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

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

doi:10.1016/j.ajhg.2017.12.006

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

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

Romain Bourcier, Solena Le Scouarnec, Stéphanie Bonnaud, Matilde Karakachoff, Emmanuelle Bourcereau, Sandrine Heurtebise-Chrétien, Céline Menguy, Christian Dina, Floriane Simonet, Alexis Moles, …

American Journal of Human Genetics, Vol.102(1), pp.133 - 141

01/2018

DOI: https://doi.org/10.1016/j.ajhg.2017.12.006

PMCID: PMC5778084

PMID: 29304371

Abstract

Intracranial aneurysms (IAs) are acquired cerebrovascular abnormalities characterized by localized dilation and wall thinning in intracranial arteries, possibly leading to subarachnoid hemorrhage and severe outcome in case of rupture. Here, we identified one rare nonsense variant (c.1378A>T) in the last exon of ANGPTL6 (Angiopoietin-Like 6)—which encodes a circulating pro-angiogenic factor mainly secreted from the liver—shared by the four tested affected members of a large pedigree with multiple IA-affected case subjects. We showed a 50% reduction of ANGPTL6 serum concentration in individuals heterozygous for the c.1378A>T allele (p.Lys460Ter) compared to relatives homozygous for the normal allele, probably due to the non-secretion of the truncated protein produced by the c.1378A>T transcripts. Sequencing ANGPTL6 in a series of 94 additional index case subjects with familial IA identified three other rare coding variants in five case subjects. Overall, we detected a significant enrichment (p = 0.023) in rare coding variants within this gene among the 95 index case subjects with familial IA, compared to a reference population of 404 individuals with French ancestry. Among the 6 recruited families, 12 out of 13 (92%) individuals carrying IA also carry such variants in ANGPTL6, versus 15 out of 41 (37%) unaffected ones. We observed a higher rate of individuals with a history of high blood pressure among affected versus healthy individuals carrying ANGPTL6 variants, suggesting that ANGPTL6 could trigger cerebrovascular lesions when combined with other risk factors such as hypertension. Altogether, our results indicate that rare coding variants in ANGPTL6 are causally related to familial forms of IA.

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Title: Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm
Creators - without role: Romain Bourcier - Institut du Thorax
Solena Le Scouarnec - Institut du Thorax
Stéphanie Bonnaud - Institut du Thorax
Matilde Karakachoff - Institut du Thorax
Emmanuelle Bourcereau - Centre Hospitalier Universitaire de Nantes
Sandrine Heurtebise-Chrétien - Institut du Thorax
Céline Menguy - Institut du Thorax
Christian Dina - Institut du Thorax
Floriane Simonet - Institut du Thorax
Alexis Moles - Centre Hospitalier Universitaire de Nantes
Cédric Lenoble - Centre Hospitalier Universitaire de Nantes
Pierre Lindenbaum - Institut du Thorax
Stéphanie Chatel - Institut du Thorax
Bertrand Isidor - Centre Hospitalier Universitaire de Nantes
Emmanuelle Génin - Génétique, Génomique Fonctionnelle et Biotechnologies
Jean-François Deleuze - Centre National de Recherche en Génomique Humaine
Jean-Jacques Schott - Institut du Thorax
Hervé Le Marec - Institut du Thorax
Gervaise Loirand - Institut du Thorax
Hubert Desal - Institut du Thorax
Richard Redon - Centre Hospitalier Universitaire de Nantes
Benjamin Daumas-Duport - Centre Hospitalier Universitaire de Nantes
Jérôme Connault - Centre Hospitalier Universitaire de Nantes
Pierre Lebranchu - Laboratoire des Sciences du Numérique de Nantes
Thierry Le Tourneau - Institut du Thorax
Pierre Viarouge
Chrisanthi Papagiannaki - Hôpital Charles Nicolle [Rouen]
Michel Piotin - Fondation Ophtalmologique Adolphe de Rothschild
Hocine Redjem - Fondation Ophtalmologique Adolphe de Rothschild
Mikael Mazighi - Centre Hospitalier Universitaire de Montpellier
Jean-Philippe Desilles - Charmo University
Olivier Naggara - Université Paris Cité
Denis Trystram - Université Grenoble Alpes
Myriam Edjlali-Goujon - Hôpitaux Universitaires de Strasbourg
Christine Rodriguez - Centre Léon Bérard
Waghi Ben Hassen
Suzanna Saleme - Hôpital Universitaire Dupuytren
Charbel Mounayer - XLIM
Olivier Levrier - Hôpital de la Timone
Pierre Aguettaz - Centre Hospitalier Universitaire de Lille
Xavier Combaz - Hôpital privé Clairval
Anne Null Pasco - Ingénierie de la vectorisation particulaire
Emeline Berthier
Marc Bintner - Écologie Marine Tropicale des Océans Pacifique et Indien
Marc Molho
Pascale Gauthier - Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement
Cyril Chivot - Centre Hospitalier Universitaire Amiens-Picardie
Vincent Costalat - Université de Montpellier
Cyril Darganzil
Alain Bonafé - Centre Hospitalier Universitaire de Montpellier
Anne Christine Januel - Hôpital Paule de Viguier
Caterina Michelozzi - Vita-Salute San Raffaele University
Christophe Cognard - Université de Montpellier, Institut des Neurosciences de Montpellier - INM
Fabrice Bonneville - Toulouse NeuroImaging Center
Philippe Tall
Jean Darcourt - Inserm
Alessandra Biondi
Cristina Iosif
Elisa Pomero
Jean-Christophe Ferré
Jean Yves Gauvrit - Centre Hospitalier Universitaire de Rennes
François Eugène - Centre Hospitalier Universitaire de Rennes
Hélène Raoult
Jean-Christophe Gentric
Julien Ognard
René Anxionnat - Imagerie Adaptative Diagnostique et Interventionnelle
Serge Bracard - Imagerie Adaptative Diagnostique et Interventionnelle
Anne Laure Derelle - Centre Hospitalier Régional et Universitaire de Nancy
Romain Tonnelet - Université de Lorraine
Laurent Spelle
Léon Ikka
Robert Fahed - Pitié-Salpêtrière Hospital
Aymeric Rouchaud
Augustin Ozanne - Bicêtre Hospital
Jildaz Caroff
Nidal Ben Achour
Jacques Moret - Institut du Thorax
Emmanuel Chabert - Inserm
Jérôme Berge
Gaultier Marnat
Xavier Barreau - Centre Hospitalier Universitaire de Bordeaux
Florent Gariel
Frédéric Clarençon
Mohammed Aggour
Fréderic Ricolfi - Centre Hospitalier Universitaire Dijon Bourgogne
Adrien Chavent - Centre Hospitalier Universitaire Dijon Bourgogne
Pierre Thouant - Centre Hospitalier Universitaire Dijon Bourgogne
Pablo Lebidinsky
Brivael Lemogne
Denis Herbreteau - Centre Hospitalier Universitaire de Tours
Richard Bibi - Institut du Thorax
Laurent Pierot - Université de Reims Champagne-Ardenne
Sébastien Soize
Marc Antoine Labeyrie
Christophe Vandendries
Emmanuel Houdart - Assistance Publique – Hôpitaux de Paris
Appoline Kazemi
Xavier Leclerc - Centre Hospitalier Universitaire de Lille
Jean Pierre Pruvo
Sophie Gallas
Stéphane Velasco
Publication Details: American Journal of Human Genetics, Vol.102(1), pp.133 - 141
Identifiers: 9939059309311
Academic Unit: Institut des Neurosciences de Montpellier - INM
Language: English
Resource Type: Journal article
Local Fields: hal-01808225