Investigating the Role of Genetics in Disease Predisposition

September 2, 2024 updated by: The Wellcome Sanger Institute

Investigating Clonal Dynamics in Gonads and Their Role in Disease Predisposition

Gametogenesis is the production of sperm and eggs; it takes place through the process of meiosis. Gametogenesis is subject to the acquisition of mutations as with other processes in the body. Many of these mutations are somatic, meaning that they occur during life as part of the process of cell division rather than being passed down from parents. When somatic mutations take place during gametogenesis, there is the potential for hereditary genetic consequences. However, the processes that cause the mutations during gametogenesis and the implications they have for heritability and disease predisposition are poorly understood.

The goal of this research is to provide a detailed description of the genetic changes in gonadal tissues, and to understand how mutations acquired during the production of germ cells (sperm and eggs) contribute to the predisposition to a wide range of rare diseases and cancer predisposition in future offspring.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Enrolling by invitation

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Detailed Description

Predisposition to rare disorders and cancers can arise due to mutations (changes in DNA) of sperm cells from father and/or eggs from mother. De novo mutations are genetic alterations that are present for the first time in one family member as a result of a variant (or mutation) in a germ cell (egg or sperm) of one of the parents, or a variant that arises in the fertilized egg itself during early embryogenesis.

Current knowledge about how changes in the sperm and eggs of parents can be inherited by children, is based on genetic sequence analysis of blood from nuclear families. This involved comparison of the changes in DNA of children with that of their parents. Changes that are not present in the blood of parents are likely to have occurred in the sperm and egg of the father and mother.

Whilst studying the nuclear family is very useful in order to look at the level of diversity, it will only allow the investigators to study a small number of germ cells making it difficult to ascertain the overall level of diversity that is shown in the sperm and eggs of fathers and mothers. There is also little knowledge of how different factors such as ageing, smoking, BMI and exposure to carcinogens might affect the germ cells of adults and since changes in sperm and eggs can be transmitted to children, it is important to understand how disease causing mutations arise in reproductive tissues. Thus, how such changes can predispose children to rare disorders and cancer predisposition syndromes.

Previous studies have shown that the FGFR3 gene accumulates more mutations in normal testes during the natural ageing process which leads to the relative enrichment of mutated sperm over time. In rare cases, it can lead to testicular cancer (spermatocytic seminomas) in older men, but also it increases the likelihood of having children with Achondroplasia, which is caused by mutations in the FGFR3 gene in the sperm of the father.

Hence, the investigators aim is to determine the effect of different factors on the recurrence risk of pathogenic (disease causing) mutations in eggs and sperm.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
1000

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Children diagnosed with disease predisposition syndromes and/or cancer and their family members (mother, father, siblings)

We may also include the wider family (maternal/paternal aunts, uncles and grandparents)

Recruitment and the sequencing of both prospectively collected samples and those retrospectively collected from tissue banks will run for the first four years of the study.

Description

Inclusion criteria:

  • Minimum of child affected with cancer pre-disposition syndromes and their father
  • Additional family members of consented father and child duos (Mother, same parent siblings, Maternal/Paternal Aunts, uncles and grandparents of affected child)
  • Reproductive tissue samples from both men and women affected by cancer collected with consent for use in research.
  • Reproductive tissue samples from both men and women unaffected by cancer collected with consent for use in research.

Exclusion:

  • Fathers who do not wish to donate a semen sample or are unable to will be excluded from the study, as will their families
  • Fathers who have had a vasectomy will be excluded from the study as will their families
  • Adults who do not have the capacity to consent for themselves will be excluded from the study.
  • Families in which both parents do not have capacity to consent will also be excluded as they will be unable to give parental consent for their children's participation.
  • In order to be eligible siblings must share the same two parents as the affected child, all other siblings will be excluded from the study.
  • Male relatives in the extended family (Maternal/Paternal Aunts, uncles and grandparents of affected child) unwilling or unable to donate both a blood or saliva sample and a semen sample will be excluded from the study.
  • Participants who do not have a good understanding of the English language will be excluded from the study.

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

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
How often mutations accumulate in healthy reproductive tissues
Time Frame: 7 years
Establish how often mutations (changes in DNA) accumulate in healthy reproductive tissues (testes and ovaries).
7 years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Identification and Characterisation of Mutations
Time Frame: 7 years
Determine the genetic changes in gonadal tissues, including the frequency, type, and nature of mutations acquired during germ cell production, and identify the genes and cellular processes that these mutations may alter.
7 years
Comparative Analysis of Mutation Rates
Time Frame: 7 years
Compare mutation rates in gonadal tissues across different age groups, sexes, and individuals with or without cancer predisposition syndromes.
7 years
Inheritance and Transmission Risk
Time Frame: 7 years
Assess the inheritance risk and rate of transmission of pathogenic mutations by analysing the proportion of germ cells carrying these mutations in affected individuals and comparing them to unaffected donors.
7 years

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
The Wellcome Sanger Institute

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 (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 20, 2021

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 1, 2027

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 1, 2027

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 4, 2024

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 2, 2024

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 5, 2024

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 5, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 2, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 273194

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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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