Genetics and ethics Past Paper PDF 2024

Newcastle University Translational & Clinical research Institute @ Centre for Life Centre for Life, Newcastle UK Genetics and ethics BGM1004-26 2024 Sir John Burn MD FRCP FMedSci Professor of Clinical Genetics, Newcastle University...

Newcastle University Translational & Clinical research Institute @ Centre for Life Centre for Life, Newcastle UK Genetics and ethics BGM1004-26 2024 Sir John Burn MD FRCP FMedSci Professor of Clinical Genetics, Newcastle University Clinical Geneticist, Newcastle Hospitals Genethics 100,000 babies to have genetic code mapped - BBC News  Ethics Topics for discussion Termination of pregnancy on medical grounds Pre implantation Genetics Sex selection Down syndrome: trisomy 21 due to non-disjunction Samantha 1 in 700 babies 1 in 100 if mother 40+ Should a woman be allowed to terminate any pregnancy where there is an abnormality in the fetus? A. Yes B. No C. Abstain Should there be any gestational limit? Family Tree of Queen Victoria and Haemophilia Haemophilia prothrombin Factor VIII thrombin Factor IX fibrinogen fibrin blot clot Should it matter if there is a cure? 2001 The U.K.’s National Institute for Health and Care Excellence (NICE) has issued draft guidance recommending …NHS should not cover the gene therapy Hemgenix (etranacogene dezaparvovec) for adults with hemophilia B. ( price is $3.3M per patient ). August 2023  Founded in 2006 by Richard Aims to collect and curate all Cotton human variation Using Gene-Disease Specific Co-Chaired by Sir John Burn Databases in LOVD Human Garry Cutting & Ingrid Winship Using country-specific nodes Global Globin Network Variome since 2015 to catalog beta globin Project renamed Global Variome gene and modifier variation UNESCO NGO renewed 2023 Chaired by Raj Ramesar and Zilfalil Bin Alwi HVP merged with HUGO in 2020 Thalassaemia 300 million carriers. 1 M affected Gene therapy for beta thalassaemia $2.8M per patient 2019 UNESCO conference Sperm Egg 2 days post-fertilisation - How many souls? If we perform preimplantation diagnosis, are we causing the death of an individual if we leave unused zygotes to die in the Petri dish? Each blastomere could become a baby so does removal of a blastomere constitute the loss of a soul?  Mitochondrial DNA is maternally inherited Each human ovum contains about 500,000 mitochondrion MII egg fertilisation male nuclear pronucleus DNA female sperm pronucleus Paternal mitochondria targeted for destruction after fertilisation  Son: 78% mtDNA carried the deletion Short stature Diabetes Adrenal failure Myopathy Ptosis Cardiac conduction 38% 0% 78% defect with pacemaker Mother Deafness 38% mtDNA carries a Died aged 7 deletion No clinical symptoms  I-1 I-2 II-5 II-1 II-6 II-2 II-3 II-4 II-8 II-7 III-3 III-4 III-7 III-1 III-2 III-5 III-6 III-8 III-9 III-10 pH pH SA TA pH Leigh’s E pH pH pH  Could we move the parental chromosomes Germinal to another oocyte? Vesicle (GV) stage Metaphase II egg Pronucleate stage Chromosomes from mother and father About to meet If we gave an embryo new mitochondria would it be “genetically modified” HFEA research licence Paragraph 3(4) of Schedule 2 to the HFE Act 1990: “a Licence under this paragraph cannot authorise altering the genetic structure of any cell while it forms part of an embryo” Problem: what is meant by the term “genetic structure”?  Germinal Vesicle (GV) stage Unaffected Metaphase zygote pronuclei II egg removed pronuclei Pronucleate Zygote with mutated stage mtDNA wild-type mitochondria mutant mitochondria  Ethics Topics for discussion Termination of pregnancy on medical grounds Pre implantation Genetics Sex selection Whole Genome Sequencing Predictive Testing in Young People Use of incidental findings Would you like your whole genome sequenced? 100,000 babies to have genetic code mapped - BBC News  Huntington’s disease Cause Repeat expansion of Huntingtin gene at 4p16.3 Recurrence 1 in 2 offspring Prevalence 1 in 10,000 affected 7 IF WE DISCOVER GENETIC VARIANTS WHICH HAVE A HIGH PREDICTIVE VALUE FOR AN UNTREATABLE DISORDER, SHOULD WE TELL PEOPLE? Newcastle family: BRCA1 Val1736Ala  BRCA1: Valine is conserved at equivalent position 1736 in all 18 species examined Human M - D L S A L R V E E V Q N V I N A M Q K I L E C P I C L E L Chimp M - D L S A L R V E E V Q N V I N A M Q K I L E C P I C L E L Gorilla M - D L S A L R V E E V Q N V I N A M Q K I L E C P I C L E L Orangutan M - D L S A V R V E E V Q N V I N A M Q K I L E C P I C L E L Rhesus M - D L S A V R V E E V Q N V I N A M Q K I L E C P I C L E L Mouse M - D L S A V Q I Q E V Q N V L H A M Q K I L E C P I C L E L Dog M - D L S A D R V E E V Q