Genetic Analysis of Immune Disorders

• ClinicalTrials.gov Identifier: NCT00001467
• Recruitment Status: Recruiting
• First Posted: November 4, 1999
• Last Update Posted: May 23, 2023
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Study Description

Brief Summary:

The purposes of this study are to 1) identify the genes responsible for certain immune disorders, 2) learn about the medical problems they cause, and 3) learn how to predict who is likely to develop these disorders and what the risk is of passing them on to children. The immune system is the body s defense system. Some immune deficiencies impair a person s ability to fight infections; others render a person susceptible to allergies, or to autoimmune diseases such as lupus or arthritis, in which the immune cells (white blood cells) attack and destroy the body s own tissues.

Patients with immune disorders known or suspected to have a genetic basis and their family members may enroll in this study. Eligibility will be determined by a review of the patient s medical records and family medical history. Participants will provide a small blood sample for genetic (DNA) and white blood cell analysis. Gene samples (but not white blood cells) may also be obtained by mouth brushing or skin biopsy. For the mouth brushing, a small brush is rubbed against the inside of the cheeks for 1 minute to wipe off some cells. For the skin biopsy, a small circle of skin (about 1/8 inch) is removed under local anesthetic. Pregnant women may be asked to provide a fetal sample (amniotic fluid cells or chorionic villus sample). All samples will be used for immune or genetic studies of the family s immune disorder.

If test results show a specific genetic variation responsible for the family s immune disorder, a report will be sent to the patient s doctor or genetic counselor, who will discuss the implications for the family. NIH researchers and genetic counselors will also be available to explain results and answer questions. Information will not be available in the case of disorders that cannot yet be linked to a specific genetic abnormality.

Information from this study will increase knowledge about the immune system and what causes immune deficiencies. Participants may also learn the underlying cause of an immune disorder that affects them or someone in their family information may be useful in guiding treatment and in making decisions regarding family planning.

Condition or disease
DOK 8; STAT1; GATA2; Immunodeficiency; STAT3

Detailed Description:

This protocol includes studies of genetic defects of the immune system that cause failure of host defenses against infections, immune dysregulation and autoimmune diseases. Numerous rare disorders result from inherited or newly arising mutations in genes involved in the development and function of innate and adaptive immune systems or both. As specific disease syndromes are defined and the responsible genes identified, mutations in individual families can be sought. Correlation of mutation sites with clinical information helps to determine how specific gene segments encode important functional domains of the proteins of the immune system within the same genetic defect. Rare, single gene disorders identify immunologic pathways that might contribute to more common conditions, such as failure to respond to vaccines, susceptibility to allergies, or autoimmune diseases like arthritis or lupus.

Members of families with immune disorders that are known or suspected to have a genetic basis may be eligible. Immunologic tests and DNA sequence analysis appropriate to each clinical condition will be performed as needed on affected individuals and at-risk family members. Healthy family members may serve as controls. Probands, parents of deceased affected individuals, or entire families, may be referred to the Investigators Initially, clinical and family history as well as laboratory data will be reviewed by the investigators to determine eligibility. Subjects considered appropriate will be invited through their referring physician to participate by signing our consent form and sending appropriate blood, DNA or other samples to our PI. Should a genetic basis for an individual s immune disorder be identified or if clinical eligibility for other protocols is met, they may be invited to visit NIH.

Study Design

• Study Type: Observational
• Estimated Enrollment: 5000 participants
• Observational Model: Other
• Time Perspective: Cross-Sectional
• Official Title: Genetic Analysis of Immune Disorders
• Actual Study Start Date: June 6, 1995

Groups and Cohorts

Group/Cohort
Blood relatives; blood related family members of proband
Proband; person initially ill/studied/diagnosed

Outcome Measures

Primary Outcome Measures :

