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 chromosomes... ...2m DNA per cell
If you read one letter per second for 24 hours a day it would take you… … 100 years!
A A C C G G T T A G VARIANT 4.5 million per person Normal Disease variation Inherited genetic Cancers diseases
GENE exon exon exon EXOME 2% of the genome pre-mRNA mRNA
Cilia
Ciliopathies
Human Genome Project • 1996 – 2003 • 7 years • £2 billion
The cost of sequencing a genome 2008 - Advent of next generation sequencing >$100 million <$1000 It now takes 2 days and less than 2003: Hum an Genom e Project complete £ 10 0 0 to sequence 1 healthy human genome 13 years an entire human £ 2 billion
https://www.genomicsengland.co.uk/
100,000 Genomes project
13 GMCs 85 NHS Trusts
Genome samples Recruitment closed September 2018 Recruitment closed January 2019
The pipeline Generally, patients who have had known disease genes excluded Education Recruitment closed September 2018/ January 2019
Rare disease groups recruited other 18 % Ciliopathies Neurology and 1% neurodevelopm e ntal disorders Tum our 39% syndrom es 5% Ultra-rare disorders 6% Ophthalm ologic al disorders 8 % Renal and urinary tract Cardiovascular disorders disorders 10 % 11% Correct at 28.2.19
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
Disease spectrum in ciliopathies … likely to be many undiagnosed ciliopathy patients in other groups
‘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
The pipeline cont. Education
Interpretation – filtering variants ~4.5 million variants Exclude common Exclude variants if variants there is only one variant Exclude in the gene variants in the which are patient both present in Mum OR both present in Dad Fewer variants – look at which of these have been linked to disease before
Interpretation – known disease genes ‘Panels’ of relevant disease genes
The pipeline cont. 6. Research Education Within your local GMC
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
pre-mRNA mRNA
pre-mRNA mRNA
pre-mRNA mRNA
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 •
Further information https:/ / www.genomicseducation.hee.nhs.uk/ resources/ videos/
Transforming personalised diagnosis and treatment We need you! MSc Genomic Medicine University of Southampton Seeking public and patient involvem ent in the revalidation of our MSc Genom ic Medicine at University of Southam pton Contact us Tel: +44 (0)23 8120 5063 Email: genomicmedicine@soton.ac.uk
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