Gene Mutations and Orthopaedic Symptoms Correlation of Multiple Hereditary Exostoses: Multicentre Project

May 16, 2022 updated by: Christine Alvarez, University of British Columbia

Genotype-Phenotype Correlation of Multiple Hereditary Exostoses: Multicentre Project

The investigator's goal for this project is to examine the causes of the wide variability of the expression of Hereditary Multiple Exostoses (HME). Previous work completed by our group shows that there exists a correlation between genotype and phenotype such that certain mutations or affected genes cause certain patterns of presentation, symptoms, and signs. The investigators intend to achieve this goal by increasing our study sample size to build upon the results generated from the pilot project of this study, in order to obtain statistical significance. This will be achieved by performing genotype-phenotype analysis on new families presenting with HME in British Columbia.

Study Overview

Status

Suspended

Conditions

Detailed Description

Subject Recruitment:

New patients presenting with HME will be identified through the offices and clinics of British Columbia Children's Hospital Orthopaedic Department. All potential participants will be educated about the study's rationale, purpose, and procedures and informed consent will be obtained.

Demographics:

All probands (affected patient), their first degree family members and extended family members willing to participate in the study will be interviewed. Information including age, gender, ethnic origin, family history, symptoms, complications and previous surgery will be elucidated.

Phenotype:

Affected patients will have their osteochondroma(s) mapped for location, size, morphology, and symptoms. A total of seventy-five phenotypic parameters divided into four major data categories will be collected. The first two categories are accumulated from physical examinations and include stature and limb segment lengths (15 (x2 for left and right). The other two categories, lesion quality (19 parameters) and limb alignment and deformity (26 parameters) will be drawn from radiographic examinations which are part of the patient's current care. All available xrays will be reviewed and the exostoses characterized radiographically. This will establish the patient's genotype.

Genotype:

Each participant whose genotype is unknown will have a 10 cc. blood sample collected at BC Children's Hospital. This sample will be processed for mutation analysis (DNA extraction from blood samples, mutation analysis) at the Clinical Molecular Diagnostic Laboratory at BC Children's Hospital. The techniques used in the pilot study will be implemented with the exception that microsatellite markers will not be used in order to save cost.

Using EXT 1 and EXT 2 primers (Appendix 1) both strands of a DNA segment are sequenced using ABI Big Dye chemistry Version 2. The resulting sequencing reaction products are then run on an ABI 3100 Avant genetic analyzer. Once a sequence is obtained it is analyzed with SeqScape version 2 software which allows comparison with reference sequence.

Data Analysis:

All information resulting from this research study will be kept strictly confidential. All documents will be identified by an ID number and kept in locked filing cabinets. Participants will not be identified by name in any reports of the completed study. Databases will be stored on project-dedicated laptop computer which is locked in the research office.

The phenotypic data collected will be used to describe family degrees (designed using Cyrillic software), phenotypes of affected individuals and mutations in the exostoses genes of interest (site and type of mutation). Subject heights and segment lengths will be converted to percentile figures to standardize for age and gender to allow for comparison amongst groups.

Genotypic data from the mutation analysis of blood samples will include location of the mutation (early in the gene versus late in the gene), type of mutation (alteration of gene as missense, frameshift, nonsense or splice site), and the amino acid change that was caused by the mutation. The data will be analyzed as follows:

Preliminary Analysis

  1. EXT 1 versus EXT 2
  2. Males versus Females

  3. EXT 1 males versus EXT 1 females versus EXT 2 males versus EXT 2 females

    Secondary Analysis

  4. Types of mutations (Missense versus Nonsense versus Splice site versus Frameshift)
  5. Early or late mutation (less than 1700 base pairs versus greater than 1700 base pairs)

With 2-way analyses, an unpaired t-test will be calculated and with greater than 2-way analyses, an ANOVA will be calculated. Power will be calculated for every comparison due to the huge variation in sample size. Statistical significance will be set to prior at 0.05 and power of 0.8.

Study Type

Observational

Enrollment (Anticipated)

2000

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V6H 3V4
        • BC Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

New patients presenting with HME will be identified through the offices and clinics of British Columbia Children's Hospital Orthopaedic Department.

Description

Inclusion Criteria:

  • Diagnosed with HME

Exclusion Criteria

  • Subjects residing outside British Columbia for whom genetic testing and X-ray measurements cannot be taken onsite at BC Children's hospital

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only
  • Time Perspectives: Retrospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
orthopedic symptoms as assessed by X-ray measurements
Time Frame: Post gene mutation identification
Post gene mutation identification

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of British Columbia

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2004

Primary Completion (Anticipated)

June 1, 2023

Study Completion (Anticipated)

June 1, 2023

Study Registration Dates

First Submitted

May 14, 2007

First Submitted That Met QC Criteria

May 15, 2007

First Posted (Estimate)

May 16, 2007

Study Record Updates

Last Update Posted (Actual)

May 18, 2022

Last Update Submitted That Met QC Criteria

May 16, 2022

Last Verified

May 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H04-70223

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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