostettler, IC;
O'Callaghan, B;
Bugiardini, E;
O'Connor, E;
Vandrovcova, J;
Davagnanam, I;
Alg, V;
... Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study, .; + view all
(2020)
ANGPTL6 genetic variants are an underlying cause of familial intracranial aneurysms.
Neurology
10.1212/WNL.0000000000011125.
(In press).
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Abstract
BACKGROUND AND PURPOSE: To understand the role of the angiopoietin-like 6 gene (ANGPTL6) in intracranial aneurysms (IA) we investigated its role in a large cohort of familial IAs. METHODS: Inclusion of individuals with family history of IA 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. RESULTS: We found six rare ANGPTL6 genetic variants in 9/275 individuals with a family history of IA (3.3%), none of them were present in controls: Five missense and one nonsense mutation leading to a premature stop codon. 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 two missense mutations lie within the coiled-coil domain of the ANGPTL6 protein. All genetic variants were well conserved across species. CONCLUSION: ANGPTL6 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 emphasise 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 EVIDENCE: This 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 those with familial aneurysms.
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