Medical Genetics It’s not my fault, it’s my genes

1. Medical GeneticsIt’s not my fault, it’s my genes Dr Richard de Ferrars

2. Why Bother? Medical genetics is a complex and highly specialised field. Why should I need to know about it as a GP? It isn’t my problem…. Why might genetics be of relevance to you as a GP?

3. Why Bother?

4. Why Bother? 10% of the patients seen in GP have a disorder with a genetic component - identifying patients with, or at risk of, a genetic condition - clinical management of genetic conditions - communicating genetic information Taking and considering a genetic family history is a key skill Role in identifying patients and families who would benefit from being referred to appropriate specialist genetic services Key part in discussing results from the antenatal and newborn screening programmes which are identifying carriers and people affected Research studies offer additional information about risk factors to aid management

5. What Should You Know? • Basic understanding of clinical genetics • Be able to draw, and understand, a family tree • Have awareness of when you should be considering a genetic condition • Have a working knowledge of the most important genetic conditions • Know how & when to refer to local specialist genetics services

6. What Types of Conditions? Can you think of conditions where “genetics” may arise in GP practice? Categorise these “genetically”

7. Categories of Genetic Disease • Genetic component of multifactorial illnesses • Polygenic conditions • Interaction of genetic & environmental factors • Addition or deletion of entire chromosomes or parts of chromosomes • Single gene disorders • Autosomal dominant • Autosomal recessive • X-linked

8. Multifactorial – Genes or Environment? 100% Environmental Struck by lightning Infection Weight Cancer Diabetes PKU –genetic basis but the damage is by an environmental agent Height 100% Genetic Sex, Down syndrome, achondroplasia

9. Categories of Genetic Disease • Genetic component of multifactorial illnesses • Polygenic conditions • Interaction of genetic & environmental factors • Addition or deletion of entire chromosomes or parts of chromosomes • Single gene disorders • Autosomal dominant • Autosomal recessive • X-linked

10. Most mutations happen in the parent’s egg/ sperm - “one off” with no established family history Duplications (whole or part) Autosome trisomies (Down, Edwards, Patau) XY duplications (Klinefelter XXY, Triple X) Deletions Autosome deletions (Cri du chat, di George’s) XY deletions (Turner XO) Translocations Leukaemias (Philedelphia Chromosome) Sarcomas (Ewings) Inversions Rings….. Chromosomal Disorders

11. Most mutations happen in the parent’s egg/ sperm - “one off” with no established family history Genetics & the role of GP? Transmission – unlikely Reassurance within affected families Antenatal screening? Bread and butter CSA station... Chromosomal Disorders

12. Categories of Genetic Disease • Genetic component of multifactorial illnesses • Polygenic conditions • Interaction of genetic & environmental factors • Addition or deletion of entire chromosomes or parts of chromosomes • Single gene disorders • Autosomal dominant • Autosomal recessive • X-linked

13. Single Gene Disorders • Transmitted in a Mendelian fashion • Autosomal dominant, autosomal recessive • X-linked, Y-linked • Variable Penetrance Some conditions have 100% penetrance eg acondroplasia Many don’t. Why not? Genetic factors – effect from genes at other alleles Environmental factors – eg BRAC & no. of pregancies Let’s go drawing......

14. / P Deceased aged 76 76 Parents and Siblings Family Tree Symbols Male Marriage / Partnership (horizontal line) Female Partnership that has ended Person whose sex is unknown Offspring (vertical line) Pregnancy Pregnancy/ abortion Age at time of event X weeks/ years Affected Male & Female Carrier Male & Female

15. JH (28) is 6w pregnant and wishes to discuss cystic fibrosis risk as her nephew RW had cystic fibrosis diagnosed on screening. His brother (JW) is unaffected Her husband, CH (29), is an only child. His father, WH (60) and mother, MH (59) are fit and well Her father, GW, died aged 66 from an MI. Her mother JW, is A&W aged 64 Her brother, JW, is aged 34 and well JW’s first marriage was to AW (33) and they have one well child DW (10) JW’s second marriage is to CW (29) . She knows no details of her parents. She had one spontaneous abortion (at 9w) before RW, who is now 3

16. GW ( 66 MI) WH (60) JW (64) MH (58) CW (29) JW (34) CH (29) AW (33) JH (28) DW (10) 6w 9w RW (10) Cystic Fibrosis Generations may appear unaffected. Often “distant” family history What inheritance pattern?

17. Parents Carrier Carrier Gametes Conception Unaffected Carrier Affected Autosomal Recessive Inheritance

18. Autosomal Recessive Inheritance Name some AR conditions: Cystic Fibrosis Haemachromatosis Sickle cell disease Thalassaemia PKU Glycogen storage diseases You must know the illnesses & inheritance pattern Bread and butter CSA cases... Discussing a FH Discussing antenatal screening & diagnosis

19. Cystic Fibrosis • One of the most common AR conditions Mutation of CTFR gene on chromosome 7 900 mutations identified (racial variations) 2 defects cause problems irrespective of type • Carrier Rates 1 in 25 carriers UK general population 2 in 3 carriers brother/sister 1 in 2 carriers aunt/ uncle 1 in 4 carriers 1st cousin 1 in 16 carriers 2nd cousin

20. Cystic Fibrosis Screening & Detection - Screening of newborn – “Immunoreactive Trypsin” - Preconceptual gene testing for positive FH - even in 2nd cousin Limitations: screen for most common mutations only (screen negative not “all clear”) does not predict disease severity Options if affected: donor egg/ sperm pre-implantion embryo screening CVS and termination

