Exome and Genome Analysis to Elucidate Genetic Etiologies and Population Characteristics in the Plain Community

Use of Whole Exome Sequencing/Whole Genome Sequencing in the Plain Communities

This study is designed to utilize whole exome and whole genome sequencing techniques to identify underlying genetic causes for undiagnosed disorders in the Plain Communities, and to do population genetic studies looking at genetic drift and founder mutations in this unique population.

Study Overview

• Status: Recruiting
• Conditions: Undiagnosed Disease

Detailed Description

The long term goal of this proposal is to establish a Translational Medicine Program for the Old Order Amish and Mennonite communities that is accessible to their members with decreasing cost and effective diagnostic strategies, and to leverage the genetic information obtained to better understand the genetic forces and risks driving the health of these populations. As a bridge to do so, next-generation sequencing technology will be used to identify genetic defects in Old Order Amish families/individuals who have a clinical picture suggestive of a Mendelian disorder but with unknown diagnosis. Investigators plan to develop targeted analytical NGS panels optimized for general use in the clinical setting when dealing with Plain Communities patients and families, yielding better and more prompt clinical intervention and improvement of outcomes. The study also involves use of whole genome sequencing for a mutant allele discovery platform to identify novel genetic risks in this population not yet identified in patients, and to use this platform to describe genetic differences in Old Order Amish communities across Pennsylvania and ultimately across the country. With WGS will be used to analyze population genetics by comparing the distribution of genetic variants among the various Amish communities and to compare these with their European ancestry variants available in 1000 genome project, to study the influence of founder-selection and genetic drift in these populations.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Jenifer Baker, MA; Phone Number: 412-6926378; Email: jennifer.baker@chp.edu
• Study Contact Backup: Name: Cate Walsh Vockley, MS, LCGC; Phone Number: 412-692-7349; Email: Catherine.WalshVockley@chp.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Recruiting
      • Children's Hospital of Pittsburgh of UPMC
      • Sub-Investigator: Gerard Vockley, MD, PhD
      • Principal Investigator: Lina Ghaloul Gonzalez, MD
      • Sub-Investigator: Roxanne Acquaro, MS, LCGC
      • Sub-Investigator: M. Michael Barmada
      • Sub-Investigator: Steven Dobrowolski
      • Sub-Investigator: Jessica Sebastian, MS, LCGC
      • Sub-Investigator: Andrew McCarty, MS, LCGC
      • Sub-Investigator: Christine Munro, BSc
      • Sub-Investigator: Jodie Vento, MS, LCGC
      • Sub-Investigator: Catherine Walsh Vockley, MS, LCGC
      • Contact: Jennifer Baker, MA; Phone Number: 412-692-6378; Email: jennifer.baker@chp.edu
      • Contact: Cate Walsh Vockley, MS, LCGC; Phone Number: 412-692-7349; Email: Catherine.WalshVockley@chp.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 100 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Families of Amish/Mennonite background which include at least one individual with a clinical phenotype and a pedigree suggestive of genetic disease will be considered for the undiagnosed disease portion of the study. Initial outreach will be to Plain Communities in western Pennsylvania, but all Pain Community members are eligible as long as they have been evaluated by a local clinical geneticist. Any individual (and their family members) from the Plain Community is eligible for the population based studies of founder effects and genetic drift.

Description

Inclusion Criteria:

• Any person of Amish or Mennonite descent

Exclusion Criteria:

• Individuals who are not of Amish or Mennonite descent

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exome and genome sequencing results for clinical diagnosis in participants.	Each participant will be sequenced and DNA data will be analyzed for gene mutations consistent with the clinical symptomatology	Within approximately one year for each participant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exome and genome sequence results for population genetic studies	Exome and genome sequencing will be used to evaluate genetic changes in specific communities within the Amish and Mennonite communities. These changes/differences will be compared among the groups to show how population migration and new genetic mutations effect the burden of genetic disease in these populations.	Through study completion, approximately 5 years

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: Horizon Pharma USA, Inc.
• Investigators: Principal Investigator: Lina Ghaloul Gonzalez, MD, University of Pittsburgh

Publications and helpful links

General Publications

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• Saunders CJ, Miller NA, Soden SE, Dinwiddie DL, Noll A, Alnadi NA, Andraws N, Patterson ML, Krivohlavek LA, Fellis J, Humphray S, Saffrey P, Kingsbury Z, Weir JC, Betley J, Grocock RJ, Margulies EH, Farrow EG, Artman M, Safina NP, Petrikin JE, Hall KP, Kingsmore SF. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med. 2012 Oct 3;4(154):154ra135. doi: 10.1126/scitranslmed.3004041.
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Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2030

Study Registration Dates

• First Submitted: September 22, 2016
• First Submitted That Met QC Criteria: October 5, 2016
• First Posted (Estimated): October 6, 2016

Study Record Updates

• Last Update Posted (Estimated): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Undiagnosed Diseases
• Other Study ID Numbers: PRO15110344

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Results relevant to the participant's clinical condition will be verified in a CLIA-certified laboratory and reported to the participant.

Drug and device information, study documents

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