Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease

Edgard Verdura (1) , Dominique Hervé (1, 2) , Eva Scharrer , Maria del Mar Amador (2) , Lucie Guyant-Maréchal (3) , Anne Philippi (1) , Astrid Corlobe (4) , Françoise Bergametti (1) , Steven Gazal (5) , Carol Prieto-Morin (2, 1) , Nathalie Beaufort (6) , Benoit Le Bail , Irina Viakhireva (1) , Martin Dichgans , Hugues Chabriat (1) , Christof Haffner (6) , Elisabeth Tournier-Lasserve (7, 1)

1 U1161 / UMR_S 1161 - Génétique et Physiopathologie des Maladies Cérébro-Vasculaires
2 Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
3 Hôpital Charles Nicolle [Rouen]
4 Hôpital Gui de Chauliac [CHU Montpellier]
5 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
6 ISD - Institute for Stroke and Dementia Research
7 USPC - Université Sorbonne Paris Cité

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 affnected members of the index family. Ten probands of 201 additional unrelated and affnected probands (4.97%) harboured a heterozygous HTRA1 mutation predicted to be damaging. There was a highly significant diffnerence in the number of likely deleterious variants in cases compared to controls (P = 4.2 10 6 ; ; ; E odds ratio = 15.4E 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 effnect. Clinical features of this autosomal dominant small vessel disease diffner 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.

Domaines: Sciences du Vivant [q-bio]

Edgard Verdura, Dominique Hervé, Eva Scharrer, Maria del Mar Amador, Lucie Guyant-Maréchal, et al.. Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain - A Journal of Neurology , 2015, 138 (8), pp.2347--2358. ⟨hal-01987719⟩