NIAID Centralized Sequencing Protocol

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.

Study Overview

• Status: Recruiting
• Conditions: Primary Immunodeficiency; Atopy; Autoinflammation; Autoimmunity

Detailed Description

Study Design: This study serves as a centralized sequencing protocol for NIH human subjects research studies to facilitate standardization and consolidate accrual of genotype and phenotype data for participating programs. Participants of other NIH studies both at the NIH CC and CNHS that include genetic testing may enroll in this protocol and genetic testing will be conducted under this

study.

Objective: Primary: To generate and analyze evidence regarding the genetic contribution to diverse immune diseases and other health

conditions studied by the NIH intramural research program (IRP).

Secondary: To generate and analyze evidence regarding the processes and outcomes of the clinical genomics and genetic

counseling services performed under this protocol.

Endpoint: Primary: Discrete genetic contributions to immune diseases and other health conditions, explicitly including:

Established genetic disorders.

Novel genetic defects.

Novel phenotypes associated with established genetic

disorders.

Secondary: Evidence base for how to improve clinical genomic services on this protocol and related programs.

PRECIS

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.

• Study Type: Observational
• Enrollment (Estimated): 10000

Contacts and Locations

• Study Contact: Name: Morgan N Similuk; Phone Number: (301) 435-6691; Email: morgan.similuk@nih.gov

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • Children's National Health System
      • Contact: Michael Keller, MD; Phone Number: 202-476-5843; Email: mkeller@childrensnational.org
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Probands and their biological relatives (primarily clinical), recruited from NIAID protocols (both at the NIH and CNHS).

Description

• PARTICIPANT INCLUSION CRITERIA:

• Must fulfill one of the following criteria:

  • Proband participants: must have a disease under investigation by another NIH protocol on which they are co-enrolled.
  • Biological relatives: biologically related to a proband participant, and does not have a disease under investigation in another NIH protocol.
  • Healthy volunteers: unrelated to a proband participant, and does not have a disease under investigation in another NIH protocol.
• 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).
• 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.

Co-enrollment guidelines:

Probands must be enrolled on another NIH - either at the NIH CC or CNHS - protocol as their primary protocol for carrying out clinical and research evaluations. Relatives of probands may be enrolled in this protocol whether or not the relatives are enrolled on another NIH protocol. However, we may prioritize enrolling relatives who are on other NIH protocols and have undergone careful phenotyping on those protocols. Careful phenotyping is important, even for participants who are apparently healthy. Because the primary research team is best suited to characterize their participants phenotypes, phenotyping of co-enrolled relatives will be performed on the primary protocols.

SUBSTUDY INCLUSION CRITERIA:

• Aged 14-99 years.
• English language proficiency.
• Ability to provide informed consent.

SUBSTUDY EXCLUSION CRITERIA:

• Have received positive genetic results from this protocol in the past.
• Any condition that, in the opinion of the investigator, contraindicates participation in this substudy.

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Biological relatives; Biological relatives of probands, who may or may not also be co-enrolled on the proband's referring protocol.
Healthy volunteers; Select internal controls
Probands; Participants with a disease under investigation by another NIAID protocol on which they are enrolled, either at the NIH or CNHS.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identifying novel genetic defects associated with immune disorders	Identifying novel genetic defects associated with immune disorders	Upon analysis of genomic data
Identifying novel clinical phenotypes associated with established genetic defects	Identifying novel clinical phenotypes associated with established genetic defects	Upon analysis of genomic data
Identifying established genetic disorders of the immune system	Identifying established genetic disorders of the immune system, as well as known genetic disorders outside of the immune system in some cases	Upon analysis of genomic data

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evidence base for how to improve clinical genomic services on this protocol and related programs.	Studies of the processes and outcomes of the clinical genomics and genetic counseling services performed under this protocol. These studies will use surveys, interviews, and other social and behavioral research methods to collect data from study participants about their perceptions, experiences, and attitudes related to their condition and participation in this protocol. The goal of these additional studies will be to improve the services provided under protocol 17-I-0122 and to generate an evidence base for other investigators conducting similar studies.	5.1.1. Enrollment/Baseline Report Comprehension Survey and Semi-Structured Phone Interviews

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Morgan N Similuk, National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• 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.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2017
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: June 30, 2017
• First Submitted That Met QC Criteria: June 30, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: February 27, 2024

More Information

Terms related to this study

• Keywords: Genetics; Natural History; Genomics; Phenotyping; Sequencing; Inborn Errors of Immunity
• Additional Relevant MeSH Terms: Immunologic Deficiency Syndromes; Immune System Diseases; Genetic Diseases, Inborn; Primary Immunodeficiency Diseases; Autoimmune Diseases
• Other Study ID Numbers: 170122; 17-I-0122

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: .The PI is on maternity leave and will discuss when they return

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No