Investigating the Role of Genetics in Disease Predisposition

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: Enrolling by invitation
• Conditions: Cancer; Fertility Disorders; Mutation; Predisposition, Genetic

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: Observational
• Enrollment (Estimated): 1000

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
How often mutations accumulate in healthy reproductive tissues	Establish how often mutations (changes in DNA) accumulate in healthy reproductive tissues (testes and ovaries).	7 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification and Characterisation of Mutations	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	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	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

• Sponsor: The Wellcome Sanger Institute

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2021
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: July 4, 2024
• First Submitted That Met QC Criteria: September 2, 2024
• First Posted (Estimated): September 5, 2024

Study Record Updates

• Last Update Posted (Estimated): September 5, 2024
• Last Update Submitted That Met QC Criteria: September 2, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Disease Susceptibility; Genetic Predisposition to Disease
• Other Study ID 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