21. Autosomal Dominant Pedigree Typically every generation affected

22. Parents Affected Conception Unaffected Affected Autosomal Dominant Inheritance Gametes

23. Autosomal Dominant Inheritance Name some AD conditions: Huntingdon’s Disease Adult polycystic kidney disease Neurofibromatosis You must know the illnesses & inheritance pattern Bread and butter CSA cases... Discussing a FH Discussing antenatal screening & diagnosis

24. Huntingdon’s Disease Gene for protein Huntingtin on Chromosome 4 Contains a sequence of “tri-nucleotide repeats”, in this case CAG Produces chains of glutamine, length depends on number of repeats - Under 26 repeats is normal - Over 36 repeats generates abnormal Huntingtin that kills cells More repeats = more severe HD at younger age

25. Huntingdon’s Disease Inheritance is autosomal dominant But long repeat sequences are “unstable” and number of repeats can alter between generations Other genes & environmental factors also affect the activity of the gene The result - strong penetrance but variety in age of onset & severity

26. Huntingdon’s Disease • John is seen in a genetics clinic after his mother has a confirmed diagnosis of HD. • He is married to Sarah and they have a 6 y/o child, Tom. • After counselling John decides that he will NOT take a test at present due to the absence of treatment and the long time interval before any symptoms would arise. • Sarah comes to see you. She explains how distressed she is by witnessing the deterioration in John’s mother. She feels she needs to be prepared if Tom has inherited the condition and requests referral for Tom to be tested. Discuss this case in 2-3 and then review “issues”

27. X-Linked Pedigree Red-green colour blindness (7%) Haemophilia Duchenne MD Fragile X Males only affected – can appear to skip generations

28. Polygenic Diseases • The most common yet still the least understood of human genetic diseases • Type I and type II diabetes • Primary generalised osteoarthritis • Hypertension • Autism • Result from an interaction of multiple genes, each with a minor effect • Some inherited mutations and some environmental factors (somatic mutations)

29. Normal Gene Normal Tissue Normal Tissue Normal Tissue Hereditary Mutation Somatic Mutation Multifactorial Diseases Cancer (Recessive Trait) Cancer

30. Normal Tissue Normal Tissue Cancer Polygenic Diseases

31. Polygenic Disease Pedigree Less pattern – more scattered

32. Cancer Families “Doc – I’ve got cancer in the family Should I be worried?” Beware of the elephant in the room….

33. Case History 2 Breast cancer 65 70 76 46 Kay 49 51 53 55

34. Breast Cancer Genes BRCA1, BRCA2 possible BRCA3? • Tumour supressor genes, generate protein involved in DNA repair, destroys cell if DNA cannot be repaired • Several hundred mutations have been identified, varying effect on gene function • Racial variation – Ashkenazi Jews • The gene functions in other tissues – hence the “related cancers” effect, most noticeably ovary (fallopian tubes & prostate) Lifetime risk of - breast cancer 50 - 85% - ovary cancer BRCA1 44%, BRCA2 27%

35. Breast/ Ovary Cancer Ignore “one cancer only, age over 40y”. Everything else – check guidelines

36. Case History 2 Low risk Manage in primary care Older age of onset Different sides of the family 65 Breast cancer 70 76 46 Kay 49 51 53 55 Reassure and explain population risk, advise on symptom awareness and to report any changes in family history

37. Case History 3 Refer –high risk Breast and ovarian cancer Multiple tumours in one individual Young age onset Different generations Equal transmission through men 42 48 breast cancer 56 ovarian cancer Breast cancer Ovarian cancer 32 Janet 35

38. Familial Colorectal Cancer Colorectal cancer common – 1 in 25 5-10% - strong genetic contribution The most important of these are: - familial adenomatous polyposis (FAP) - hereditary non-polyposis colorectal cancer (HNPCC) Most are autosomal dominant – not all!

39. Bowel & Related Cancers A close relative is any 1st or 2nd degree relative (parent, sibling, aunt, uncle, grandparent) on either paternal or maternal side of the family Related Cancers: endometrial, ovarian, gastric, biliary, renal, small bowel & brain Ignore 1 cancer aged over 45yrs or 2 cancers both over 70yrs. Everything else - check guidelines

40. Case History 4 Refer –moderate risk Two close relatives average age under 70 yrs 35 died in war 68 73 60’s 77 78 73 75 43 Colorectal cancer 32 Peter

41. Case History 5 Refer –high risk Young age of onset Endometrial cancer with bowel family history (other related cancers: ovarian, ureteric, renal pelvis, gastric) Two generations Polyps 55 69 49 42 George 80 75 48 78 Endometrial cancer 39 Polyps 30 Martin Colorectal cancer 42

42. Assessing Cancer Risk • Stop and think ….. • young age of onset, • pattern of similar tumours in a family • multiple primaries in one individual • Remember: • Related tumours • Ethnicity matters Ashkenazi Jewish ancestry • Use national/local guidelines • e.g. NICE familial breast cancer, websites • Over 200 hereditary cancer syndromes described – individually rare, but as a GP you will meet some • Contact the CGS if you are unsure

43. Resources GP Curriculum Map: InnovAiT 1;8 Websites

44. Australian Handbook for GPs http://www.nhmrc.gov.au/your_health/egenetics/practitioners/gems.htm In my opinion, easier to find useful information about specific cancers

45. MacMillan - Cancer Genetics http://www.macmillan.org.uk/Cancerinformation/Causesriskfactors/Genetics/Cancergenetics/Cancergenetics.aspx

46. University of Texas – Teaching Cases http://genes-r-us.uthscsa.edu/resources/genetics/primary_care.htm A good series of case reports to work through • Explore various aspects of genetics in primary care • American flavor but still useful!

47. And Finally….. • What should you accumulate in your portfolio over the 3 years? • Teaching session… • Log entries involving breast/ bowel cancer that link to further educational activity • Reading on National MacMillan/ Australian website • University of Texas case reports

48. The End