Mrs Jones (2) – Risk - PowerPoint Presentation

1. Mrs Jones (2) – Risk of transmission of genetic disease Dr Andrew WalleyDept of Genomics of Common Disease, School of Public HealthCourse code (MBBS): Genetics 2Course code (BMS): NAGE-L8

2. She is pregnantShe has heard that 1 in 50 babies born have a congenital malformationHer uncle has haemophiliaHer husband’s first cousin has a child with cystic fibrosisprobandMrs Jones First Consultation

3. Risk of transmission of genetic diseaseGenetic diseasePedigree diagramsModes of inheritanceMechanisms of genetic diseaseEstimating genetic riskproband

4. What is genetic disease?

5. Monogenic Clear inheritanceNo environment RareHuntington diseaseCystic fibrosisHaemophiliaComplex disordersNo clear inheritanceEnvironment essentialCommon Type 2 diabetesObesityParkinson’s diseaseGenetic Disease

6. The process whereby individuals inherit and transmit to their offspring one out of the two alleles present in homologous chromosomes.Mendelian Inheritance

7. What is an allele?Alleles: Alternate forms of gene or DNA sequence at the same chromosome location (locus)Homologous chromosomes are a matching (but non-identical) pair, one inherited from each parentDifferent alleles may be described as mutations or polymorphismsAllele ‘A’Allele ‘a’Homologous chromosomes

8. Mutation vs polymorphismA mutation is any heritable change in the DNA sequencePolymorphisms at >1% frequency in a given populationUsually still called mutations if they cause monogenic diseasePolymorphisms may contribute to complex diseases

9. Types of mutationMissenseNonsenseBoth are also point mutations

10. More types of mutation Insertion DeletionInDelBoth can be frameshift mutations

11. Pedigree diagrams

12. Taking a genetic family history: Why?To identify genetic disease in a familyTo identify inheritance patternsTo aid diagnosisTo assist in management of conditionsTo identify relatives at risk of disease

13. Drawing a family pedigreeBuild up the tree from the ‘bottom’starting with affected child and siblingsRecord names, dates of birthI:3NormanPughI:4ElsieII:3HowardPughII:4JudyIII:4DuncanIII:5MarkII:2Judith21/2/1951III:1Kirsty16/3/1980III:2Stephen20/3/1982III:3Richard5/8/1984III:1Kirsty16/3/1980III:2Stephen20/3/1982III:3Richard5/8/1984Choose one parentAsk about sibs and their children,then parents

14. I:1Arthur Smith18/3/1918I:2Elizabeth27/6/1918II:1Peter Smith1/10/1950I:3NormanPughI:4ElsieII:3Howard PughII:4JudyIII:4DuncanIII:5MarkIII:1Kirsty16/3/1980III:2Stephen20/3/1982III:3Richard5/8/1984II:2Judith21/2/1951Colour in the symbol if the personis affectedPut a sloping line through the symbol(from the bottom left hand corner) if the person has diedRecord names, dates of birth and maiden namesAsk for miscarriages, stillbirths or deathsin each partnershipUse clear symbols: circles for femalessquares for malesAdd information on other side of family

15. I:1ArthurSmith18/3/1918I:2Elizabeth27/6/1918II:2PeterSmith1/10/1950II:3Judith21/2/1951I:3NormanPughI:4ElsieII:4HowardPughII:5JudyIII:5DuncanIII:6MarkIII:2Kirsty16/3/1980III:3Stephen20/3/1982III:4Richard5/8/1984II:1AnnSmith3/9/1953III:1JulianSmith14/11/1969Ask about children with other partners

16. malefemalesex unknownaffectedunaffectedcarriersdeceasedconsanguineous marriagetwinsPedigree diagrams: more symbols

17. Mendelian Inheritance patternsAutosomal DominantAutosomal RecessiveX-linked dominant – Rare – Rett SyndromeX-linked RecessiveMitochondrial – Genetics 3Complications….

18. At least one affected parent Transmitted by M or FVertical transmissionM or F affected 50% affectedAutosomal Dominant

19. An autosomal dominant disease: Huntington diseaseFirst described by Dr George Huntington in 1872Motor, cognitive, and psychiatric dysfunction: ‘hyperkinesia’Mean age of onset is 35 to 44 years Median survival time is 15 to 18 years after onsetTreatment can ease symptoms, but no cure

20. The HTT gene on encodes a protein called huntingtinHuntington diseaseHD patients inherit one copy of a mutated form of the huntingtin geneAltered gene encodes a toxic form of the protein that forms ‘clumps’ Cell death in basal ganglia of brain, leading to symptoms

21. Down the generations:Age of onset decreases Severity increasesHuntington DiseaseMyotonic dystrophyType of mutation?Mechanism?50304144Genetic Anticipation

