Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm

Scouarnec, Solena Le; Bonnaud, Stéphanie; Karakachoff, Matilde; Bourcereau, Emmanuelle; Heurtebise-Chrétien, Sandrine; Menguy, Céline; Dina, Christian; Simonet, Floriane; Moles, Alexis; Lenoble, Cédric; Livet, Pierre; Chatel, Stéphanie; Génin, Emmanuelle; Deleuze, Jean‐François; Schott, Jean‐Jacques; Marec, Hervé Le; Loirand, Gervaise; Redon, Richard; Desal, Hubert; Bourcier, Romain; Daumas‐Duport, Benjamin; Isidor, Bertrand; Connault, J.; Lebranchu, Pierre; Tourneau, Thierry Le; Viarouge, Marie Pierre; Papagiannaki, Chrisanthi; Piotin, Michel; Redjem, Hocine; Mazighi, Mikaël; Desilles, Jean‐Philippe; Naggara, Olivier; Trystram, Denis; Edjlali, Myriam; Rodriguez, C.; Hassen, Waghi Ben; Saleme, Suzanna; Mounayer, Charbel; Lévrier, O.; Aguettaz, Pierre; Combaz, X; Pasco, A.; Berthier, Emmanuel; Bintner, M.; Molho, M.; Gauthier, Pascale; Chivot, Cyril; Costalat, Vincent; Darganzil, Cyril; Bonafé, Alain; Januel, Anne Christine; Michelozzi, Caterina; Cognard, Christophe; Bonneville, Fabrice; Tall, Philippe; Darcourt, Jean; Biondi, Alessandra; Iosif, Cristina; Pomero, Elisa; Ferré, J.-C.; Gauvrit, J.-Y.; Eugène, François; Raoult, Hélène; Gentric, Jean-Christophe; Ognard, Julien; Anxionnat, René; Bracard, Serge; Derelle, Anne Laure; Tonnelet, Romain; Spelle, Laurent; Ikka, Léon; Fahed, Robert; Rouchaud, Aymeric; Ozanne, Augustin; Caroff, Jildaz; Achour, Nidal Ben; Moret, Jacques; Chabert, Emmanuel; Berge, Jérôme; Marnat, Gaultier; Barreau, Xavier; Gariel, Florent; Clarençon, Frédéric; Aggour, M.; Ricolfi, F.; Chavent, Adrien; Thouant, Pierre; Lebidinsky, Pablo; Lemogne, Brivaël; Herbreteau, Denis; Bibi, Richard; Piérot, Laurent; Soize, Sébastien; Labeyrie, Marc Antoine; Vandendries, Christophe; Houdart, Emmanuel; Kazemi, Appoline; Leclerc, Xavier; Pruvo, J. P.; Gallas, Sophie; Velasco, Stéphane

doi:10.1016/j.ajhg.2017.12.006

Cited by 38 publications

(31 citation statements)

References 34 publications

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“…[9][10][11][12] Recently, a rare coding variant in the ANGPTL6 gene (c.1378A>T) was identified in a family with IA and was present in all affected individuals in addition to 5 of 22 unaffected family members. 13 Given the clinical heterogeneity and environmental influences in IA and cerebrovascular disease, large families with mendelian patterns of disease inheritance are uncommon. In the current study, we performed exome sequencing in 3 families with a likely autosomal dominant IA inheritance pattern to look for candidate mutations and novel disease genes.…”

Section: Resultsmentioning

confidence: 99%

PCNT point mutations and familial intracranial aneurysms

et al. 2018

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ObjectiveTo identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing.MethodsWe performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants.ResultsWe identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases.ConclusionThe PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt−/−) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.

