1. Genetics Technology: Next Generation Sequencing in Clinical Practice
Dr Yvonne Wallis FRCPath
Principal 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 NHS
9th November 2012

2. Next Generation Sequencing: a technology worth getting excited about
Estimated 100 trillion cells in human body

3. Next generation sequencing invented
Landmarks in Genetics
Sanger sequencing first reported
Draft sequence of human genome Cost: $2.7 bn
Mendel publishes work on inheritance
Cost of sequencing a human genome reduced to < $10,000
1866
1953
1977
1983
2001
2005
2012
The structure of DNA is described
Kary Mullis invented Polymerase Chain Reaction
Next generation sequencing invented
300,000th of the price

4. 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

5. Next Generation Sequencing-a game changer
Capillary 2005
60,000 bases
0.002% of genome
10 genes
MiSeq
150,000,000 bases
2% of genome
>20,000 genes
At WMRGL
Sequencing Facility
HiSeq
6,000,000,000 bases
2 whole genomes
joint initiative
At WMRGL
Sequencing Facility

6. How is NGS improving patient care?
Massively Parallel Sequencing
Reduces cost per base >1000x
Increases data throughput per run
More genes More Patients
Increasing diagnostic yield
Reducing time to diagnosis

7. 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

8. Developed NGS service panels
Paraganglioma and Phaeochromocytoma
9 genes
Renal Cell Carcinoma
5 genes
Colorectal Cancer
6 genes
Neonatal liver disease

9. NGS service performance metrics
181 reports issued in 2012 using NGS technology
Increasing number reported every month
Genetic cause confirmed in 21 patients

10. Improved service for our users/patients
Phaeochromocytoma gene panel
Previous strategy
NGS strategy
5 genes analysed
Cost = £1700
Time = 10 months
9 genes analysed
Cost = £500
Time = 4 months

11. Case Study 1 Next generation sequencing screen:
RET SDHB SDHC SDHD VHL
MAX* SDHA * SDHF2* TMEM127*
DNA testing now available to appropriate family members
Pathogenic mutation identified
TMEM127* c.268G>A p.Val90Met
54 years
Mesenteric paraganglioma
No F/H
3 children

12. Case Study 2 Next generation sequencing screen
ABCB4 ABCB11 ATP8B1 NPC1 NPC2 SLC25A13
2 weeks
Neonatal choleostasis
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

13. 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

14. NGS-driven landmarks in Genomic Medicine for Genetics Laboratories
Whole exome sequencing:
Missing heritability
Stratified medicine
Gene panel screens:
Across all areas of medicine
2012
300,000th of the price
Deep sequencing for non- invasive testing:
Prenatal diagnosis
Circulating tumour markers
Whole genome sequencing:
“One-stop shop”

15. Partnership for NGS-driven Genomic Medicine
High Quality Patient Care
Academic
Commercial
NHS

16. NGS: Changing Healthcare

17. Acknowledgements NGS Team Head of Cancer Programme Director of WMRGL
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