Genetic Susceptibility to Severe Infections
ConditionInfectious Disease
Trial statusRecruiting
Trial phaseNot listed
Trial typeObservational
Biological sexAll
AgeNot listed
SponsorInstitut National de la Santé Et de la Recherche Médicale, France
About this trial
Only a fraction of individuals infected with microbes develop clinical disease. This observation raises fundamental questions about the pathogenesis of infectious diseases. There is a complex interaction between environmental (microbial and non-microbial) and human (genetic and non-genetic) factors. This will determine the quality of the immune response against the infectious agent and the clinical manifestation. By definition, individuals who die from an infection have defective immunity to the pathogen in question (immune agent (immune deficiency).
The investigation of individual variability in the development of infectious diseases began in the early 20th. The first evidence to support the hypothesis that individual variability variability and immune deficiencies were hereditary came from observations of familial cases or genetic isolates genetic isolates (from a homogeneous population) of rare or common infectious diseases, which in some cases Mendelian heredity hat predisposition to infectious diseases runs in families even more so than diseases associated with less determined environmental factors, such as certain cancers. such as certain cancers. Finally, studies comparing the rate of concordance of infectious diseases between monozygotic and dizygotic twins also implicate genetic factors in disease susceptibility.
These observations were validated by the discovery of genetic defects associated with severe infectious diseases, leading to proof of concept. While a number of hereditary immune deficiencies associated with susceptibility to multiple pathogens or microorganisms, a growing number of new and rare new and rare immune deficiencies conferring restricted susceptibility to infections caused by a single caused by a single pathogen family, or even a single pathogen, in otherwise healthy children, have recently been identified (one gene, one pathogen). As a result, a dozen Mendelian clinical syndromes characterized by restricted susceptibility are now known. Over the last 20 years, it has been proven that these "idiopathic" infections were immune deficiencies.
The investigators now wish to study new severe infections, including but not limited to viral, fungal and bacterial infections. viral, fungal, bacterial and parasitic infections. This should lead to a better understanding of the pathophysiology of each disease, the development of new therapeutics and better patient care.
Eligibility criteria
This trial accepts healthy volunteersQualifiers
to sign the informed consent signed by the patient. In the case of a minor patient, consent is signed by the holders of parental authority. In the case of a protected adult patient, the consent is signed by their legal representative. In the case of an adult patient unable to consent at the time of inclusion, consent is signed by a family member.
to have a proven rare and severe infection
to be hospitalized or followed in a specialized hospital department, in the emergency room or in intensive care
to be affiliated to the French Social Security system
Disqualifiers
to have an acquired immunodeficiency (having received immunosuppressive treatment in the 3 months preceding the onset of the disease or being HIV positive)
pregnant woman at the time of illness
Trial population
1. Patients (index cases) will be recruited on the basis of a proven diagnosis of severe infection, including in particular but not exhaustively severe viral, parasitic, fungal and/or bacterial infections, prospectively. 2. Relatives of the applicant: Father, Mother, Brother, Sister, Grandparents, Uncles, Aunts, Cousins, Nephews, Nieces
Trial design
Design model
Cohort
Time perspective
Prospective
Treatments tested in this trial
Blood samples drawing
Other intervention10 ml of periferal blood
Skin biopsy
Other interventionSkin biopsy only in some index cases depending of the pathology at the recruitment
Treatment groups
2,000 Participants
are divided into 1 treatment groupGroup A: Predisposition2 interventions
Trial outcomes
Primary outcomes
1
Identification of chromosomal regions associated with the disease through a "homozygosity mapping" study on multiplex and/or consanguineous families.
Whole genome genotyping using high density microarrays (Affymetrix 6.0 type or equivalent) on the gDNA of the index case and its relatives. Exome data will also be used for homozygosity calculation.
Time frame
through study completion, an average of 10 years2
Identification of candidate genes for genetic susceptibility to infectious diseases
1. To sequence using the high-throughput sequencing technique (exome or genome). 2. To check the genetic segregation of mutations identified in relatives in each family.
Time frame
through study completion, an average of 10 years3
Validation of candidate genes as factor of susceptibility to infectious diseases
To validate the pathogenic effect of the mutation by functional and complementation tests on patient cells and control cells, and in an overexpression system
Time frame
through study completion, an average of 10 yearsSponsors and contacts
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Source ClinicalTrials.gov