Genetics Technology:Next Generation Sequencing in
Clinical Practice
Dr Yvonne Wallis FRCPathPrincipal Clinical Scientist
Head of Familial Cancer Services/Head of Research, Academic and Service Developments
West Midlands Regional Genetics Laboratory
Healthcare Science Making an Impact in the New NHS9th November 2012
Next Generation Sequencing: a technology worth getting excited about
Landmarks in Genetics
1866 1953 1977 1983 2001 2005 2012
Mendel publishes work on
inheritance
The structure of
DNA is described
Sanger sequencing
first reported
Kary Mullis invented
Polymerase Chain
Reaction
Draft sequence of
human genome
Cost: $2.7 bn
Next generation sequencing
invented
Cost of sequencing
a human genome
reduced to < $10,000
The importance of DNA sequencing
Sequencing decodes DNA to produce the precise order of four component bases A, C, G and T
The order of these bases defines who and what we are now and in the future
Changes to base sequence cause disease either inherited or acquired during our lifetime
Next Generation Sequencing-a game changer
MiSeq
150,000,000 bases
2% of genome
>20,000 genes
At WMRGL Sequencing Facility
HiSeq
6,000,000,000 bases
2 whole genomes
BGI@Bham joint initiative
Capillary 2005
60,000 bases
0.002% of genome
10 genes
At WMRGL Sequencing Facility
How is NGS improving patient care?
Massively Parallel Sequencing
Reduces cost per base >1000x
Increases data throughput per run
More genes More Patients
Reducing time to diagnosisIncreasing diagnostic yield
Challenges of NGS implementation
Technology is demanding, relatively new & evolving Few standard protocols/Limited agreed best practise All new NGS workflows require significant validation
Fit for purpose Best possible quality
Specialist equipment and data storage requirements
Trained workforce: Bioinformatics skills required for data analysis Clinical interpretation of base changes
Paraganglioma and Phaeochromocytoma
9 genes
Renal Cell Carcinoma
5 genes
Colorectal Cancer
6 genes
Neonatal liver disease
6 genes
Developed NGS service panels
NGS service performance metrics
• Increasing number reported every month
• Genetic cause confirmed in 21 patients
181 reports issued in 2012 using NGS technology
Improved service for our users/patients
Previous strategy
5 genes analysed Cost = £1700 Time = 10 months
NGS strategy
9 genes analysed Cost = £500 Time = 4 months
Phaeochromocytoma gene panel
54 years
Mesenteric paraganglioma
No F/H
3 children
Next generation sequencing
screen:
RET SDHB SDHC
SDHD VHL
MAX* SDHA * SDHF2*
TMEM127*
Pathogenic mutation
identified
TMEM127* c.268G>A p.Val90Met
DNA testing now available to appropriate
family members
Case Study 1
Case Study 2
Next generation sequencing
screen
ABCB4 ABCB11 ATP8B1
NPC1 NPC2 SLC25A13
2 pathogenic mutations
identified
NPC1
c.2000C>T p.Ser667Phe
c.3182T>C p.Ile1060Thr
Diagnosis of Niemann Pick disease
Appropriate treatment
Prenatal testing available for
future pregnancies
2 weeks
Neonatal choleostasis
Diverse clinical applications of NGS in development
Inherited breast cancer gene panel
11 genes
Diseases of sexual
differentiation panel
20 genes
Genomic profiling in
acute myeloid leukaemia gene panel
59 genes
Somatic cancer-stratified medicine
gene panel
60 genes
NGS-driven landmarks in Genomic Medicine for Genetics Laboratories
2012
Gene panel screens:
Across all areas of
medicine
Whole exome sequencing:
Missing heritability
Stratified medicine
Deep sequencing for non- invasive
testing:
Prenatal diagnosis
Circulating tumour markers
Whole genome sequencing:
“One-stop shop”
2015-2020
Partnership for NGS-driven Genomic Medicine
High Quality Patient Care
Academic
CommercialNHS
NGS: Changing Healthcare
Acknowledgements• NGS Team
– Eleanor Rattenberry– Kim Reay– Kirsten McKay– Lindsey Vialard– Anna Yeung– Hayley Bair
• Head of Cancer Programme– Jennie Bell, FRCPath
• Director of WMRGL– Professor Mike Griffiths