Clinical trial NCT02712892: I-CAN Biocollection
Official title: IntraCranial ANeurysms: From Familial Forms to Pathophysiological Mechanisms
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Intracranial Aneurysm
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2016-03-18
Enrollment: 3078
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: FAMILY_BASED
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The initial stage of this biocollection based on the recruitment of large families for genetic linkage analysis. This is a first step to identify patients with intracranial aneurysms occurring in a family context, and to conduct a comprehensive investigation according to clinical guidelines in force to assess the potentially informative family and ensure their adherence to the prior biocollection. The next step is the fine and accurate phenotyping of each of the family members (imaging) and the collection of a blood sample for DNA extraction for molecular genetic analysis.

The population recruited will be composed of index and their healthy relatives and cases with sporadic cases and IA. The kinship links will be established from family trees.

Brief summary: Intracranial aneurysm (IA) is an asymptomatic cerebrovascular abnormality affecting 3.2% of the general population. The devastating complication of IA is its rupture, resulting in subarachnoid haemorrhage that can lead to severe disability and death. Unfortunately, there are neither reliable clues nor diagnostic tools to predict the formation and/or the fate of an IA in a given individual. Also, there is no pharmacological drug available to prevent the rupture of aneurysm and subsequent subarachnoid haemorrhage. Current treatments are invasive with a significant risk of procedural morbidity. Thus, still now, the management of patients with IA remains extremely challenging and still controversial. Although the pathogenesis of IA has been the subject of many studies for the last decade, the mechanisms underlying IA formation, growth and rupture are still mostly unknown and relevant animal models of IA are not available. Familial history of IA predisposes to IA formation and rupture and increasing evidence suggest a genetic component of IA formation, with heterogeneous modes of inheritance and penetrance. This project, gathering neuroradiologists, geneticists and vascular biologists, addresses the urgent need to understand the pathogenic mechanisms of IA to develop diagnostic and predictive tools of risk of IA. The investigators propose to identify IA-causing variants by whole-exome sequencing in familial forms of the disease. The investigators hypothesises that the functional analysis of the causal/susceptibility variants thus identified will provide clues to understanding the pathological mechanisms of IA formation, and the bases for developing diagnostic tools. This project aims at meeting this challenge. Based on preliminary data that already allowed to identify such a variant, and the combination of genetic and functional investigations, the specific objectives of this project are: - To identify IA-causing variants in familial forms of the disease by whole-exome sequencing; - To understand the function of these genes/variants in the formation and rupture of IA by molecular and cellular approaches and generation of relevant animal models; - To discover potential biomarkers of risk of IA formation and/or rupture.


Eligibility criteria: Inclusion criteria indexes and related cases (familial) of intracranial aneurysms:

* Index: Any patient consulting for a major IA and some typical bifurcation with at least one other case reached akin IA 1st degree
* Related: All similar to the first degree, aged 20 or more, patients with a family background of IA and some typical bifurcation (≥2 achieved) For the latter, directed by screening with Magnetic resonance imaging (MRI) sequence Time of Flight (TOF), axial T2, EGT2.
* biocollection of Written Consent for participation in the collection of biological samples

Inclusion criteria sporadic cases of IA:

* Any patient consulting for IA and some typical bifurcation
* Patients aged 20 years or older
* biocollection of Written Consent for participation in the collection of biological samples

Non Inclusion Criteria:

* Patients who have shown the inability or refusal to sign the consent informed biocollection
* syndromic diagnosis known as AIC provider

  * Marfan Syndrome
  * AOS with SMAD 3
  * Danlos Syndrome Elhers type II and IV
  * Autosomal Dominant Polycystic
  * Moyamoya Syndrome
* character of IA:

  * Dissecting or fusiform
  * Combined with an arteriovenous malformation
  * Blister-like
  * mycotic
* Pathology of the cerebral white matter detected on MRI suggestive:

  * Mutation COL4A1

Primary outcomes:
measure: Presence or absence of genetic abnormalitie
timeFrame: Until one year
Secondary outcomes:
Other outcomes:
Locations:
city: Angers
country: France
facility: Angers University Hospital
city: Besançon
country: France
facility: Besançon University Hospital
city: Bordeaux
country: France
facility: Bordeaux University Hospital
city: Créteil
country: France
facility: Henri Mondor Hospital (AP-HP)
city: Dijon
country: France
facility: Dijon University Hospital
city: Grenoble
country: France
facility: Grenoble University Hospital
city: La réunion
country: France
facility: La Reunion University Hospital
city: Le Kremlin-Bicêtre
country: France
facility: Kremlin-Bicêtre University Hospital (AP-HP)
city: Limoges
country: France
facility: Limoges University Hospital
city: Nancy
country: France
facility: Nancy University Hospital
city: Nantes
country: France
facility: Nantes University Hospital
city: Paris
country: France
facility: Lariboisière University Hospital (AP-HP)
city: Paris
country: France
facility: La Pitié-Salpétrière University Hospital (AP-HP)
city: Paris
country: France
facility: Sainte Anne Hospital
city: Paris
country: France
facility: Rotschild Fundation
city: Poitiers
country: France
facility: Poitiers University Hospital
city: Rennes
country: France
facility: Rennes University Hospital
city: Rouen
country: France
facility: Rouen University Hospital
city: Toulouse
country: France
facility: Toulouse University Hospital
city: Tours
country: France
facility: Tours University Hospital
Study officials:
affiliation: Nantes University Hospital
name: Hubert DESAL, Pr
role: PRINCIPAL_INVESTIGATOR
References:
citation: L'Allinec V, Chatel S, Karakachoff M, Bourcereau E, Lamoureux Z, Gaignard A, Autrusseau F, Jouan S, Vion AC, Loirand G, Desal H, Naggara O, Redon R, Edjlali M, Bourcier R. Prediction of Unruptured Intracranial Aneurysm Evolution: The UCAN Project. Neurosurgery. 2020 Jul 1;87(1):150-156. doi: 10.1093/neuros/nyaa093.