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Section: Resultsmentioning

confidence: 99%

PCNT point mutations and familial intracranial aneurysms

et al. 2018

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“…In addition to GWAS providing associations between genomic regions and a disease, novel advanced approaches using exome sequencing (ES) promise to detect causal relations. Indeed, recent studies applied ES in families affected with IA/SAH and identified alterations in ANGPTL6 (angiopoietin-like 6), RNF213 (ring finger protein 213), THSD1 (thrombospondin type 1 domain containing protein 1), ARHGEF17 (Rho guanine nucleotide exchange factor 17) and PCNT (pericentrin) as genetic risk factors for this disease [4][5][6][7][8]. Other family-based ES studies reported on various candidate disease variants and genes including ADAMTS15, LOXL2 and TMEM132B, and emphasize the need of validation of their presented data [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Exome sequencing in 38 patients with intracranial aneurysms and subarachnoid hemorrhage

et al. 2020

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Objective Genetic risk factors for unruptured intracranial aneurysms (UIA) and aneurysmal subarachnoid hemorrhage (aSAH) are poorly understood. We aimed to verify recently reported risk genes and to identify novel sequence variants involved in the etiology of UIA/aSAH. Methods We performed exome sequencing (ES) in 35 unrelated individuals and 3 family members, each with a history of UIA and/or aSAH. We searched for sequence variants with minor allele frequency (MAF) ≤ 5% in the reported risk genes ADAMTS15, ANGPTL6, ARHGEF17, LOXL2, PCNT, RNF213, THSD1 and TMEM132B. To identify novel putative risk genes we looked for unknown (MAF = 0) variants shared by the three relatives. Results We identified 20 variants with MAF ≤ 5% in 18 individuals: 9 variants in PCNT (9 patients), 4 in RNF213 (3 patients), 3 in THSD1 (6 patients), 2 in ANGPTL6 (3 patients), 1 in ADAMTS15 (1 patient) and 1 in TMEM132B (1 patient). In the affected family, prioritization of shared sequence variants yielded five novel putative risk genes. Based on predicted pathogenicity of identified variants, population genetics data and a high functional relevance for vascular biology, EDIL3 was selected as top candidate and screened in additional 37 individuals with UIA and/or aSAH: a further very rare EDIL3 sequence variant in two unrelated sporadic patients was identified. Conclusions Our data support a role of sequence variants in PCNT, RNF213 and THSD1 as susceptibility factors for cerebrovascular disease. The documented function in vascular wall integrity, the crucial localization of affected amino acids and gene/variant association tests suggest EDIL3 as a further valid candidate disease gene for UIA/aSAH.

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“…On certain organs, the vascular system becomes denser, the arteries, capillaries or veins split into several branches, forming a vascular tree. Several environmental factors or a genetic anomaly (Bourcier et al, 2018) can lead to a weakened vascular system. In this work, we particularly focus on the formation of Intra Cranial Aneurysms (ICA).…”

Section: Contextmentioning

confidence: 99%

Characterization of 3D bifurcations in micro-scan and MRA-TOF images of cerebral vasculature for prediction of intra-cranial aneurysms

Nouri

Autrusseau

Bourcier

et al. 2020

Computerized Medical Imaging and Graphics

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An aneurysm is a vascular disorder where ballooning may form in a weakened section of the wall in the blood vessel. The swelling of the aneurysm may lead to its rupture. Intra-cranial aneurysms are the ones presenting the higher risks. If ruptured, the aneurysm may induce a subarachnoid haemorrhage which could lead to premature death or permanent disability. In this study, we are interested in locating and characterizing the bifurcations of the cerebral vascular tree. We use a 3D skeletonization combined with a graph-based approach to detect the bifurcations. In this work, we thus propose a full geometric characterisation of the bifurcations and related arteries. Aside from any genetic predisposition and environmental risk factors, the geometry of the brain vasculature may influence the chance of aneurysm formation. Among the main achievements, in this paper, we propose accurate, predictive 3D measurements of the bifurcations and we furthermore estimate the risk of occurrence of an aneurysm on a given bifurcation.

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Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm

Cited by 38 publications

References 34 publications

PCNT point mutations and familial intracranial aneurysms

PCNT point mutations and familial intracranial aneurysms

Exome sequencing in 38 patients with intracranial aneurysms and subarachnoid hemorrhage

Characterization of 3D bifurcations in micro-scan and MRA-TOF images of cerebral vasculature for prediction of intra-cranial aneurysms

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