Genetics in Primary Care Curriculum Statement 6. Dr Dave Harniess PCME Stockport

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1 Genetics in Primary Care Curriculum Statement 6 Dr Dave Harniess PCME Stockport

2 Learning Objectives Understanding of genetic component of disease Screening for genetic conditions and risk assessment in general practice Skill of family tree mapping Ethical issues involved in genetics When to consider referral to the regional genetic centre

3 Brainstorm of Genetics in General Practice

4 Any personal experiences?

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6 Classification of genetic disorders Multifactorial + environment Single gene Chromosomal Male Mitochondrial (DNA contains 37 genes several cancers and inherited conditions e.g. maternal diabetes + deafness) Somatic mutations (genetic alteration acquired by a cell passed to progeny of mutated cell in cell division - cancer)

7 Continuum of penetrance. There is a continuum of penetrance from fully penetrant conditions, where other genes and environmental factors have no effect, through to low-penetrance genes that simply play a small part, along with other genetic and environmental factors, in determining a person s susceptibility to a disease. Multiple sclerosis is used as an example of a multifactorial condition where genetic factors play a major part in determining susceptibility, but current research suggests that each individual factor has a very low penetrance. Fig Scion Publishing Ltd

8 Genetic factors Mutations in single genes (often causing loss of function) Male Variants in genes causing alteration of function Chromosomal imbalance causes alteration in gene dosage

9 Classification of genetic disorders Single Gene Disorders Mutations in single genes Male Multifactorial diseases Variants in genes + environment Chromosome disorders Chromosomal imbalance

10 Dominant Heterozygotes with one copy of the altered gene are affected Recessive Homozygotes with two copies of the altered gene are affected X-linked recessive Male Males with one copy of the altered gene on the X-chromosome are affected

11 Autosomal Dominant Inheritance

12 Autosomal Recessive Inheritance

13 X Linked Inheritance

14 X Linked Inheritance

15 Chromosomes Gene for cystic fibrosis (chromosome 7) Gene for sickle cell disease (chromosome 11) Chromosomes are made of DNA. Each contains genes in a linear order. Human body cells contain 46 chromosomes in 23 pairs one of each pair inherited from each parent Chromosome pairs 1 22 are called autosomes. The 23rd pair are called sex chromosomes: XX is female, XY is male.

16 Chromosomes p Centromere q Chromosome 5

17 Chromosome anomalies Cause their effects by altering the amounts of products of the genes involved. Three copies of genes (trisomies) = 1.5 times normal amount. One copy of genes (deletions) = 0.5 times normal amount. Altered amounts may cause anomalies directly or may alter the balance of genes acting in a pathway.

18 Anomalies of chromosome structure Translocations Robertsonian Reciprocal Deletions Duplications Ring chromosomes

19 Chromosomal deletions and duplications (not caused by translocations) Are usually one off /de novo events occurring in meiosis. Have a very low recurrence risk in future pregnancies.

20 Most frequent numerical anomalies in liveborn Autosomes Down syndrome (trisomy 21: 47,XX,+21) Edwards syndrome (trisomy 18: 47,XX,+18) Patau syndrome (trisomy 13: 47,XX+13) Sex chromosomes Turner syndrome 45,X Klinefelter syndrome 47,XXY All chromosomes Triploidy (69 chromosomes)

21 Chromosomal findings in recurrent early miscarriages 40% apparently normal 60% abnormal: Trisomy (47 chromosomes one extra) 30% 45,X (45 chromosomes one missing) 10% Triploidy (69 chromosomes three sets) 10% Tetraploidy (92 chromosomes four sets) 5% Other chromosome anomalies 5% (e.g. structural anomalies)

22 Summary of Chromosome Anomalies Change in number e.g. trisomy 21 Down syndrome; Edwards syndrome; Turner syndrome. Usually an isolated occurrence. Trisomy 21 Change in structure e.g. translocations May be inherited.

