Clinical trial NCT02848495: Biocollection on the Familial Forms of Intracranial Aneurysm
Official title: Genetic Study on the Familial Forms of Intracranial Aneurysm
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Intracranial Aneurysm
Keywords: Aneurysm
Biocollection
Familial Form
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
First posted: 2016-07-28
Enrollment: 411
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.

In the first instance, we 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 consists on 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 :

* 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.
  * Consent oral and in writing to the Biocollection consent Form 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 of 20 years or older
  * Consent oral and in writing to the Biocollection consent Form for participation in the collection of biological samples

Exclusion Criteria :

- Non Inclusion Criteria:

* Patients who have shown the inability or have refused to sign the consent informed biocollection
* Syndromic diagnosis known as IA 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, evoking:
* COL4A1 mutation

Primary outcomes:
measure: DNA analysis to identify new genes (and new physiological pathways) associated to the risk of intracranial aneurysm
timeFrame: Until one year
Secondary outcomes:
Other outcomes:
Locations:
city: Créteil
country: France
facility: AP-HP, Henri Mondor hospital
city: La Roche sur YON
country: France
facility: CHD La Roche sur YON
city: Nantes
country: France
facility: Nantes University Hospital
city: Poitiers
country: France
facility: University Hospital Poitiers
city: Rennes
country: France
facility: University Hospital Rennes
city: Rouen
country: France
facility: Rouen University Hospital
city: Talence
country: France
facility: Bordeaux University Hospital
city: Tours
country: France
facility: Tours University Hospital
Study officials:
affiliation: Nantes University Hospital
name: Romain BOURCIER, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Bakker MK, van der Spek RAA, van Rheenen W, Morel S, Bourcier R, Hostettler IC, Alg VS, van Eijk KR, Koido M, Akiyama M, Terao C, Matsuda K, Walters RG, Lin K, Li L, Millwood IY, Chen Z, Rouleau GA, Zhou S, Rannikmae K, Sudlow CLM, Houlden H, van den Berg LH, Dina C, Naggara O, Gentric JC, Shotar E, Eugene F, Desal H, Winsvold BS, Borte S, Johnsen MB, Brumpton BM, Sandvei MS, Willer CJ, Hveem K, Zwart JA, Verschuren WMM, Friedrich CM, Hirsch S, Schilling S, Dauvillier J, Martin O; HUNT All-In Stroke; China Kadoorie Biobank Collaborative Group; BioBank Japan Project Consortium; ICAN Study Group; CADISP Group; Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study investigators; International Stroke Genetics Consortium (ISGC); Jones GT, Bown MJ, Ko NU, Kim H, Coleman JRI, Breen G, Zaroff JG, Klijn CJM, Malik R, Dichgans M, Sargurupremraj M, Tatlisumak T, Amouyel P, Debette S, Rinkel GJE, Worrall BB, Pera J, Slowik A, Gaal-Paavola EI, Niemela M, Jaaskelainen JE, von Und Zu Fraunberg M, Lindgren A, Broderick JP, Werring DJ, Woo D, Redon R, Bijlenga P, Kamatani Y, Veldink JH, Ruigrok YM. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors. Nat Genet. 2020 Dec;52(12):1303-1313. doi: 10.1038/s41588-020-00725-7. Epub 2020 Nov 16.
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