The rise of Genomics The rise of machines Types of genetic testing - PowerPoint PPT Presentation

Dr Julian Barwell Dr Pradeep Vasudevan Consultants in Clinical Genetics at the University Hospitals of Leicester and Honorary Professors in Genomics Medicine at the University of Leicester jgb8@le.ac.uk The Dawn of Genomic Medicine and Personalised Medicine Leicester Medical Society March 2019

The rise of Genomics The rise of machines Types of genetic testing Variant Triage Analysis Population stratification Ethical problems in counselling Precision Medicine

Aberdeen Inverness Belfast Leeds Birmingham Leicester Bristol Liverpool Cambridge London Cardiff Manchester Dublin Newcastle Dundee Nottingham Edinburgh Oxford Exeter Sheffield Glasgow Southampton 40 years for post code internationally http://www.con contexo xo.inf nfo/DNA_B NA_Bas asics/ cs/Me Meiosis. sis.htm 2 months lost per kilo overweight What’s more important -your DNA code or post code? 7 years lost per packet per day DNA code currently wins in less than 5% 20% variation in life-span inherited Sanitation and immunisations key

Is our role of making a diagnosis changing? Jo Lowry, GMC Project Manager

Who has a right to know? CRC CRC (STK11) Concern about paternity.

Genethics Club Genomics Pradeep Vasudevan HoD Vanita Jivanji Matron Jo Lowry Julian Barwell Claire Curtis Luke, Rachel Emily Craft Beckie Kaemba Judith, Sandra Huw Dorkins Penny Van Besouw Patricia, Patrina Shirley Hodgson Shanta Patel Terry, Lauren Corrina Powell SpR Neeta Lakhani

Computer modelling and mendelian risk http://ccge.medschl.cam.ac.uk/boadicea/ Can the machine beat the human in calculating risk?

Pedigree showing bilateral breast cancer, male breast cancer and prostate cancer, which are Classic BRCA1 pedigree common in BRCA2.

3,2,1 score: Action: Rory O’Sullivan 1. Missed opportunity: Refer 2. Refer 3. Seek advice 4. Do not refer: Relatives seek advice 5. Do not refer: Referral not indicated

3,2,1 score: Action: 1. Missed opportunity: Refer 2. Refer 3. Seek advice 4. Do not refer: Relatives seek advice 5. Do not refer: Referral not indicated

3,2,1 score: Action: 1. Missed opportunity: Refer 2. Refer 3. Seek advice 4. Do not refer: Relatives seek advice 5. Do not refer: Referral not indicated

3,2,1 score: Action: 1. Missed opportunity: Refer 2. Refer 3. Seek advice 4. Do not refer: Relatives seek advice 5. Do not refer: Referral not indicated

Jo Lowry, GMC Project Manager

Genetic Testing in Phaeos

DDD: Progress Update DDD Collaborators’ Meeting, Glasgow 5 th June 2015

Highlights of DDD

Prevalence of severe dominant disorders Based on 4,300 families from the DDD study • • Estimate 1/300 pregnancies carry new, pathogenic mutation – >500 genes associated – Only know gene for ~60% of these disorders – Many not visible by ultrasound (e.g. severe intellectual disability) • Equivalent burden to trisomies – Doesn’t include recessive disorders – Single gene disorder burden > trisomy burden Can we identify subset at high risk? • – Neither parent affected – Pre-conception testing is uninformative Nature, January 2017

Increasing parental age, more mutations, increased risk 75-80% of de novo mutations come from Dad D E 3.0 3.0 high confidence mutations (n) high confidence mutations (n) 2.5 2.5 2.0 2.0 1.5 1.5 1.5 (1.1-2.0) DNMs/genome/year 0.9 (0.3-1.4) DNMs/genome/year 20 25 30 35 40 20 30 40 50 p) Mother's age (years) Father's age (years)

Estimated age-dependent birth prevalence Density Paternal age (years) 0.00 0.03 0.06 20 25 30 35 40 45 Prevalence (%) 20 UK 0.45 0.24 0.26 0.28 0.29 0.31 0.33 0.35 0.37 0.39 DDD 0.25 0.27 0.29 0.31 0.32 0.34 0.36 0.38 0.40 25 0.40 Maternal age (years) 0.26 0.28 0.30 0.32 0.34 0.35 0.37 0.39 0.41 0.35 30 0.27 0.29 0.31 0.33 0.35 0.36 0.38 0.40 0.42 0.28 0.30 0.32 0.34 0.36 0.38 0.39 0.41 0.43 0.30 35 0.29 0.31 0.33 0.35 0.37 0.39 0.40 0.42 0.44 0.25 0.30 0.32 0.34 0.36 0.38 0.40 0.42 0.43 0.45 40 0.31 0.33 0.35 0.37 0.39 0.41 0.43 0.45 0.46 45 0.32 0.34 0.36 0.38 0.40 0.42 0.44 0.46 0.47 0.00 Density Globally: ~400,000 born/year 0.03 UK DDD Nature, January 2017 0.06

