Genetics Technology: Next Generation Sequencing in Clinical Practice

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Oct 2, 2013 (4 years and 1 month ago)

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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

9
th

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 diagnosis

Increasing 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 *
SDHF
2
*
TMEM
127
*

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

ABCB
4
ABCB
11
ATP
8
B
1
NPC
1
NPC
2
SLC
25
A
13

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

Commercial

NHS

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