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24 1. What is the prevalence of autosomal dominant single gene inheritance per 1000 population in the UK? A B C D. 1 or less Genetic Quiz

25 2. According to a study in general practice in 2004 what was the minimum of patients seen in primary care had a disorder with a genetic component? A. 1 in 10 B. 1 in 3 C. 1 in 50 D. 1 in 15

26 3. If you saw this on a newborn baby check what other features would you examine for?

27 4a What does this family have? 4b What clinical features do you know about this condition?

28 5. Can you identify which chromosomal disorders these children have? A B C D

29 6. What is the most common Mendelian disorder in the UK? A. Familial hypercholesterolaemia B. Dominant Otosclerosis C. Adult Polycystic Kidney Disease D. Familial combined hypercholesterolaemia

30 7. What do the following terms mean? 7a Allele 7b Robertsonian translocation 7c Heterozygote 7d Genotype 7e Recessive trait 7f Dizygotic twin 7g Oncogenes

31 8. What do the following family tree A. B. C. symbols represent? D. E. F. G.

32 9. Which risk factor below is least likely to indicate high risk of familial breast or ovarian cancer? A. Developing cancer below age of 40 B. 1 relative with ovarian cancer C. Bilateral breast cancer D. Male breast cancer

33 10. Family Tree - Scenario 1

34 10. Family Tree - Case Scenario 1 A. What mode of inheritance do the pattern of affected people suggest? B. What is the probability that Ryan Johnson s (III:1) children will be affected by the condition? C. What is the probability that Gemma Fox s (III:4) children will be affected by the condition?

35 11. Family Tree Scenario 2

36 11. Family Tree Scenario 2 A. What mode of inheritance do the affected people suggest? B. What is the probability that Sarah West III:1 is a carrier for the condition? C. What is the probability that Sam Webb s (IV:1) children will be affected with the same condition that his uncle Stephen (III:3) has?

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38 Definition of terms 7a Allele 7b Robertsonian translocation 7c Heterozygote 7d Genotype 7e Recessive trait 7f Dizygotic twin 7g Oncogenes 2 versions of same gene Whole chromosome from 1 pair comes attached to end of a whole chromosome on another pair Individual with 2 different alleles The set of alleles a person has Condition only expressed in homozygotes Non-identical twins Cancer genes

39 Robertsonian Translocation

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41 Case 1. A tired man A 45 year old man comes to you complaining of tiredness, weakness and painful knuckles. People have commented that he has a bronze appearance of his skin. You find an enlarged liver on examination A. What is the likely diagnosis of this man? B. How is this inherited? C. What blood test is used to diagnose it? D. How is this managed in secondary care?

42 Case 2. A Familial Story?

43 Assessing for Familial Hypercholesterolaemia Simon Broome criteria for index individuals and indication for starting a statin: Adult cholesterol above 7.5 mmol/l AND FHx MI in 1 st degree relative younger than 60yrs or MI in 2 nd degree relative younger than 50years Familial Hypercholesterolaemia NICE Guidelines August 2008

44 Case 3. A Concerned Relative

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46 Assessing Breast Cancer Risk Familial Breast Cancer NICE Guidelines October 2006

47 Assessing Breast Cancer Risk Familial Breast Cancer NICE Guidelines October 2006

48 Assessing Breast Cancer Risk Familial Breast Cancer NICE Guidelines October 2006

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50 Drawing a family pedigree Build up the tree from the "bottom" starting with affected child and siblings Record names, dates of birth III:1 Kirsty 16/3/1980 III:2 Stephen 20/3/1982 III:3 Richard 5/8/1984 I:3 Norman Pugh I:4 Elsie Choose one parent Ask about sibs and their children, then parents II:2 Judith 21/2/1951 II:3 Howard Pugh II:4 Judy III:1 Kirsty 16/3/1980 III:2 Stephen 20/3/1982 III:3 Richard 5/8/1984 III:4 Duncan III:5 Mark

