title: Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.
abstract: Cerebral small vessel disease represents a heterogeneous group of disorders leading to stroke and cognitive impairment. While most small vessel diseases appear sporadic and related to age and hypertension, several early-onset monogenic forms have also been reported. However, only a minority of patients with familial small vessel disease carry mutations in one of known small vessel disease genes. We used whole exome sequencing to identify candidate genes in an autosomal dominant small vessel disease family in which known small vessel disease genes had been excluded, and subsequently screened all candidate genes in 201 unrelated probands with a familial small vessel disease of unknown aetiology, using high throughput multiplex polymerase chain reaction and next generation sequencing. A heterozygous HTRA1 variant (R166L), absent from 1000 Genomes and Exome Variant Server databases and predicted to be deleterious by in silico tools, was identified in all affected members of the index family. Ten probands of 201 additional unrelated and affected probands (4.97%) harboured a heterozygous HTRA1 mutation predicted to be damaging. There was a highly significant difference in the number of likely deleterious variants in cases compared to controls (P = 4.2 × 10(-6); odds ratio = 15.4; 95% confidence interval = 4.9-45.5), strongly suggesting causality. Seven of these variants were located within or close to the HTRA1 protease domain, three were in the N-terminal domain of unknown function and one in the C-terminal PDZ domain. In vitro activity analysis of HTRA1 mutants demonstrated a loss of function effect. Clinical features of this autosomal dominant small vessel disease differ from those of CARASIL and CADASIL by a later age of onset and the absence of the typical extraneurological features of CARASIL. They are similar to those of sporadic small vessel disease, except for their familial nature. Our data demonstrate that heterozygous HTRA1 mutations are an important cause of familial small vessel disease, and that screening of HTRA1 should be considered in all patients with a hereditary small vessel disease of unknown aetiology.
authors.affiliation: 1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, UMR-S1161, Paris, France.
authors.forename: Edgard
authors.initials: E
authors.lastname: Verdura
authors.affiliation: 1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, UMR-S1161, Paris, France 3 AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Hervé
authors.affiliation: 4 Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians University, Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Scharrer
authors.affiliation: 5 AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Génétique Moléculaire Neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), Paris, France.
authors.forename: Maria Del Mar
authors.initials: Mdel M
authors.lastname: Amador
authors.affiliation: 6 Service de Neurophysiologie, Hôpital Charles Nicolle, Rouen, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Guyant-Maréchal
authors.affiliation: 1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, UMR-S1161, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Philippi
authors.affiliation: 7 Service de Neurologie, Hôpital Gui de Chauliac, Montpellier, France.
authors.forename: Astrid
authors.initials: A
authors.lastname: Corlobé
authors.affiliation: 1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, UMR-S1161, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Bergametti
authors.affiliation: 8 Plateforme de Génomique Constitutionnelle du GHU Nord, Assistance Publique des Hôpitaux de Paris (APHP), Hôpital Bichat, Paris, France.
authors.forename: Steven
authors.initials: S
authors.lastname: Gazal
authors.affiliation: 1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, UMR-S1161, Paris, France 5 AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Génétique Moléculaire Neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), Paris, France.
authors.forename: Carol
authors.initials: C
authors.lastname: Prieto-Morin
authors.affiliation: 4 Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians University, Munich, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Beaufort
authors.affiliation: 9 Service de Neurologie, CH Bretagne Sud, Lorient, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Le Bail
authors.affiliation: 1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France.
authors.forename: Irina
authors.initials: I
authors.lastname: Viakhireva
authors.affiliation: 4 Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians University, Munich, Germany 1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.affiliation: 1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, UMR-S1161, Paris, France 3 AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), Paris, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Chabriat
authors.affiliation: 4 Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians University, Munich, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Haffner
authors.affiliation: 1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, UMR-S1161, Paris, France 5 AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Génétique Moléculaire Neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), Paris, France tournier-lasserve@univ-paris-diderot.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Tournier-Lasserve
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D046589:CADASIL / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D000074289:High-Temperature Requirement A Serine Peptidase 1; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases
keywords: CADASIL; CARASIL; HTRA1; small vessel disease; vascular dementia