Clinical trial NCT03206099: NIAID Centralized Sequencing Protocol
Official title: NIAID Centralized Sequencing Protocol
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Atopy
Primary Immunodeficiency
Autoimmunity
Autoinflammation
Keywords: Phenotyping
Genetics
Sequencing
Inborn Errors of Immunity
Genomics
Natural History
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2017-07-02
Enrollment: 20000
Sex: ALL
Minimum age (years): 1
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: FAMILY_BASED
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Probands and their biological relatives (primarily clinical), recruited from NIAID protocols (both at the NIH and CNHS).

Brief summary: Background:

Genetic testing called "sequencing" helps researchers look at DNA. Genes are made of DNA and are the instructions for our bodies to function. We all have thousands of genes. DNA variants are differences in genes between two people. We all have lots of variants. Most are harmless and some cause differences like blue or brown eyes. A few variants can cause health problems.

Objective:

To understand the genetics of immune disorders various health conditions, as well as outcomes of clinical genomics and genetic counseling services performed under this protocol.

Eligibility:

Participants in other NIH human subjects research protocols - either at the NIH Clinical Center (CC) or at Children s National Health System (CNHS) - (aged 0-99 years), and, in select cases, their biological relatives

Design:

Researchers will study participant s DNA extracted from blood, saliva, or another tissue sample, including previously collected samples we may have stored at the NIH. Researchers will look at participant s DNA in great detail. We are looking for differences in the DNA sequence or structure between participants and other people.

Participants will receive results that:

* Are important to their health
* Have been confirmed in a clinical lab
* Suggest that they could be at risk for serious disease that may affect your current or future medical management.

Some genetic information we return to participants may be of uncertain importance.

If genetic test results are unrelated to the participant s NIH evaluations, then we will not typically report:

* Normal variants
* Information about progressive, fatal conditions that have no effective treatment
* Carrier status (conditions you don t have but could pass on)

The samples and data will be saved for future research.

Personal data will be kept as private as possible.

If future studies need new information, participants may be contacted.

Detailed description: Investigators at the National Institute of Allergy and Infectious Diseases (NIAID) use next-generation sequencing technologies to help determine genetic contributions to immune diseases. These efforts have increased rates of molecular diagnosis for a subset of NIAID

participants as well as uncovered fundamental insights into the cellular and signaling pathways in host defense and immune regulation.

Despite these successes, analysis and interpretation of genomic data remain a substantial challenge. Simply, researchers do not understand the functional and clinical consequences of most human genetic variation. This is true at NIAID and across the intramural research program. Making progress in this area requires a coordinated, systematic, and transparent approach to clinical genomics research.

This protocol is specific to genetic testing and explicitly aims to both strengthen clinical care and enhance research throughout participating programs at the NIH. Probands will provide biological specimens for genetic testing and will be required to be enrolled on a primary protocol, which will execute the primary clinical and research evaluations. This protocol serves as a vehicle for a

programmatic effort that includes standardized phenotyping, test ordering through the Clinical Research Information System (CRIS), sample collection and isolation, nucleic acid analysis, bioinformatics, clinical interpretation, reporting in CRIS, genetic counseling, and supporting effective use of genomics as a research tool throughout the intramural program. Genetic testing results and data (upon request) will be shared with the research teams for protocols on which a given participant is co-enrolled. Overall, increased process standardization will support data integrity and efficiency while still accommodating the need for investigator flexibility.

Eligibility criteria: * PARTICIPANT INCLUSION CRITERIA:
* Must fulfill one of the following criteria:

  * Proband participants: must be individuals under investigation by another NIH protocol on which they are co-enrolled, or are referred from the GDMCC protocol "Defining the Genetic Etiology of Suppurative Lung Disease in Children and Adults" (NCT04702243). Probands may have a disease under investigation or be healthy volunteers
  * Biological relatives: biologically related to a proband participant.
* Aged 0-99 years.
* Participants must be willing to undergo genetic testing.
* Participants must be willing to allow samples to be stored for future research.
* Participants must be willing to have their de-identified genomic data shared, for example in a controlled access databases like the Database of Genotypes and Phenotypes (dbGaP).
* To complete surveys and interviews:

  * Proficient with the English language.
  * Able to provide informed consent.
* Adult healthy volunteers must be able to provide informed consent.

PARTICIPANT EXCLUSION CRITERIA:

Any condition that, in the opinion of the investigator, contraindicates participation in this study is a reason for exclusion.

Primary outcomes:
measure: Identifying novel genetic defects associated with immune disorders
timeFrame: Upon analysis of genomic data
measure: Identifying novel clinical phenotypes associated with established genetic defects
timeFrame: Upon analysis of genomic data
measure: Identifying established genetic disorders of the immune system
timeFrame: Upon analysis of genomic data
Secondary outcomes:
measure: Evidence base for how to improve clinical genomic services on this protocol and related programs.
timeFrame: 5.1.1. Enrollment/Baseline Report Comprehension Survey and Semi-Structured Phone Interviews
Other outcomes:
Locations:
city: Washington
country: United States
facility: Children's National Health System
state: District of Columbia
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Morgan N Similuk
role: PRINCIPAL_INVESTIGATOR
References:
citation: Similuk MN, Yan J, Ghosh R, Oler AJ, Franco LM, Setzer MR, Kamen M, Jodarski C, DiMaggio T, Davis J, Gore R, Jamal L, Borges A, Gentile N, Niemela J, Lowe C, Jevtich K, Yu Y, Hullfish H, Hsu AP, Hong C, Littel P, Seifert BA, Milner J, Johnston JJ, Cheng X, Li Z, Veltri D, Huang K, Kaladi K, Barnett J, Zhang L, Vlasenko N, Fan Y, Karlins E, Ganakammal SR, Gilmore R, Tran E, Yun A, Mackey J, Yazhuk S, Lack J, Kuram V, Cao W, Huse S, Frank K, Fahle G, Rosenzweig S, Su Y, Hwang S, Bi W, Bennett J, Myles IA, De Ravin SS, Fuss I, Strober W, Bielekova B, Almeida de Jesus A, Goldbach-Mansky R, Williamson P, Kumar K, Dempsy C, Frischmeyer-Guerrerio P, Fisch R, Bolan H, Metcalfe DD, Komarow H, Carter M, Druey KM, Sereti I, Dropulic L, Klion AD, Khoury P, O' Connell EM, Holland-Thomas NC, Brown T, McDermott DH, Murphy PM, Bundy V, Keller MD, Peng C, Kim H, Norman S, Delmonte OM, Kang E, Su HC, Malech H, Freeman A, Zerbe C, Uzel G, Bergerson JRE, Rao VK, Olivier KN, Lyons JJ, Lisco A, Cohen JI, Lionakis MS, Biesecker LG, Xirasagar S, Notarangelo LD, Holland SM, Walkiewicz MA. Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations. J Allergy Clin Immunol. 2022 Oct;150(4):947-954. doi: 10.1016/j.jaci.2022.06.009. Epub 2022 Jun 24.