Next Generation Sequencing: A Policy...

Next Generation

Sequencing:

A Policy Perspective

Koen Devriendt

Centre for Human Genetics

University of Leuven, Leuven, Belgium

METAFORUM Total genome analysis 25 statements

Prof. Jan Aerts (bio-informatics)

Prof. Pascal Borry (medical ethics)

Prof. Koen Devriendt (human genetics)

Prof. Kris Dierickx (medical ethics)

Prof. Gert Matthijs (human genetics)

Prof. Yves Moreau (bio-informatics)

Prof. Erik Schokkaert (economics)

Prof. Ann Swillen (educational psychology)

Prof. Hilde Van Esch (human genetics)

Mevr. Griet Verhenneman (ICT-law)

Prof. Joris Vermeesch (human genetics)

http://www.kuleuven.be/metaforum/page.php?FILE=wg_text&ID=14&TID=3&LAN=E

enthousiasm

expectations

(time) pressure

exome and genome sequencing

- hereditary risks?

- presumed causes can be disproved

- predictive test for late onset disorders

- prognosis – sometimes even personalized therapy

long term vision

rational use

priorities

ATTGTACGTGATGACCAGTGGAAT

ACCGTAAGGTAAAGTACCGTGTAC

TTGGTTGGAACGTAGACTGAATGC

CAACCCTGGTATTGGTGTCCCGTG

TACAAGGTTAGTAATGTACCATTGA

TTCCGTAATACGTGTGGCGCGTGC

GTAACACACTGACTGACCATCCTG

GTAGCTAGTCAAGTCGTAGCTGTC

GTGACGTAACGTATATGACACACG

TCAGTACGGTCAGTACACACATGC

TGTGGTGCAGTACAGATACAGTAC

AGATTAGCAGAAATGCAGATTTAGT

intelligence

height

physical strength

attractivity

variationin normalcharacteristics

personality

cleft lip and palate

obesity

cystic fibrosis

dementia

variation

in disease

Monogenic

albinism

Multifactorial

























lipverhemeltespleet

zwaarlijvigheid

mucoviscidose

dementie

variatie

in ziekten

Monogeen

albinisme

Multifactorieel

intelligentie

gestalte

Fysische kracht

attractiviteit

VARIATIE IN NORMALEKENMERKEN

persoonlijkheid

interpretation ?

statement

In the debate, it is essential to distinguish

the uninterpreted (raw) genome sequence

and interpreted genomic information.

biobank

TTGGTTGGAACGTAGACTGAATGCGACTGAATGC

CAACCCTGGTATTGGTGACTGAATGCGTCCCGTG

TACAAGGTTAGTAATGTACGACTGAATGCCATTGA

CCAGTGGAATTTCCGTAATACGTGTGGCGCGTGC

GTAACAGACTGAATGCCACTGACTGACCATCCTG

GTAGCTAGTCCCAGTGGAATAAGTCGTAGCTGTC

GTGACGACTGAATGCGTAACGTATATGACACACG

TCAGCCAGTGGAATTACGGTCAGTACACACATGC

TGTGGTGCAGGACTGAATGCTACAGATACAGTAC

AGATTAGCAGAAATGCGACTGAATGCAGATTTAGT

sequence database

statement

The (uninterpreted) genome sequence

is an annex of the medical file

with a special status of uninterpreted data.

genome sequence and

genetic testing ?

Long QT syndrome ?

LQT1

LQT2

LQT3

LQT4

LQT5

LQT6

LQT7

LQT8

LQT9

LQT10

LQT11

LQT12

LQT13





































sequence

database

LQTS?













LQT1 LQT2 LQT3

LQT4 LQT5 LQT6

LQT7 LQT8 LQT9

LQT10 LQT11 LQT12

LQT13

expert and analysis

system

clinical question

LQTS ?

LQT5medical

file

• real-time = faster and cheaper

• limited to clinically relevant information

at this moment

• avoiding too much information

- irrelevant at this moment

- not interpretable (unclassified variants)

- unwanted (incidental findings)

• when this occurs: there is a clinical context

to deal with these issues

sequence

database

LQTS?













LQT1 LQT2 LQT3

LQT4 LQT5 LQT6

LQT7 LQT8 LQT9

LQT10 LQT11 LQT12

LQT13 LQTS14 LQTS15

LQTS16

expert and analysis

system

unanswered

clinical questions

MEDICAL FOLLOW-UP

LQT15medical

file

statement

The genome sequence is preserved

thus ensuring optimal medical care

for a specific medical problem

through a continuous interpretation

of the genome sequence

based on novel insights.

“In the debate, it is essential to distinguish the uninterpreted genome

sequence from the interpreted genomic information.”

