Genetic Susceptibility to Severe Infections

NCT06102070 | Recruiting

• 1 other identifier: C18-41
• Study Type: observational
• Target: 2,000
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Infectious Disease

Outcome Measures

Primary Outcomes (3)

• 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.

  through study completion, an average of 10 years

• 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.

  through study completion, an average of 10 years

• 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

  through study completion, an average of 10 years

Study Arms (1)

Predisposition

individuals suffering of having previously suffered of severe infectious diseases

Other: Blood samples drawing; Other: Skin biopsy

Interventions

Blood samples drawing OTHER

10 ml of periferal blood

Predisposition

Skin biopsy OTHER

Skin biopsy only in some index cases depending of the pathology at the recruitment

Predisposition

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study 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

You may qualify if:

• 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
• for relatives, to be related to the index case up to the 3rd degree: Parents, Children, Brother, Sister, Grandparents, Uncles, Aunts, Cousins, Nephews, Nieces

You may not qualify if:

• 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

Sponsors & Collaborators

• Institut National de la Santé Et de la Recherche Médicale, France: lead

Study Sites (1)

Centre d'Etudes des Déficits Immunitaires (CEDI), Hôpital Necker-Enfants

Paris, Île-de-France Region, 75015, France

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

Blood samples (10 ml) Skin biopsy (only for specific diseases as specified in the protocol) Saliva

MeSH Terms

Conditions

Communicable Diseases

Condition Hierarchy (Ancestors)

Infections; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Jacinta Md BUSTAMANTE, MD-PhD

CONTACT

01 71 19 60 04; jacinta.bustamante@aphp.fr

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2023
• First Posted: October 26, 2023
• Study Start: February 18, 2022
• Primary Completion (Estimated): February 17, 2037
• Study Completion (Estimated): October 18, 2038
• Last Updated: March 19, 2025

Record last verified: 2025-01

Locations

FR (1)