51 Add information on the other side of the family Use clear symbols: circles for females squares for males Colour in the symbol if the person is affected I:1 Arthur Smith 18/3/1918 II:1 Peter Smith 1/10/1950 I:2 Elizabeth 27/6/1918 II:2 Judith 21/2/1951 I:3 Norman Pugh I:4 Elsie II:3 Howard Pugh II:4 Judy Put a sloping line through the symbol (from the bottom left hand corner) if the person has died III:1 Kirsty III:2 Stephen III:3 Richard III:4 Duncan III:5 Mark 16/3/ /3/1982 5/8/1984 Record names, dates of birth and maiden names Ask for miscarriages, stillbirths or deaths in each partnership

52 I:1 Arthur Smith 18/3/1918 I:2 Elizabeth 27/6/1918 I:3 Norman Pugh I:4 Elsie II:1 Ann Smith 3/9/1953 II:2 Peter Smith 1/10/1950 II:3 Judith 21/2/1951 II:4 Howard Pugh II:5 Judy III:1 Julian Smith 14/11/1969 III:2 Kirsty 16/3/1980 III:3 Stephen 20/3/1982 III:4 Richard 5/8/1984 III:5 Duncan III:6 Mark May I ask: have you had any children with other partners?

53 Other pedigree symbols Affected male Unaffected female who has died Affected female Double line joins union of consanguineous couple SB Stillborn baby of unknown sex Spontaneous abortion Twins: identical; non-identical Therapeutic abortion Unaffected person whose sex is unknown

54 Drawing a family pedigree Ask about consanguinity "Are you and your partner related? Are there any surnames in common?" Date and sign the pedigree For a known diagnosis (eg autosomal recessive) it may not be necessary to collect as much detail Record at least basic information on both sides of the family even if a disorder is segregating on only one side

55 Have a go.

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61 Ethical Issue 1 Mr P was recently diagnosed with autosomal dominant PKD. Having realised that each of his children has a 50% chance of having inherited the condition from him, Mr P asks his GP to organise a kidney ultrasound for his two children aged 10 and 7, to see whether they have inherited the condition. The GP should do so. Strongly Agree Agree Neutral Disagree Strongly Disagree

62 Ethical Issue 2 Duchenne Muscular Dystrophy (DMD) is a progressive neuromuscular disorder affecting approx 1 in 3000 male births. Boys with DMD are usually diagnosed between 4-5 yrs of age. In about 2/3 of cases, the boy s mother is a carrier for the condition, and at risk of having another affected boy. There is no treatment for DMD. Neonatal screening of all male births should be performed to identify affected boys so that their mothers can be tested to see if they are carriers and so are at risk of having further affected children. Strongly Agree Agree Neutral Disagree Strongly Disagree

63 Roleplay

64 Tara Clancy Consultant Genetic Counsellor Tel Fax Manchester Regional Genetic Medicine 6th Floor St Mary's Hospital CMFT Oxford Rd M13 9WL Genetics Centre

65 What is genetic counselling? An education process that seeks to assist affected (and/or at risk ) individuals to understand the nature of the genetic disorder, the nature of its transmission and the options open to them in management and family planning.

66 Reasons for Clinical Genetics Referral Affected child/adult for investigation or diagnosis Family history of genetic disorder or condition with genetic component Fetal loss/abnormality Recurrent miscarriages Information Strong family history of cancer Diagnostic Testing Predictive testing Carrier testing Prenatal testing

67 Aims of genetic counselling Give information: What is the condition? Inform people of the medical facts Talk about treatment and prognosis Explain inheritance Discuss chance of happening again.

68 Genetic testing of Children Beneficial if: Confirming a suspected diagnosis Removing need for invasive procedures. Problematic if: Carrier testing a healthy child Predictive testing for adult-onset condition.

69 Making a genetic diagnosis Family tree to detect a pattern of inheritance Physical examination to give precise diagnosis Genetic tests Chromosomes (karyotype) Genes (DNA testing).

70 Resources on Genetics egp modules (currently 7!) NICE guidelines on Familial Hypercholesterolaemia and Breast Cancer Regional Genetics Centre