TY - JOUR
T1 - ANGPTL6 Genetic Variants Are an Underlying Cause of Familial Intracranial Aneurysms
AU - on behalf of the Genetics and Observational Subarachnoid Haemorrhage (GOSH) study investigators
AU - Hostettler, Isabel C.
AU - O'Callaghan, Benjamin
AU - Bugiardini, Enrico
AU - O'Connor, Emer
AU - Vandrovcova, Jana
AU - Davagnanam, Indran
AU - Alg, Varinder
AU - Bonner, Stephen
AU - Walsh, Daniel
AU - Bulters, Diederik
AU - Kitchen, Neil
AU - Brown, Martin M.
AU - Grieve, Joan
AU - Werring, David J.
AU - Houlden, Henry
AU - Roberts, Gareth
AU - Critchley, Giles
AU - Sharma, Pankaj
AU - Nelson, Richard
AU - Whitfield, Peter
AU - Ross, Stuart
AU - Patel, Hiren
AU - Eldridge, Paul
AU - Saastamoinen, Kari
AU - Patel, Umang
AU - Lawrance, Enas
AU - Vandabona, Subha
AU - Mendelow, David
AU - Teal, Rachel
N1 - Publisher Copyright:
© American Academy of Neurology.
PY - 2021/2/9
Y1 - 2021/2/9
N2 - Purpose To 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. Methods Individuals 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. Results We 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. 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 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 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 individuals with familial aneurysms.
AB - Purpose To 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. Methods Individuals 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. Results We 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. 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 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 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 individuals with familial aneurysms.
UR - http://www.scopus.com/inward/record.url?scp=85102088708&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000011125
DO - 10.1212/WNL.0000000000011125
M3 - Article
C2 - 33106390
AN - SCOPUS:85102088708
SN - 0028-3878
VL - 96
SP - E947-E955
JO - Neurology
JF - Neurology
IS - 6
ER -