Increased medical knowledge

• uninterpreted genome sequence

= permanent, constant, static

• interpreted genome sequence

= a snapshot, changing, dynamic

=> Need to continuously

interrogate and interpret the genome sequence

during follow-up for an existing clinical problem

or in a novel clinical situation

Other questions in the course of life

sequence

database













Mutation(s)

in genes for

cleft lip and palate?

expert and analysis

system

clinical question :

• cause

• recurrence risk

• prognosis

medical

file

sequence database

clinical question :

• cause

• recurrence risk

• prognosis

medical

files













de novo mutation

in a gene

that can explain

the syndromic

presentation?

expert and analysis

system

father child mother

sequence

database

clinical question :

increased genetic risks?

medical

files













carrier for mutation(s)

in genes for

autosomal recessive

or X-linked

disorders ?

expert and analysis

system

sequence

database

clinical question

heredity?

medical

file













mutation(s) or

risk variants

in genes for

breast cancer?

expert and analysis

systemBreast cancer

Familial

sequence

database

clinical question :

prognosis, treatment …

medical

file

Breast cancer ATTGTACGTGATGACCAGTGGAAT












Which mutation(s) /

variants

in genes that

determine the type of

cancer

expert and analysis

system

statement

The genome sequence is preserved

thus ensuring optimal medical care

for a specific medical problem

through a continuous interpretation

of the genome sequence

based on novel insights.

High requirements :

•To the users

•To the expert system

• to the DNA sequence

interpretation of the DNA sequence :

- only based on validated genotype-phenotype correlations

- include all additional variables that determine the

significance of a genetic variant :

- family history

- personal history

- clinical findings

- results of other tests

…

High requirements : to the users

& expert system

gene A7

gene C38gene B1

gene J01

environment

1

environment

11

environment

9

environment

3

environment

17

environment

35

gene ZA8

gene LL4

gene E2

gene ZA2

gene O0

gene 7l

gene M81

gene Z21gene F3

gene 007

gene N45

gene II

statement

The physician can interrogate the genome sequence

only for a specific clinical question / situation

for which he is qualified

High requirements : to the users

high requirements : to the users

Statement :

Total genome analysis for minors

is only justifiable if the interests

of the minor in question

are given priority.

clinical activity

sequence

database

medical

file

high requirements : to the users

statement

The genome sequence

and genomic information

are confidential

statement

Given the fact that genetic analysis is generally only

conducted once in a person’s life,

false-positive and false-negative results may have severe

consequences.

The technology must be advanced enough on this point

before information is passed from the research to the

clinical context,

and the service should meet the highest standards of

quality.

high requirements : to the technologie

Genetic results :

• medical implications for the person himself

• implications regarding heredity ?

- genetic risks

- family members :

* carrier diagnosis

* predictive testing

* prenatal / preimplantation diagnosis

counselling in Centre for Human Genetics

interpretation of the DNA sequence

in other situations ?

information

with clinical utility,

independently from

a direct medical context or

question













sequence

database

• farmacogenetics

• risk factors for late-onset

disorders

• carrier for X-linked or

recessive conditions

• …

expert and analysis

system

?

Introduction at a population level is not straightforward:

- limited insight into the significance of many variants

(=> caution with interpretation)

- large differences in clinical utility for different diseases

(effect size of risk, prevention, severity, …)

- changing questions during life

(e.g. neonatally or at reproductive age)

- how to deal with informing family members

-…

statement

It will become possible to generate systematically

additional genomic information with clinical utility

independently from a specific medical question.

However, it is not feasible

to provide the required extensive counselling

on an individual basis

within our current public health system

* Will be realized progressively

* transfer = depending on clinical utility,

based on the acquired medical evidence

for each specific disorder.

Long term goal :

statement

In the light of the growing amount of information

there will be an increasing need for a sufficient number of

well trained professionals who are capable of interpreting the

genetic information and translating this into health measures

In additional it wil be essential to inform the general public

on the opportunities and limitations of genetic information.

Who oversees all of this ?

sequence

database

interpreted genomic information

* Clinical questions

* Additional information with clinical utility

* screening

(global) medical file

statement : the general physician ?

METAFORUM Total genome analysis 25 statements

Prof. Jan Aerts (bio-informatics)

Prof. Pascal Borry (medical ethics)

Prof. Koen Devriendt (human genetics)

Prof. Kris Dierickx (medical ethics)

Prof. Gert Matthijs (human genetics)

Prof. Yves Moreau (bio-informatics)

Prof. Erik Schokkaert (economics)

Prof. Ann Swillen (educational psychology)

Prof. Hilde Van Esch (human genetics)

Mevr. Griet Verhenneman (ICT-law)

Prof. Joris Vermeesch (human genetics)

http://www.kuleuven.be/metaforum/page.php?FILE=wg_text&ID=14&TID=3&LAN=E

Date post:	08-Aug-2020
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Next Generation Sequencing: A Policy...

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