NIAID Clinical Center Genomics Opportunity Protocol

Investigators at National Institute of Allergy and Infectious Diseases (NIAID) are actively
developing the infrastructure and capability for identifying the cause of heterogeneous
immune-mediated disorders through whole exome and whole genome sequencing (WES/WGS). This
effort received additional support through the establishment of the NIAID Clinical Genomics
Program (CGP), a Division of Intramural Research (DIR)-supported cross-lab collaboration to
increase the effectiveness of NIAID s basic and applied genomic research. The disorders under
investigation include primary immunodeficiencies, immune homeostasis disorders, autoimmune
conditions, and allergic diseases for which the hypothesized causative genetic mutations(s)
have not yet been identified. Given recent discoveries of the genetic bases of many
immunological disorders, we are also expanding the disorders studied to include those with
prominent extra-immune manifestations in which a strong inherited immunological pathogenic
basis has been identified; such as the Pediatric Autoimmune Neuropsychiatric Disorders
associated with Streptococcal infections (PANDAS) or Sydenham s chorea. Despite the breadth
of clinical presentations under investigation, these immune-mediated disorders share
significant overlap in underlying molecular pathophysiology and thus represent a coherent
study target.

This protocol will facilitate the discovery of genes contributing to selected immune-mediated
disorders as well as generating experience with genetic secondary finding disclosure and will
further assess participant s perceptions and preference for WES and future secondary finding
procedures. Ultimately, a better understanding of the genetic contribution to immune
dysregulation will not only provide valuable diagnostic and, potentially, prognostic
information to affected families, but also has the potential to lead to the development of
novel therapeutic targets. Further, developing experience-tested and evidenced-based
procedures for secondary finding management is beneficial for NIAID CGP researchers and
participants.

This protocol is specific for genetic testing. Probands, or the affected person serving as
the starting point for the genetic study of family, will be required to be enrolled on a
primary protocol, which will execute the clinical and research evaluations. Unaffected
relatives may be enrolled on this protocol only. Participants unable to travel to National
Institutes of Health (NIH) Clinical Center (NIHCC) may be evaluated through mailin blood
samples, although evaluation at the NIHCC is strongly preferred, particularly for affected
participants. This study aims to enroll 200 participants for exome sequencing, including both
patients and relatives with heterogeneous immune-mediate disorders; all participants
receiving exome sequencing plus those who decline will be offered participation in the survey
(i.e., up to the accrual ceiling of 200).

- INCLUSION CRITERIA:

Whole Exome Sequencing with Secondary Findings Disclosure

The following inclusion criteria apply to all research participants on this protocol:

1. Age 0-100 years old. Clinical evaluation at the NIHCC requires age >2 years. Affected
relatives <2 years of age may be included in genetic family studies despite the fact
that he/she is too young for evaluation at the clinical center. Including affected
relatives in family-based whole exome sequencing is critically important, even if the
study team has to rely only on medical records because NIHCC evaluation is not
permitted due to age.

2. Willingness to allow sharing of genetic information in shared controlled access
databases like dbGaP.

3. Willingness to receive secondary finding report.

Probands (i.e., affected individuals serving as the starting point for genetic study of a
family) must have:

1. Primary enrollment on a NIH Institutional Review Board (IRB) approved protocol (e.g.,
05-I-0213 or 93-I-0063), which will execute the majority of clinical and research
evaluations.

2. A suspected genetic basis for the presenting immune disorder with features including
but not limited to autoimmunity, autoinflammatory conditions, lymphadenopathy,
end-organ dysfunction, unusual infections, allergies, or laboratory abnormalities
consistent with immune dysregulation that has not been previously identified and/or
with a family history suggesting genetically-based immune dysfunction (e.g., similar
phenotypes among relatives and/or consanguinity).

EXCLUSION CRITERIA:

Any participant can be excluded for the following:

1. Any condition which in the opinion of the investigator may interfere with the research
that is the focus of this protocol.