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