Every conception is a lottery 1/1,400 eggs contains a pathogenic de novo mutation 1/400 sperm contains a pathogenic de novo mutation

100,000 genomes project Sir John Chisholm, Professor Mark Caulfield, Professor Sue Hill OBE and Tom Fowler

Discussion Points: Potential patients in the 100.000 Genome Project - Integrated EPR, stored for life, for use in healthcare. - Anonymised and data protected. Data Storage - Patient agrees to allow viewing of unidentifiable data with researchers and approved companies but the data cannot be taken off the database. - Patient may be contacted by future research projects (participation optional). - Uses whole genome sequencing and is the best chance of identifying a causative mutation. Finding no mutation does not exclude an inherited link. Testing - Not NHS diagnostic lab grade testing and results will need NHS lab confirmation. - Need to confirm any findings through appropriate clinical and molecular investigations. - Patient can withdraw at any time. - Incidental findings are OPTIONAL and include; - Additional Findings (Table 1), Carrier status if both parents agree-mother only required if Incidental X-linked (Table 2). This list is likely to change through the project. Findings - May not detect all mutations with this technology e.g. SMA and thalassaemia - Need to confirm any findings through appropriate clinical investigations. - Findings of unknown clinical significance will not be reported. - Any findings from 100,000 Genome project DO NOT need to be disclosed to insurer - Disclosure is not required if confirmed with NHS molecular testing - Is disclosure required if confirmed with NHS clinical investigations i.e. if have a disease? Yes Insurance - Need to disclose: Strong Family History, Medical investigations and Medical Treatment - Diagnostic findings may affect ALL types of Insurance - Predictive findings may affect: Life, Critical Illness, Income protection insurances, ONLY.

Table 1: Additional Findings Table 2: Carrier Testing Adult onset: Autosomal recessive conditions (both parents will be tested for these): – Hereditary non-polyposis colorectal − cancer / Lynch-syndrome Sickle Cell Anaemia – − MYH-Associated Polyposis Cystic Fibrosis – − Hereditary Breast and Ovarian Alpha Thalassemia Cancer − Beta Thalassemia – Child and adult onset: − Congenital Adrenal Hyperplasia 21 – Familial Adenomatous Polyposis − Spinal Muscular Atrophy Type I – Von HippelLindau Syndrome – Multiple endocrine Neoplasia Type 1 X-Linked conditions (only the mother will be – Multiple endocrine Neoplasia Type 2 tested for these): – − Familial Medullary Thyroid Cancer Duchenne Muscular Dystrophy – − Familial Hypercholesterolaemia Adrenoleukodystrophy − Haemophillia A Child onset: – Retinoblastoma Dr Corrina Powell

Recruitment

Top 20 recruited diseases (pilot) and diagnostic yield 140 Closed cases % diagnostic yield 120 100 80 60 40 20 0 346 families with only 12 diagnoses 27

Test Directory: candidate clinical indications for WGS in 2018/19 RARE DISEASE CLINICAL INDICATIONS • A range of conditions Acutely unwell infants with a likely monogenic disorder Congenital malformation and dysmorphism syndromes where Whole Genome Floppy infant with a likely central cause Sequencing should be used Moderate, severe or profound intellectual disability Ultra-rare and atypical monogenic disorders have been identified Rare syndromic craniosynostosis or isolated multisuture synostosis • NHS England will Skeletal dysplasia Neonatal diabetes commission and fund WGS Likely inborn error of metabolism - targeted testing not possible - Additional funding has Arthrogryposis Cerebellar anomalies been allocated Cerebral malformation Childhood onset hereditary spastic paraplegia CANCER CLINICAL INDICATIONS Childhood onset leukodystrophy Neurological Tumour Early onset or syndromic epilepsy Sarcoma Hereditary ataxia with onset in adulthood Acute Myeloid Leukaemia Hereditary ataxia with onset in childhood Holoprosencephaly - NOT chromosomal Acute Leukaemia other Hydrocephalus Blastic Plasmacytoid Dendritic Cell Neoplasm Other rare neuromuscular disorders Acute Lymphoblastic Leukaemia Severe microcephaly Paediatric tumours Cystic renal disease

Recruitment to the GLH test directory Personal communication of Dr Barwell, shared with permission

5 ways of interpretation of genetic result Literature search for the variant in other individuals affected by bowel cancer databasing Do members of the family who have a mutation develop the disease- co-segregation Is the variant associated with change in amino acid or change in reading frame may have variable effect on the protein Chemistry Normal sequence: CAT GCT AAC Frame shift: CAT GTA ACC (truncated protein) Base change: CAT TCT AAC (variable effect) Is the protein produced result in normal function? Functional in vitro studies Is the position preserved in other species which would be suggestive that it is important for survival Sequence homology through evolution