1. To search for modifiers of phenotype in subjects with disorders of the immune system in which penetrance and expressivity are variable. [ Time Frame: blood draw and testing once or can be repeated ]
   Greater understanding of the variable penetrance and expressivity of modifiers of phenotype in subjects with disorders of the immune system
2. genetic testing for known or suspected mutations related to primary immune deficiencies [ Time Frame: blood draw and testing once or can be repeated ]
   diagnosis of genetic mutations or deficiencies causing rare primary immune diseases under study

Secondary Outcome Measures :

1. To track the natural history of disease outcome in selected disorders. [ Time Frame: over time via history and assignment to other protocols ]
   understanding of natural history of selected disorders
2. To perform genotype/phenotype analysis in subjects with immune defects of known genetic cause, leading to basic research on interactions between components of receptors in immune system pathways. [ Time Frame: blood draw and testing once or can be repeated ]
   understanding of interactions between components of receptors in immune system pathways in immune defects of know genetic cause
3. To identify by clinical and laboratory studies, including mutation detection in patients and healthy relatives who may be carriers, subjects who may be eligible for related protocols or who may derive clinical benefit from molecular diagnosis. [ Time Frame: upon known or suspected diagnosis ]
   To follow patients and relatives that are affected or carriers of genetic defects over time and gain of further understanding of the natural history of diseases/conditions of the immune system.caused by genetic mutations/deficiencies

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Probands and their blood relatives, of any age, gender, and ethnicity, who are affected, or suspected of being affected with genetic conditions and immune dysregulations under study are eligible to enroll as patients or family member enrollees. Fetal samples may be studied in selected cases where benefit, such as expedited postnatal treatment, could be realized.@@@

Criteria

• INCLUSION / EXCLUSION CRITERIA:

Probands and their blood relatives, of any age, gender, and ethnicity, who are affected, or suspected of being affected with genetic conditions and immune dysregulations under study are eligible to enroll as patients and family member enrollees.

Contacts and Locations

Contacts

Contact: Steven M Holland, M.D.; (301) 402-7684; sholland@mail.nih.gov

Contact: Gulbu Uzel, M.D.; (301) 451-9035; guzel@niaid.nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Gulbu Uzel, M.D.; National Institute of Allergy and Infectious Diseases (NIAID)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Puck JM. Molecular and genetic basis of X-linked immunodeficiency disorders. J Clin Immunol. 1994 Mar;14(2):81-9. doi: 10.1007/BF01541340.

Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, Strober W, Lenardo MJ, Puck JM. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995 Jun 16;81(6):935-46. doi: 10.1016/0092-8674(95)90013-6.

Pepper AE, Buckley RH, Small TN, Puck JM. Two mutational hotspots in the interleukin-2 receptor gamma chain gene causing human X-linked severe combined immunodeficiency. Am J Hum Genet. 1995 Sep;57(3):564-71.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

West RR, Hsu AP, Holland SM, Cuellar-Rodriguez J, Hickstein DD. Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation. Haematologica. 2014 Feb;99(2):276-81. doi: 10.3324/haematol.2013.090217. Epub 2013 Sep 27.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00001467
• Other Study ID Numbers: 950066; 95-I-0066
• First Posted: November 4, 1999
• Last Update Posted: May 23, 2023
• Last Verified: April 13, 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: .We will share human data generated in this study for future research as follows:@@@@@@-Identified data in the Biomedical Translational Research Information System (BTRIS, automatic for activities in the NIH CC).@@@@@@-De-identified or identified data with approved outside collaborators under appropriate agreements.@@@@@@-Data sharing may be complicated or limited in certain cases by contractual obligations or agreements with outside collaborators, such as cooperative research and development agreements, clinical trial agreements, other restraints, etc.
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: PD and supporting information will be available after completion of the study.
• Access Criteria: Data will be shared through:@@@@@@-Approved outside collaborators under appropriate individual agreements.@@@@@@-Publication and/or public presentations.@@@@@@Data might be shared before publication.@@@@@@The PI will review all requests for sharing data.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

Primary Immunodeficiency Disorders; Immunologic Disorders; Mutation; Genetic Analysis; Natural History

Additional relevant MeSH terms:

Immunologic Deficiency Syndromes; Immune System Diseases