Whole genome sequencing Flashcards
(15 cards)
What is a human genome?
A genome is a complete set of genetic instructions. Each genome contains all of the information needed to allow you to grow and develop.
- most cells in the human body have a
complete set genes - it’s a while set of genes plus all the DNA
between your genes - there are around 20,000 genes in your
genome
Why do we want to study it?
Looking at the whole genome will help us understand how disease develops and which treatments will be most effective
80% of rare diseases are genomic
Around 40,000 people with cancer and rare diseases will take part in the project
Over 330,000 new cases of cancer reported every year and growing
Genetics vs genomics
Genetic testing = single genes or panels
E.g mutation in Ccdc78/ C16orf25
Disease = congenital myopathy
Exome = all coding (genes)
Genome = all coding and non coding
Targeted exome/ genome = phenotype-related genes
Whole genome sequencing:
Advantages
Ability to identify more variants
- in known gene
- in new genes
- in regulatory regions
WGS is cheaper and quicker than serial Sanger
- however, the analysis is time consuming
All sequence information available
- aerial analysis without additional sequencing
Whole genome sequencing:
Potential pitfalls
May detect variants of unknown significance (VoUS)
Incidental or additional findings
- mutation with no family history - what to
do ?
- mutation in gene with reduced penetrance
- non-treatable conditions
Exome/ genome in disease
Estimated 50% of children who receive gene testing due to developmental delay/syndromic features do not receive a diagnosis- ~ 6000 children
Pharmacogenetics/ genomics: targeted medication, examples in cancer (BRAF melanoma, KRAS colon cancer, HER2+ Breast cancer) and HIV
Importance of diagnosis
Patient care
- treatment
- prognosis
- screening
- palliative care
A name ‘helps’
- explain to family
- understanding ‘why’
Recurrence risk
Avoids additional investigation
Exome sequencing
Available on the NHS
- cost variable ~ £800-£2000
Variable TAT
- best case probably three weeks
- usually much longer
Whole exome/ genome sequencing
WES
- cheaper
- majority of disease causing variants will be
in the exome
- less analysis time required
- highly variable coverage
WGS
- capture info on all genome (future proof)
- more reliable sequence coverage
- limited ability to interpret
Genomics in NHS
100,000 genome project announced in 2012
Aims:
- investigate rare/ inherited diseases and common cancers
- establish world leading genomics services
- develop partnership with world-leading genomics services
- simulate the development of diagnostic, devices, medicines and treatments based on a new understanding of the genetic and molecular basis of disease
- hybrid diagnostic research project
• clinical results for families
• creating a research database - paired genomic and healthcare data
• GP, hospital and social care
• ongoing prices up till and after death unless withdrawn - aim to sequence 100,000 genomes
• 50,000 rare disease families (proband and parents)
• 50,000 cancer patients (proband and tumour)
Why is it important to patients?
They could potential find out why they have a certain condition
Enables them to plan for the future
Families/ relatives will be informed of risks
Pathway
Referral ( with eligibility category)
Invite family and give PIS
Contact family to arrange appointment
Receive consent and take blood samples
Registered on GENIE
Phenotyping competed on GENIE
DNA extracted and quality checked
Sent to Genomics England
(ALL LIST CONDUCTED IN ORDER)
FOLLOWING:
- Genome sequencing
- Cambridge - Variant calling
- identifying changes compared to reference sequence - Annotation
- identify which changes are likely (and not likely) to be related to the condition based on population data and disease gene database - Feedback to clinical team
- lists of likely and non likely results to be assessed based on clinical and patient knowledge (MDT)
Results of testing
Main genetic findings
- results related to main phenotypes
- currently estimating 1-2 years
- feed back to UCLH clinicians
Additional health related findings -adults and children
- serious but actionable
- bowel, breast , ovarian and other cancers
- familial hypercholesterolaemia
Additional reproductive findings - adults only
- cystic fibrosis
————————————————————-
Results beginning to be returned
MDTs set up across the GMC
Significant impact on patients:
“ when they said they had found something it was one of the biggest days of my life”
Genomic medicine service
Build on the legacy of the 100,000 genomes project
Deliver high throughput, high quality rapid testing, including whole genome sequencing
Based on a National test directory for rare and inherited diseases and somatic cancer testing
Embed genomic testing in mainstream medicine
Ensure comprehensive and equitable access to genomic testing for the e ntire population
- clinicians are able to directly order WGS for eligible patients
- fresh blood sales are taken or stored DNA can be used
- members of clinical team obtain informed consent after explaining the process to the patients
- a record of discussion must be completed for each patient/ family member being treated
- a WGS request form is also completed and sent to the lab
- samples are provided at the regional labs before being sent for sequencing
-turn around times at the moment are approximately 6 months - once results are analysed they are then discussed at MDT’s before results are released to the patient by clinicians’s, CNS or genetic counsellors.