22. Molecular basis of HDHuntington Disease is caused by an unstable triplet repeat: the number of repeats may expand with each generation10-35 CAG repeats: unaffected 35-40 sometimes affected, sometimes not40-120 repeats: affected27-35 repeats: unaffected, but at risk of having affected child

23. No affected parent Transmitted by M or FUsually no family historyM or F affected 25% affected(50% inherit one copy ofdefective gene) Autosomal Recessive

24. Carriers consanguinityAutosomal Recessive

25. An autosomal recessive disease: Cystic FibrosisA chronic, life-threatening conditionThick mucus in lungs causes breathing problems and repeated infectionsBlockages in pancreas affect digestive enzymesTreatment consists of daily enzymes and physiotherapyIn the UK, 1 person in 22 is a CF carrier (no symptoms)

26. The CFTR gene encodes a protein called the CF transmembrane conductance regulatorCystic fibrosisCF patients inherit two copies of a mutated form of the CFTR geneAbsence of functional CFTR protein affects chloride ion channel function in epithelial cells Disruption of salt /water regulation causes thick mucus and leads to symptoms

27. Molecular basis of CFOver 1000 different mutations identifiedMost common mutation is delta F508CF testing part of UK newborn screening programmeAffects folding of CFTR protein and prevents it from moving to its correct place (the cell membrane)

28. Same gene, different symptomsCongenital absence of the vas deferens (CAVD) is a condition in which the vasa deferentia fail to form properlyCauses infertility (azoospermia)Affects around 1 in 2500 menMost cases of CAVD are caused by mutations in the CFTR gene

29. No affected parentsM affected Transmitted by carrier F50% sons affected50% daughter carriers X-Linked Recessive

30. An X-linked disease: HaemophiliaA blood-clotting disorderAffected people bruise easily and bleed for longer Two main types, A and B, which together affect about 6500 people in the UKCan be successfully treated with injections of clotting factor

31. The F8 gene encodes a protein called coagulation factor VIIIHaemophilia ABoys with Haemophilia A inherit one copy of a mutated form of the F8 gene Lack of functioning Factor VIII causes symptoms of disorder

32. Same disease, different genes… Haemophilia B is caused by mutations in the F9 gene, also on the X chromosomeF9 gene codes for coagulation factor IXSymptoms are identical to those of Haemophilia AHaemophilia B is much rarer than Haemophilia A

33. Genetic heterogeneity Same gene, different mutations, different symptoms - eg. cystic fibrosis and CAVD are both caused by mutations in the CFTR geneSame disease, different genes – eg. Bardet-Biedl Syndrome caused by defects in 15 different genesSame disease, different genes, different inheritance patterns – eg. different forms of epidermolysis bullosa can be autosomal dominant or autosomal recessive

34. Penetrance – frequency with which symptoms are present in an individual who inherits a disease-causing mutation. Variable expressivity – degree of severity in an individual who inherits a disease-causing mutationPhenocopy - having the same disease but with a different underlying causeEpistasis – interaction between disease gene mutations and other modifier genes can affect phenotype‘Simple’ Mendelian inheritance patterns can get complicated…

35. Mechanisms of genetic disease

36. Dominant vs recessive: molecular mechanisms Dominant conditions usually caused by gene mutations that results in a toxic protein (eg. HD) – ie. effects of mutated gene ‘mask’ normal copyRecessive conditions: Caused by absence of a working protein (eg. CF, haemophilia) – ie. effects of mutated gene only seen when normal copy is absentCo-dominant conditions: Effects of both mutated and normal genes apparent in people with both, eg. sickle cell trait

37. Dominant vs recessive: implications for therapyDominant conditions – need to neutralise the effects of the toxic protein or ‘switch off’ the mutant gene, “unmasking” the normal geneRecessive conditions – need to restore the activity of the missing protein, by replacing the gene or protein product, or even affected tissues

38. Her uncle has haemophiliaBUT it is her paternal uncleChance of a son with haemophilia= new mutation onlyHad it been her maternal uncle she could have been a carrierx4probandhBack to Mrs Jones: risk of haemophilia

39. Her husbands first cousin has a child with CFMrs Jones’ husband has a 1:8 chance of being a CF carrierMrs Jones has a 1:22 chance of being a CF carrierif both are carriers there is a 1:4 the child is affectedOverall chance of affected foetus = 1:704probandx4CFBack to Mrs Jones: risk of cystic fibrosis

40. Mrs Jones RisksSpecific risksLow risk of Haemophilia – 1/50001/704 chance of Cystic FibrosisN.B. Miscarriage rate of her mother is a concern

41. Find out moreWebsites: National Genetics Education and Development Centre http://www.geneticseducation.nhs.uk/Textbook: “New Clinical Genetics” Read and Donnai , Scion Publishing