Genetics

1. Genetics 15th June 2010

2. Learning objectives • Be able to identify genetic disorders • Knowledge of genetic basis & inheritance patterns • Awareness of clinical features of common & important genetic conditions seen in GP • Ability to take & interpret FH • Awareness of implications of antenatal & neonatal screening programmes • Clinical management • Ability to seek help with patients with possible/definite genetic disorders & refer appropriately • Awareness of management options & issues surrounding genetic testing • Communicating genetic information

3. Other learning objectives?

4. Modes of inheritanceChromosomal inheritance • Incidence increases with increasing maternal age • Consider chromosomal translocation if children with multiple malformations & stillbirths in several generations

5. Chromosomal disorders • Down’s syndrome (47 T21) • Turner’s syndrome (45 XO) • Klinefelter’s syndrome (47 XXY) • Edward’s syndrome (47 T18) • Patau’s syndrome (47 T13)

6. Turner’s syndrome • 1/2500 female births • Sporadic, low risk recurrence • Gonadal hypoplasia • Features • Short stature • Webbed neck • Low set ears • Widely spaced nipples • Short 4th metacarpal • Hypoplastic nails • Normal IQ

7. Modes of inheritanceAutosomal dominant • Males & females affected in equal proportions • Transmitted from one generation to next (vertical transmission) • All forms transmission observed (I.e. male to male, female to female, male to female)

9. Autosomal dominant disorders • Adult polycystic kidney disease • Neurofibromatosis • Tuberous sclerosis • Huntingdon’s disease • Hypercholesterolaemia • Achondroplasia

10. Achondroplasia • Affects 1/26,000 births, most are sporadic • Diagnosed in first years of life • Full penetrance & little variation in expressivity • Normal trunk but short limbs, enlarged skull vault • Normal IQ • Complications – hydrocephalus & spinal stenosis

11. Neurofibromatosis • 2 types • Type 1 • Type 2 • Type 1 • Chromosome 17 • 1/3000 births • ½ have affected family members • Multi-system • Type 2 • Chromosome 22 • Bilateral acoustic neuromas

12. Modes of inheritanceAutosomal recessive • Males & females affected in equal proportions • Individuals affected in single sibship in one generation (horizontal transmission) • Consanguinity provides further support of AR inheritance

14. Autosomal recessive disorders • Cystic fibrosis • Sickle cell disease • Thalassaemia • Haemochromatosis

15. Cystic fibrosis • Most common AR disease in UK • Affects 1/2500 infants • 1/20 are carrier • Chronic suppurative lung disease & exocrine pancreatic insufficiency • 10% newborns have meconuim ileus • Other features – male infertility & cirrhosis

16. Modes of inheritanceX-linked recessive • Males affected almost exclusively • Transmitted through carrier females to sons (knight’s move pattern) • Affected males cannot transmit disorder to sons

18. X-linked recessive disorders • Duchenne & Becker muscular dystrophy • Haemophilia • Fragile X

19. Duchenne muscular dystophy • Aggressive & progressive course • 30% new mutations • 1/3500 male births & 1/50,000,000 female births • Clinical features • Delayed walking • Waddling gait • Gowers sign • Muscular weakness/wasting • Present between 3-6yrs • Frequently fatal by 20yrs

20. Modes of inheritanceX-linked dominant • Males & females affected but affected females occur more frequently than affected males • Females usually less severely affected then males • While affected females can transmit disorder to sons & daughters, affected males transmit only to daughters (all affected)

22. X-linked dominant disorders • Rett syndrome • Vitamin D resistant rickets • Incontinentia pigmenti • Alport’s syndrome

23. Features suggestive of genetic condition?

24. Features suggestive of genetic condition • Multiple closely related individuals affected with same condition, particularly if rare condition • Disorders with earlier age onset than typical, e.g. • Breast ca <45-50yrs (premenopausal) • Colon ca <45-50yrs • Dementia <60yrs • Heart disease <40-50yrs • Bilateral disease in paired organs, e.g. eyes/lungs • Sudden cardiac deaths in people who seemed healthy • Individual or couple with 3 or more pregnancy losses • Medical problems in offspring of parents who are blood related • 2 or more medical conditions occurring together, e.g. hearing loss & renal disease • Multiple congenital anomalies, dysmorphic features; developmental delay & growth delay

25. Taking a FH • Start from case & work up • Ideally include 3 generations • Record names & dob • Be careful to ask (sensitively!) about: • Previous relationships • Whether half-siblings/children • Consanguinous relationships • Miscarriages/stillbirths/childhood deaths

26. Now it’s your turn…. • Jane is in early stages of pregnancy & consults you about the risks to her baby having CF. Her nephew (brothers son) diagnosed as having CF as a result of the neonatal CF screening programme. She wants to know if this is a cause for concern as he is the only person affected in the family and his brother does not have the condition. • More information: Jane 6 weeks pregnant with 1st pregnancy. Husband Chris is 29 & fit and well. He has no brothers or sisters. His parents William & Margaret fit and well and aged 60 & 59. • Jane has brother John who is 34 & well. Their father George died at age of 66 of MI but mother Joan is fit and well at age 64. • In Johns first marriage to Alice (aged 33), they had a son David who is 10 & well. His second marriage is to Cathy (29), knows no details of her parents and family (adopted). Had miscarriage at 9 weeks before Richard, who is 4 and has CF. No couples are blood relations.

