Evaluating scientific and ethical approaches to newborn screening with whole genome sequencing using large-scale population cohorts
Lead Research Organisation:
UNIVERSITY OF EXETER
Department Name: Institute of Biomed & Clinical Science
Abstract
All babies in the UK are now screened at birth for nine treatable diseases through the newborn blood spot test. However, many more genetic conditions exist that are very rare but also treatable. In some cases, early detection and treatment shortly after birth can prevent the disease from occurring, thus offering enormous and life-long benefits to individuals, families, and society. It is now possible to sequence all the DNA from an individual (a whole genome) and determine their entire genetic makeup with just one test. This technology offers the opportunity to detect and prevent many genetic conditions at the same time. Expert groups are now working to decide which diseases and genes are suitable to screen in newborn babies using whole genome sequencing. However, one of the biggest challenges is that changes to the DNA sequence can have different effects in different people, so a change that causes disease in one family may have no effect in another. Finding genetic changes that don't cause disease in babies would be extremely distressing for parents and result in unnecessary extra work for healthcare services. We are trying to lessen this problem by looking at more than 200,000 people in the UK that have already had their genome sequenced. Some of these genomes are from healthy adults, who volunteered to help with medical research, while others are from very sick babies. We will look at genes that have been linked to treatable childhood diseases before and compare the number of types of genetic changes we find in healthy adults versus sick babies. We will also look at their hospital notes and medical records to see if they have the disease. In addition, we will survey experts and members of the public to better understand the key ethical issues relating to this kind of testing. We are particularly keen to explore attitudes towards massively increasing the number of diseases included in newborn screening, which could lead to more false positive results. This research will help decide which genes and conditions should be screened for in newborns, and which should not. By working with Genomics England and NHS England, we will work make sure that our research is used to improve health and maintain patient safety.
Technical Summary
Workstream 1: SCIENCE
1. Develop an inclusive list of genes in which variants cause treatable childhood onset monogenic conditions, including mode of inheritance and mechanism of pathogenicity.
2. Create different variant prioritisation approaches for rare deleterious sequence variants, and detect rare intragenic deletions and duplications overlapping specific disease genes
3. Determine the number of variants that will be prioritised in individual genes and across the gene panel using different variant filtering approaches in two contrasting cohorts: first, a population cohort of 500,000 relatively healthy older adults (UK Biobank) and, second, a growing patient cohort of several thousand acutely ill babies (NHS R14 test).
4. Determine the pathogenicity of prioritised variants using hospital records and relevant biomarker data, and estimate the sensitivity/specificity of different approaches
Workstream 2: ETHICS
1. Investigate key ethical issues in newborn genome screening using genome sequencing.
2. Conduct a programme of qualitative longitudinal research with parents, future parents and health care professionals to explore their experiences and perspectives of newborn screening, and the factors that influence how these might change over time.
3. Develop and pilot a quantitative survey to elicit attitudes and opinions of the public to clinical validity (i.e. the potential for massively expanded screening to increase the number of false positives).
4. Commission and analyse a survey of ~10,000 representative members of the public to evaluate attitudes towards screening using newborn genome sequencing.
Workstream 3: ADVICE
Advise on approaches for disease-gene inclusion and variant filtering, particularly through a close partnership with Genomics England and the NHS Newborn Conditions Framework Working Group, plus wider dissemination and outreach.
1. Develop an inclusive list of genes in which variants cause treatable childhood onset monogenic conditions, including mode of inheritance and mechanism of pathogenicity.
2. Create different variant prioritisation approaches for rare deleterious sequence variants, and detect rare intragenic deletions and duplications overlapping specific disease genes
3. Determine the number of variants that will be prioritised in individual genes and across the gene panel using different variant filtering approaches in two contrasting cohorts: first, a population cohort of 500,000 relatively healthy older adults (UK Biobank) and, second, a growing patient cohort of several thousand acutely ill babies (NHS R14 test).
4. Determine the pathogenicity of prioritised variants using hospital records and relevant biomarker data, and estimate the sensitivity/specificity of different approaches
Workstream 2: ETHICS
1. Investigate key ethical issues in newborn genome screening using genome sequencing.
2. Conduct a programme of qualitative longitudinal research with parents, future parents and health care professionals to explore their experiences and perspectives of newborn screening, and the factors that influence how these might change over time.
3. Develop and pilot a quantitative survey to elicit attitudes and opinions of the public to clinical validity (i.e. the potential for massively expanded screening to increase the number of false positives).
4. Commission and analyse a survey of ~10,000 representative members of the public to evaluate attitudes towards screening using newborn genome sequencing.
Workstream 3: ADVICE
Advise on approaches for disease-gene inclusion and variant filtering, particularly through a close partnership with Genomics England and the NHS Newborn Conditions Framework Working Group, plus wider dissemination and outreach.
