Autoimmune and Autoinflammatory Genetics Study

Study Overview
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Brief Summary
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This is an exploratory natural history protocol that will enroll patients with known genetic diseases, such as VEXAS syndrome, or as yet undiagnosed disorders of inflammation with the goal of improving our understanding of disease processes. Blood, saliva, hair, nail, or buccal samples may be collected for genetic analysis, blood samples will be obtained for immunologic and other functional studies, and a small number of subjects may undergo skin biopsy.

Detailed Description
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This is a single-site protocol designed to test the hypothesis that genetic factors contribute to susceptibility to human disorders of inflammation, and the hypothesis that identifying such genetic susceptibility factors will contribute to our understanding of the immunologic mechanisms of these diseases. There are 3 main objectives: Primary Objective: To discover the genetic basis of human disorders of inflammation or autoinflammatory diseases. Secondary Objective: To enumerate immunologic features and genotype-phenotype associations in specific inflammatory diseases, such as VEXAS syndrome. Tertiary/Exploratory Objective: To describe the clinical features of poorly characterized or newly defined disorders of inflammation, such as VEXAS syndrome, through the retrospective chart review of standard medical practice follow up

Official Title
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Natural History and Genetics of VEXAS Syndrome and Related Autoinflammatory Syndromes

Conditions
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VEXAS Syndome, Autoinflammatory Disease, Autoimmune Disease, Rheumatic Disease

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible to participate in this study as a subject with known or suspected autoinflammatory disease, an individual must meet all of the following criteria: Stated willingness to participate in study procedures (which at the very least includes providing a mail-in blood or saliva sample for genetic analysis); Regardless of sex assigned at birth, at least one month of age; A medical history that, in the expert opinion of the PI and study team, is consistent with the possibility of autoinflammatory disease or known diagnosis of an autoinflammatory disease, such as VEXAS syndrome; and Ability of the subject, parents (in the case of children), or Legally Authorized Representative to understand and the willingness to sign a written informed consent document. In order to be eligible to participate in this study as a family member of a subject with known or suspected autoinflammatory disease, an individual must meet all of the following criteria: Stated willingness to participate in study procedures (which at the very least includes providing a mail-in sample for genetic analysis); Regardless of sex assigned at birth, at least one month of age; Relationship, either by blood or marriage, to an individual enrolled or about to be enrolled in the study with known or suspected autoinflammatory disease; Likelihood, in the expert opinion of the PI and study team, that analysis of a sample from the individual would advance genetic or functional analysis of the affected relative's possible autoinflammatory condition; and Ability of the subject, parents (in the case of children), to understand and the willingness to sign a written informed consent document. In order to be eligible to participate in this study as a healthy volunteer, an individual must meet all of the following criteria: Stated willingness to participate in study procedures for healthy volunteers; Regardless of sex assigned at birth, at least five years old, and not pregnant (by history of a missed menstrual period); Likelihood, in the expert opinion of the PI that a sample from the individual would advance the functional analysis of an autoinflammatory condition under study; and Ability of the subject to understand and the willingness to sign a written informed consent document by a capacity assessment provided by the PI and study team. Exclusion Criteria: For any of the three categories of subjects, an individual will be excluded from participation in this study for the following reasons: Probands: an individual will not be enrolled as a proband if the study team has a low suspicion of having an autoinflammatory disease or a genetic cause for an autoinflammatory disease. Family Members: an individual will not be enrolled as a family member if the study team believes they may have an autoinflammatory disease, in which case, they will be enrolled as a proband. Healthy controls: an individual will not be enrolled as a healthy control if they have an autoinflammatory disease, or any condition that may mimic an autoinflammatory disease, such as hematologic malignancy, rheumatologic disease.

Ages Eligible for Study
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Minimum Age: 1 Month

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Participants with known or suspected autoinflammatory diseases<br>Participants with known or suspected autoinflammatory diseases (i.e., Probands) | |
| Family member<br>Family member, either by blood or marriage, to an individual enrolled or about to be enrolled in the study with known or suspected autoinflammatory disease. | |
| Healthy control<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of newly discovered rare, high penetrance germline variants that cause human inflammatory disease |  | Study End (Up to Year 5) | 
| Number of newly discovered structural genomic variants that cause human inflammatory disease |  | Study End (Up to Year 5) | 
| Number of newly discovered common, low penetrance germline variants that confer susceptibility to human inflammatory disease |  | Study End (Up to Year 5) | 
| Number of newly discovered somatic mutations that give rise to human inflammatory disease |  | Study End (Up to Year 5) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic)