Novel Genetic Disorders of the Immune System

This study is designed to evaluate patients with suspected or identified novel immune
disorders, with a focus on abnormal immune homeostasis potentially due to defects in
activation or apoptosis. Blood relatives of enrolled patients will also be evaluated.
Affected individuals may have Mendelian gene defects involving mostly single or occasionally
multiple genes. These patients may have signs and symptoms suggestive of clinically
significant lymphocyte homeostasis disorders. However, some selected patients manifesting
autoimmunity, autoinflammatory conditions, end-organ dysfunction, Epstein-Barr virus (EBV)
and cytomegalovirus (CMV) viremia, frequent infections, allergies, or laboratory
abnormalities consistent with immune defects of research interest to the Laboratory of
Clinical Infectious Diseases may also be studied under this protocol at the discretion of the
Investigators.

This protocol will facilitate the discovery of the role of genetic pathways and modes of
inheritance associated with pathophysiological events leading to immune system dysregulation,
particularly disorders of immune cell homeostasis. A better understanding of the genetics as
well as biochemical and molecular basis of complex immune disorders could also lead to the
development of novel therapeutic targets and approaches.

Patients will undergo clinical evaluations that include history and physical examinations,
blood sampling, radiological exams, genetic testing, skin biopsy, and other medically
indicated procedures. Genetically related family members of patients may also be evaluated or
screened for clinical, in vitro, and genetic correlates of immune abnormalities. Patients and
relatives unable or too sick to travel to NIH Clinical Center (CC) may be evaluated through
mail-in blood samples. Patients and their relatives will remain enrolled on this study to
observe the natural history of the disorder and obtain blood, saliva, skin biopsy, or other
specimens at periodic intervals. This study aims to enroll up to a total of 500 patients and
their family members.

- INCLUSION CRITERIA:

The following inclusion criteria apply to all subjects:

- Patient and relatives aged 0-99 years old to include women who are pregnant or
breastfeeding. Only patients >2 years of age will be physically evaluated at the NIH
CC.

- Willingness to allow storage of blood, saliva, and other tissue specimens for future
use in medical research.

- Willingness to participate in genetic testing and allow sharing of genetic information
in secure databases like dbGAP. These tests may include, but are not limited to, whole
exome and whole genome sequencing.

- Priority may be given to individuals with a family history (if readily available)
suggestive of multiple affected members with a constellation of signs and symptoms
suggestive of immune dysfunction among first- or second-degree relatives.

- Eligibility of special populations

- A. NIH employees are eligible

- B. Women who are pregnant or breast feeding are eligible to enroll as probands or
relatives. This protocol is not actively seeking women who are pregnant.

Patients must have:

- An identified genetic basis for an immune disorder or signs and symptoms suggestive of
clinically significant immune dysregulation and/or immunodeficiency manifesting with
features including but not limited to autoimmunity, autoinflammatory conditions,
lymphadenopathy, end-organ dysfunction, unusual infections, allergies, or laboratory
abnormalities consistent with immune dysregulation.

- A primary physician outside of the NIH and will be required to submit a letter or
clinical summary from their referring physician that documents their relevant health
history.

EXCLUSION CRITERIA:

Patients will be excluded for any of the following:

- Known genetic disorders that are already well characterized, such as severe combined
immunodeficiency (SCID), chronic granulomatous disease (CGD), etc., and those in which
we do not have an enduring research interest in the LCID.

- Patients with unknown immune disorders will be excluded if they have received
chemotherapy within the last 6 months for a malignancy or have infections such as HIV
or mycobacterial infections.

- Severe clinical illness requiring highly specialized teams and institutions. The NIH
may not be able to provide appropriate care for certain referred cases. The Principal
Investigator (PI) may determine that the patient is eligible for enrollment but
ineligible for admission to the Clinical Center. Patients and relatives with certain
obstetric issues may pose a safety risk for travel and evaluation here. Eligibility
for this group will be determined on a case by case basis by the PI.

- Patients with well-defined autoimmune conditions such as systemic lupus erythematosus
(SLE), Hashimoto s thyroiditis, Addison s disease, Graves disease, sarcoidosis and
rheumatoid arthritis, among others.

Blood relatives will be excluded for the following:

-Any condition which in the opinion of the investigator may interfere with evaluation of an
immune system abnormality that is the subject of study under this protocol.