27. Interpreting family trees • CASE 1 • Ryan Johnson (III-1) is concerned that he, or his children, might be at risk of fractures. Several members of his family have sustained fractures – in varying numbers and degree of severity. Some members of his family have fractured a bone after very minor trauma. The information that Ryan has provided about his family is shown in the family tree.

28. Interpreting family trees • From the family tree, what are the likely features of the condition associated with the fractures & who in Ryan’s family is likely to be affected? • Does the pattern of affected people suggest a mode of inheritance? • What is probability that Ryan Johnson’s children will be affected by the condition? • What is the probability that Gemma Fox’s children will be affected by the condition?

29. Interpreting family trees • Mode of inheritance • Is condition present in each generation? • Are males & females both affected? • What forms transmission seen between affected patients & their children, ie male to male? • Do affected people have affected or unaffected children? • Do unaffected people have affected children? • How are affected people related to each other? • What are proportions of affected to unaffected people in a generation?

30. Interpreting family trees • CASE 2 • Sam Webb (IV:1) is thinking of getting married and is concerned about the risk to his children of developing kidney problems and of needing a renal transplant. As part of a recent examination for life insurance he was found to have haematuria. The information he has about his family is shown in the family tree

31. Interpreting family trees • What are the likely features of the condition associated with the kidney problem & who in Sam’s family is likely to be affected? • Does the pattern affected people suggest a mode of inheritance? • What is the probability that Sarah Webb (III:1) is a carrier for the condition? • What is the probability of Lucy Webb (IV:2) being a carrier for the condition?

32. Communicating genetics • Supporting families & decision making • Signposting appropriately • Remember to treat patients as individuals • Consider ethical, cultural & social impact • Communicating risk • Avoid jargon • Statistics can be common misconception for patients, ie ¼ risk

33. Communicating genetics • Listening skills • Always listen to patients agenda • Consent & confidentiality • RCP guidance available • Remember that some patients may not want information shared • Remember to ask for help if needed • Psychiatrist/psychologist/Genetics etc. • Regional Genetics Centre (RGC) has genetic counsellor – resource for patients & practitioners

34. Ethical issues in genetics

35. Ethical issues in genetics • Identifying others at risk • Tension between preserving individual confidentiality & communication of genetic risk to others • Confidentiality can be breached if considered in public interest to do so • Confidentiality • Need to consider both patients (ie. Both parents) if test results carry information about both • Good practice would be to discuss non-paternity at outset, ie before testing • Needs to be approached sensitively

36. Ethical issues in genetics • Testing of children & indirect testing • UK Clinical Genetics Society guidelines on predictive genetic testing in children • Where no anticipated medical benefit, testing should be deferred until child old enough to make decision • Added dilemma – by testing child, parent can also receive their test result • Prenatal genetic diagnosis • Law recognises women’s right to choose to test baby, without the involvement & independent of wishes of father • Moral argument – rights of father • Counselling can help to facilitate discussion & possible disclosure • Consider preimplantation genetic diagnosis as alternative

37. Antenatal sceening • Individuals need to understand: • Issues associated with actual test • Implications of positive test • They have the right to accept or decline screening • GPs therefore need to aware of screening available & patient pathway

38. Antenatal screeningWhat tests and when?

39. Antenatal screeningWhat tests & when? • Booking • Blood for • Sickle cell & thalassaemia if appropriate • Hb, group & rhesus antibodies • Syphilis, Hep B, HIV, Rubella Ab • 10-20 weeks • Blood/USS for Downs screening • 11-13+6 weeks for NT screening • 18-21 weeks • Detailed anomaly scan

40. Neonatal screeningWhat tests & when?

41. Neonatal screeningWhat tests & when? • 1st 5 weeks of life • Newborn hearing screen • Approximately 7 days old • Newborn blood spot • Sickle cell disease • Phenylketonuria • Congenital hypothyroidism • Cystic fibrosis • Medium chain acyl CoA dehydrogenase deficiency (MCADD)

42. AKT question • A pregnant patient, originally from Indonesia is found at antenatal screening to have a mild hypochomic anaemia. DNA testing for alpha thalassaemia reveals her genotype to be --/⍺⍺. Her partner is -⍺/⍺⍺. Which one of the following statements is correct?

43. AKT question • The baby has a ¼ chance of not surviving due to hydrops foetalis • Baby has ½ chance of not having clinical manifestations of anaemia • Baby will inevitably have some form of anaemia • Baby will inevitably pass on an altered gene to future generations • Baby will have a mild hypochromic anaemia as a worst case scenario

44. AKT answer • Baby has ½ chance of not having clinical manifestations of anaemia • Worst case scenario for baby is ¼ chance of moderately severe anaemia (--/⍺-) • ½ chance of appearing normal (-⍺/⍺⍺ & ⍺⍺/⍺⍺) • Remainder will have mild hypochromic anaemia like mother (--/⍺⍺)

45. Resources • Contact a Family • www.geneticseducation.nhs.uk • NHS National Genetics Education & Development Centre – education & training • www.pcgs.org.uk • Primary Care Genetics Society • NICE CG41 • Guidelines on referral of certain conditions for genetic testing • www.ukgtn.nhs.uk • Information on genetic testing • www.screening.nhs.uk/an & www.screening.nhs.uk/primarycare/ • NHS antenatal screening programmes • www.newbornscreening-bloodspot.org.uk