Ciliopathies in the 10 0 ,0 0 0 Genom es Project Dr Gabrielle - - PowerPoint PPT Presentation

▶

Jan 16, 2023 251 likes •609 views

Ciliopathies in the 10 0 ,0 0 0 Genom es Project Dr Gabrielle Wheway Lecturer in Functional Genomics University of Southampton g.wheway@soton.ac.uk A T C G G C A T ..... 3.2 billion bases.... ...across 23 pairs of

SLIDE 1

Ciliopathies in the 10 0 ,0 0 0 Genom es Project

Dr Gabrielle Wheway Lecturer in Functional Genomics University of Southampton g.wheway@soton.ac.uk

SLIDE 2

A T C G T G C A

… ..... 3.2 billion bases....

SLIDE 3

...across 23 pairs of chromosomes... ...2m DNA per cell

SLIDE 4

If you read one letter per second for 24 hours a day it would take you… … 100 years!

SLIDE 5

A T C G A T C G 4.5 million per person VARIANT Normal variation Disease

Inherited genetic diseases Cancers

G A

SLIDE 6

pre-mRNA GENE exon exon exon mRNA EXOME 2% of the genome

SLIDE 7

Cilia

SLIDE 8

Ciliopathies

SLIDE 9

SLIDE 10

SLIDE 11

1996 – 2003
7 years
£2 billion

Human Genome Project

SLIDE 12

2008 - Advent of next generation sequencing >$100 million <$1000

2003: Hum an Genom e Project complete

1 healthy human genome 13 years £ 2 billion

It now takes 2 days and less than £ 10 0 0 to sequence an entire human

The cost of sequencing a genome

SLIDE 13

https://www.genomicsengland.co.uk/

SLIDE 14

100,000 Genomes project

SLIDE 15

13 GMCs 85 NHS Trusts

SLIDE 16

Genome samples

Recruitment closed September 2018 Recruitment closed January 2019

SLIDE 17

SLIDE 18

The pipeline

Recruitment closed September 2018/ January 2019 Generally, patients who have had known disease genes excluded Education

SLIDE 19

Neurology and neurodevelopm e ntal disorders 39% Cardiovascular disorders 11% Renal and urinary tract disorders 10 % Ophthalm ologic al disorders 8 % Ultra-rare disorders 6% Tum our syndrom es 5% Ciliopathies 1%

ther

18 %

Rare disease groups recruited

Correct at 28.2.19

SLIDE 20

Ciliopathy patients recruited

Congenital malformations caused by ciliopathies:

Bardet-Biedl Syndrome: 30 probands (54

individuals in total)

Joubert syndrome: 8 probands (14 individuals

in total)

Rare multisystem ciliopathy disorders: 14

probands (23 individuals in total)

Respiratory ciliopathies

Primary ciliary dyskinesia: 34 probands (138

individuals in total)

Non-CF bronchiectasis: 93 probands (163

individuals in total)

28.2.19 data release

SLIDE 21

Disease spectrum in ciliopathies

… likely to be many undiagnosed ciliopathy patients in other groups

SLIDE 22

‘Hidden’ ciliopathy patients (?) recruited

Cystic kidney disease: 24 4 probands (1573 total) Ultra rare undescribed monogenic disorders (1740 total) Rod-cone dystrophy (1265 total) Rod dysfunction syndrome 75 Cone dysfunction syndrome 70 LCA/ EOSRD 143 Isomerism and laterality disorders: 13 probands Thoracic dystrophies 9 Unexplained skeletal dysplasias 308 Unexplained monogenic fetal disorders 27 Obesity syndromes 110 28.2.19 data release

SLIDE 23

The pipeline cont.

Education

SLIDE 24

Interpretation – filtering variants

~4.5 million variants Exclude common variants Exclude variants which are both present in Mum OR both present in Dad Exclude variants if there is only

ne variant

in the gene in the patient Fewer variants – look at which of these have been linked to disease before

SLIDE 25

Interpretation – known disease genes

‘Panels’ of relevant disease genes

SLIDE 26

The pipeline cont.

Within your local GMC Education

6. Research

SLIDE 27

What if a genetic diagnosis can’t be made immediately?

Example: Rare multisystem ciliopathies - 23 individuals recruited, including 14

affected individuals

4 variants definitely capable of causing disease
34 variants likely to be capable of causing disease
2393 variants possibly capable of causing disease

Research by clinical interpretation partnerships

SLIDE 28

pre-mRNA mRNA

SLIDE 29

pre-mRNA mRNA

SLIDE 30

pre-mRNA mRNA

SLIDE 31

SLIDE 32

The future

Future diagnoses for patients who have had whole

genome testing

TIMELINE UNCLEAR
Whole genome sequencing frontline diagnostic test for
Cystic kidney disease
Ultra-rare and atypical monogenic disorders
Congenital malformation and dysmorphism syndromes - likely

monogenic

Moderate, severe or profound intellectual disability
Skeletal dysplasia
And 17 other conditions
Whole exome sequencing frontline diagnostic test for
Bardet-Biedl syndrome
Retinal disorders
Respiratory ciliopathies including non-CF bronchiectasis
Laterality disorders and isomerism
And 57 other conditions

SLIDE 33

Further information

https:/ / www.genomicseducation.hee.nhs.uk/ resources/ videos/

SLIDE 34

Transforming personalised diagnosis and treatment MSc Genomic Medicine University of Southampton

We need you! Seeking public and patient involvem ent in the revalidation

f our MSc Genom ic Medicine

at University of Southam pton