1. Medical Genetics It’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. Chromosomal Disorders
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…..

11. Chromosomal Disorders
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...

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. Family Tree Symbols / Male Marriage / Partnership (horizontal line)
Female /
Partnership that has ended
Person whose sex is unknown P
Offspring (vertical line)
Pregnancy
Pregnancy/ abortion
Age at time of event
X weeks/ years
Parents and Siblings
Deceased aged 76 76
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. What inheritance pattern?
JW (64)
GW ( MI)
WH (60)
MH (58)
CH (29) 6w
JH (28)
RW (10)
Cystic Fibrosis
AW (33)
DW (10)
CW (29) 9w
JW (34)
Generations may appear unaffected.
Often “distant” family history
What inheritance pattern?

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

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 Carrier Rates
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. Autosomal Dominant Inheritance
Parents
Affected
Gametes
Conception
Unaffected
Affected

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

30. Polygenic Diseases
Normal Tissue
Cancer
Normal Tissue

31. Polygenic Disease Pedigree
Less pattern – more scattered

32. Beware of the elephant in the room….
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 Kay 65 70 76
A 46 year old woman approaches you concerned about her family history of breast cancer.
What would you advise her?
Low risk (using guidelines)
Reassure
discuss population risk
‘breast aware’
report symptoms promptly and changes in family history
national screening programme from age 50 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 %
- ovary cancer BRCA1 44%, BRCA2 27%
Variable penetrance (e.g. 15% no cancer and variable expression e.g. breast alone, ovary alone etc)
(other cancers BRCA1 stomach 2.5, Colon 2.5 (6%), Pharynx 3.6 males only, liver 8.2, cervix 4.4, endometrium 2.9, brain 5. BRCA2 pancreas 5.9, prostate 2.7, bone 14.4, pharynx 7.3)

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
A 46 year old woman approaches you concerned about her family history of breast cancer.
What would you advise her?
Low risk (using guidelines)
Reassure
discuss population risk
‘breast aware’
report symptoms promptly and changes in family history
national screening programme from age 50 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
A 32 year old woman approaches you as she has been advised by her cousin she is at risk of breast cancer - she herself feels the risk must be low as there is no history on her mothers side.
What do you think her risks are?
How would you advise her?
Moderate risk (using guidelines 2 close relatives average age under 60)
refer to family history clinic
Mammography commence at yrly intervals (after 50 at least 2yrly until 75 – mutation carriers indefinite surveillance)
offered referral to clinical genetics service to discuss options including possibility of genetic testing (worth checking if cousin is pursuing) – there would in this family be more than a 20% chance of finding a BRCA mutation (more about the detail of genetic testing later)
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!
As you know after lung and breast cancer colorectal cancer is the most common cause of death from malignant disease in the West. Approximately 1 in 25 people will develop at sometime in their lives.
As for breast cancer most is sporadic and or due to low risk genes in 5-10% strong genetic contribution
Most important predisposing genetic syndromes are familial adenomatous polyposis(FAP) and hereditary non-polyposis colorectal cancer (HNPCC) both are dominantly inherited

39. Bowel & Related Cancers
Note - when counting relatives - either maternal or paternal side one at a time
Related cancers: When there is, in addition to at least one bowel cancer, a history of endometrial, ovarian, gastric, biliary, renal, small bowel or brain cancer in other close relatives.
If low risk then discuss
1 in 25 in the population will get BC sometime in life
healthy diet and lifestyle
report symptoms changes in family history
moderate or high refer - dept surgery E floor West Block QMC
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
60 yr old man approaches you concerned about his family history of bowel cancer.
What would you say to him?
What do you think his risks are?
Both parents lived to a reasonable age unaffected - not suggestive of dominantly inherited gene.
Using guidelines - low risk – ensure patient is symptom aware and also reports any changes in family history 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
30 year old comes to see you concerned because polyps had recently been discovered in his older brother and he has a family history of colorectal and endometrial cancer.
On guidelines moderate to high – 3 same side any age ( 2 bowel and one related)
Looks like dominant gene - HNPCC probably at 50% risk (endometrial cancer risk 50% lifetime 35x general population)
refer to family history clinic
colonoscopy and poss gene testing uncle
Endometrial cancer
Colorectal
cancer 30
Martin 39
Polyps 42

42. Assessing Cancer Risk Stop and think ….. Remember:
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
Chinese and Indian origin – breast cancer less common so any family history maybe more significant. Ashkenazi, Finnish and Icelandic populations have a higher frequency of mutations in BRCA1/2 . If ovarian cancer maybe at an older age but still significant if also family history of breast cancer or another ovarian cancer

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

44. Australian Handbook for GPs
In my opinion, easier to find useful information about specific cancers

45. MacMillan - Cancer Genetics

46. University of Texas – Teaching Cases
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

50. Ø         A close relative is any first or second degree relative (parent, brother, sister, child, aunt, uncle, grandparent). Please remember if there are intervening male relatives then more distant relationships maybe relevant.
Ø         The family history should be of affected blood relatives through either the maternal or paternal side of the family.
Ø         If there is Jewish ancestry in the family, the history may be more significant – seek advice from the Clinical Genetics service.
Ø         For enquiries about a patient’s family history, or if there is a history of unusual cancers, please contact the Clinical Genetics Service on :

51. Note - when counting relatives - either maternal or paternal side one at a time
Related cancers: When there is, in addition to at least one bowel cancer, a history of endometrial, ovarian, gastric, biliary, renal, small bowel or brain cancer in other close relatives.
If low risk then discuss
1 in 25 in the population will get BC sometime in life
healthy diet and lifestyle
report symptoms changes in family history
moderate or high refer - dept surgery E floor West Block QMC