Clinical trial NCT03632239: Reverse Phenotyping Core
Official title: Reverse Phenotyping Core (RPC)
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Harboring of Unexpected Genetic Variant
Keywords: Resource
Variant
Sequencing
Genome
Phenotype
Natural History
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2018-08-15
Enrollment: 1000
Sex: ALL
Minimum age (years): 4
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Individuals who have undergone genome sequencing under separate protocol

Brief summary: Background:

Genes tell a person's body how to grow and work. All people have variations in their genes. Some of these cause differences that show up in a person's traits or their health, others do not. Researchers want to gather more data on people based on their genes. They want to use this data to learn more about diseases and possible treatments.

Objectives:

To develop a cohort of participants who can be contacted again for phenotyping and collect their genetic data. To share those data with other researchers and make them searchable.

Eligibility:

People already enrolled in a wide variety of protocols. They will be of varying health status, age, and sex. They will have had or plan to have exome or genome sequencing under their protocol. They can be re-contacted by the research team for possible other studies.

Design:

Participants will give basic details like contact and demographic information.

Participants may answer questions about their personal health history, their family medical history, or their thoughts or reactions to data.

Participants may have basic health tests. Their height, weight, or blood pressure may be checked.

Participants may have tests of heart function. They may have an ultrasound or other non-invasive test.

Participants may provide blood, urine, or other samples.

Participants may have scans or other tests.

Participants will get the results of all clinical tests in a letter.

If any tests are abnormal, someone from the study will call the participant to explain what the results mean and what to do about them.

Participants will get genetic testing results only if researchers think they could affect the health of the participant or their relatives.

Detailed description: Study Design:

RPC will be a data resource of genetic variants with the capability of performing phenotyping for selected study participants who have undergone genome or exome sequencing and were consented for data sharing and re-contact. De-identified genome or exome data will be collected as the RPC Genomic Data Archive and available in a web browser quantifying alleles in aggregate. Investigators may request additional data for research on the basis of variants of interest identified in the browser. Individuals with genetic variants of interest may be offered phenotyping under RPC. Phenotyping performed under RPC will include obtaining medical information, gathering biologic samples, and selected diagnostic studies that can be performed in the NIHCC (NIH Clinical Center). RPC will enable investigation of phenotypic consequences of genetic variation in humans by using a genomic ascertainment strategy to minimize the bias of phenotypic ascertainment.

Primary Objective:

1. To pilot the development of a cohort of individuals with genome or exome sequencing data who can be re-contacted for phenotyping and make those data available to and searchable by collaborators.
2. To facilitate the completion of genotype-driven research projects by RPC or other investigators.

Secondary Objectives:

Secondary objectives will relate to the studies that will address phenotypic consequences of specific genetic variants identified in the RPC cohort. Such studies will include investigation of the phenotypic spectrum associated with genetic variation.

Endpoints:

This is a hypothesis-generating research study and therefore has no concrete endpoints.

Eligibility criteria: * INCLUSION CRITERIA:
* Participants in the RPC Genomic Data Archive must have exome or genome sequencing available that collaborators have permission to share for inclusion in our resource.
* Participants in the RPC Genomic Data Archive must be re-contactable by the primary study team (e.g., the collaborator who contributes their data must be able to contact the participants).
* All participants must be \>= 4 years old.

Primary outcomes:
measure: Hypotheses from RPC to be tested
timeFrame: yearly
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Human Genome Research Institute (NHGRI)
name: Clesson E Turner, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wilczewski CM, Obasohan J, Paschall JE, Zhang S, Singh S, Maxwell GL, Similuk M, Wolfsberg TG, Turner C, Biesecker LG, Katz AE. Genotype first: Clinical genomics research through a reverse phenotyping approach. Am J Hum Genet. 2023 Jan 5;110(1):3-12. doi: 10.1016/j.ajhg.2022.12.004.
citation: Garnai SJ, Brinkmeier ML, Emery B, Aleman TS, Pyle LC, Veleva-Rotse B, Sisk RA, Rozsa FW, Ozel AB, Li JZ, Moroi SE, Archer SM, Lin CM, Sheskey S, Wiinikka-Buesser L, Eadie J, Urquhart JE, Black GCM, Othman MI, Boehnke M, Sullivan SA, Skuta GL, Pawar HS, Katz AE, Huryn LA, Hufnagel RB; Genomic Ascertainment Cohort; Camper SA, Richards JE, Prasov L. Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice. PLoS Genet. 2019 May 2;15(5):e1008130. doi: 10.1371/journal.pgen.1008130. eCollection 2019 May.
citation: Manthiram K, Preite S, Dedeoglu F, Demir S, Ozen S, Edwards KM, Lapidus S, Katz AE; Genomic Ascertainment Cohort; Feder HM Jr, Lawton M, Licameli GR, Wright PF, Le J, Barron KS, Ombrello AK, Barham B, Romeo T, Jones A, Srinivasalu H, Mudd PA, DeBiasi RL, Gul A, Marshall GS, Jones OY, Chandrasekharappa SC, Stepanovskiy Y, Ferguson PJ, Schwartzberg PL, Remmers EF, Kastner DL. Common genetic susceptibility loci link PFAPA syndrome, Behcet's disease, and recurrent aphthous stomatitis. Proc Natl Acad Sci U S A. 2020 Jun 23;117(25):14405-14411. doi: 10.1073/pnas.2002051117. Epub 2020 Jun 9.
citation: Johnston JJ, Brennan ML, Radenbaugh B, Yoo SJ, Hernandez SM; NHGRI Reverse Phenotyping Core; Lewis KL, Katz AE, Manolio TA, Biesecker LG. The ACMG SF v3.0 gene list increases returnable variant detection by 22% when compared with v2.0 in the ClinSeq cohort. Genet Med. 2022 Mar;24(3):736-743. doi: 10.1016/j.gim.2021.11.012. Epub 2021 Nov 18.
citation: Spontarelli K, Young VC, Sweazey R, Padro A, Lee J, Bueso T, Hernandez RM, Kim J, Katz A, Rossignol F, Turner C, Wilczewski CM, Maxwell GL, Holmgren M, Bailoo JD, Yano ST, Artigas P. ATP1A1-linked diseases require a malfunctioning protein product from one allele. Biochim Biophys Acta Mol Cell Res. 2024 Jan;1871(1):119572. doi: 10.1016/j.bbamcr.2023.119572. Epub 2023 Sep 1.