N V L N A M Q K I L E C P I C L E L Cow M - D L S A D H V E E V Q N V L N A M Q K I L E C P I C L E L Opossum M - D L P T V T I E E V K N V L I G M Q K I L E C P I C L E L Chicken M - D L S V I A I G D V Q N V L S A M Q K N L E C P V C L D V Frog M - T C S R M D I E G I C S V I S V M Q K N L E C P I C L E L Pufferfish M - E - - A P T A T D V K K R I S L L W E T L Q C P I C L D L Sea urchin M A E - - V R L K K I T D S I G L M Q K N L E C S I C L D L Tunicate M - D - - - - - - N S V L H C L Q Q L Q K V V E C S I C L E T C elegans M A D - - - V A L R - I T E T V A R L Q K E L K C G I C C S T Arabidopsis M A D - - - - - - - - - T S H L E R M G R E L K C P I C L S L Courtesy of Sean Tavtigian  Variant of Uncertain “the lab says it was classified Significance VUS in October 2014 as a 3. However….in their opinion its not a polymorphism, they have been thinking about it already and are concerned it may be About 8 hours work pathogenic (a 4)” Inconsistent reports No correction mechanism “We have seen this change only “a 4-see hasn’t changed much, once ….evidence “we’ve seen a John’s case… except: 18X in BIC still VUS,13X in DMuDB, email…” mainly VUS except Likely Guys designated probably “it’s pathogenic. Mark is an pathogenic” pathogenicauthor usingonnew protein prediction the paper…” program (Mutation Taster).. High class 3, close to4?”  Melissa Cline 2019 >72,000 deduplicated variants in BRCA1&2 www.brcaexchange.org BRCA Exchange App IF WE DISCOVER GENETIC VARIANTS WHICH HAVE A HIGH PREDICTIVE VALUE FOR A TREATABLE DISORDER, SHOULD WE TELL PEOPLE?  Ethics Topics for discussion Termination of pregnancy on medical grounds Pre implantation Genetics Sex selection Whole Genome Sequencing Predictive Testing in Young People Use of incidental findings Insurance DNA theft Consent to research Risk of problems getting insurance after genetic testing SHOULD INSURANCE COMPANIES BE ALLOWED TO USE GENETIC INFORMATION IN THEIR DECISIONS ON PREMIUMS AND WHETHER TO OFFER COVER? Who’s your father? The threat of DNA Theft December 2002 “St James Palace had no comment on an alleged plot to set a “honey trap” to get a lock of Harry’s hair to test against James Hewitt. Hewitt insists he is not Harry’s father” Human Tissue Act 2006 All sites holding tissues and organs require a licence and are subject to external regulation It is illegal to hold samples with a view to extracting DNA Once extracted, DNA is exempt from the regulation Other Legal Issues for consideration Data Protection Act 1998 research without consent is permissible under certain conditions Section 251 NHS Act 2006 usual confidentiality may be set aside if consent for use of identifiable data is not practicable Article 8 Euro. Convention on Human Rights Intrusion permissible if proportionate, legitimate and necessary Courtesy Jonathan Montgomery and Anneke Lucasson Should researchers be allowed access to YOUR medical records in the NHS to perform anonymised research? A. Yes B. No C. Abstain  Stephen Sutton: classic symptoms ignored despite being from a Lynch syndrome family Died of metastatic colon cancer age 19 In 2014 In 2019, 37,092 people in England diagnosed with colorectal cancer > thousand had Lynch syndrome 210 were referred for germline testing (Paper under review) By age 75, 80% of MSH2 After almost three decades carriers will get We have identified 9030 LS pts in England cancer of the est. 200,000 people with a Lynch syndrome Pathogenic variant in one of the four 1st MSH2 case www.plsd.eu MMR genes underlying Lynch Syndrome Fishel et al 1993 1st DNA Dx family Colorectal Cancers in 2019 in England (under review-JB corresponding author) Dr Steven Hardy Dr Fiona McRonald 37,662 (37,090 patients) MMR+ MSI/IHC: We missed around 90% 43% Of people with LS ~85% 32000 16,111 210 referred for ~2000 seq MMR Germline ~1000 new sequence LS © 2021 National Disease Registration Service (NDRS). All Rights 19/03/2022 Reserved 40  Ethics Topics for discussion Termination of pregnancy on medical grounds Pre implantation Genetics Sex selection Whole Genome Sequencing Predictive Testing in Young People Use of incidental findings Insurance DNA theft Consent to research Eugenics: selecting people Francis Galton Put forward the concept of eugenics Ellis Island, New York Early 20th century eugenics clinic  Genetics and ethics: summary The UK can no longer presume a judeo-christian model of morality New technologies will make it necessary to adopt positions where individual choice is in conflict with the ethics of others We must be conscious of the “unforeseen adverse consequences” Always put protection of the individual at the centre of your consideration