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PENGANTAR GENETIKA KEDOKTERAN

KULIAH BLOK 6 KULIAH BLOK 6 FK UMPFK UMP

MENGAPA KITA BELAJAR GENETIKA KEDOKTERAN

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?


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


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

What Types of Conditions?

Can you think of conditions where “genetics” may arise in GP practice?

Categorise these “genetically”

CATEGORIES OF GENETIC DISEASE

Genetic component of multifactorial illnessesPolygenic conditionsInteraction of genetic & environmental factors

Addition or deletion of entire chromosomes or parts of chromosomes

Single gene disordersAutosomal dominantAutosomal recessiveX-linked

100%Environmental

Struck by lightning

Infection

Weight

Cancer

Diabetes

Height

Sex, Down syndrome, achondroplasia100% Genetic

MULTIFACTORIAL – GENES OR ENVIRONMENT?

PKU –genetic basisbut the damage is by an environmental agent





CHROMOSOMAL DISORDERSMost 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

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...





SINGLE GENE DISORDERS

Transmitted in a Mendelian fashionAutosomal dominant, autosomal recessive X-linked, Y-linked

Variable PenetranceSome conditions have 100% penetrance eg

acondroplasiaMany don’t. Why not?

Genetic factors – effect from genes at other allelesEnvironmental factors – eg BRAC & no. of pregancies

Let’s go drawing......

Male

Female

Person whose sex is unknown

PregnancyP

Marriage / Partnership

(horizontal line)

Offspring (vertical line)

Affected Male & Female

Carrier Male & Female

Partnership that has ended

FAMILY TREE SYMBOLS

/

X weeks/ years

Pregnancy/ abortion

Age at time of event

Parents and Siblings

Deceased aged 76

76

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 unaffectedHer husband, CH (29), is an only child. His father, WH (60) and mother, MH (59) are fit and wellHer father, GW, died aged 66 from an MI. Her mother JW, is A&W aged 64Her brother, JW, is aged 34 and wellJW’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

6w

JH (28)

RW (10)Cystic

Fibrosis

WH (60)MH (58)

CH (29)

JW (64) GW ( 66 MI)

AW (33)

DW (10)

JW (34) CW (29)

9w

Generations may appear unaffected.

Often “distant” family historyWhat inheritance pattern?

AUTOSOMAL RECESSIVE INHERITANCE

CarrierUnaffected

Conception

Affected

Gametes

Parents

Carrier Carrier

AUTOSOMAL RECESSIVE INHERITANCE

Name some AR conditions:Cystic FibrosisHaemachromatosisSickle cell diseaseThalassaemiaPKUGlycogen storage diseases

You must know the illnesses & inheritance pattern

Bread and butter CSA cases...

Discussing a FH

Discussing antenatal screening & diagnosis

CYSTIC FIBROSISOne of the most common AR conditions

Mutation of CTFR gene on chromosome 7900 mutations identified (racial variations)2 defects cause problems irrespective of type

Carrier Rates1 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

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/ spermpre-implantion embryo screeningCVS and termination

AUTOSOMAL DOMINANT PEDIGREE

Typically every generation affected

AUTOSOMAL DOMINANT INHERITANCE

Affected

Gametes

Conception

Unaffected

Parents

Affected

AUTOSOMAL DOMINANT INHERITANCEName 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

HUNTINGDON’S DISEASEGene 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

HUNTINGDON’S DISEASEInheritance 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

HUNTINGDON’S DISEASEJohn 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”

X-LINKED PEDIGREE

Males only affected – can appear to skip generations

Red-green colour blindness (7%)

Haemophilia

Duchenne MD

Fragile X

POLYGENIC DISEASESThe most common yet still the least

understood of human genetic diseases Type I and type II diabetesPrimary generalised osteoarthritisHypertensionAutism

Result from an interaction of multiple genes, each with a minor effect

Some inherited mutations and some environmental factors (somatic mutations)

Normal Tissue

Normal Gene

Hereditary Mutation

Somatic Mutation

Normal Tissue

Normal Tissue

Cancer

Cancer

MULTIFACTORIAL DISEASES

(Recessive Trait)

POLYGENIC DISEASES

Cancer

Normal Tissue

Normal Tissue

POLYGENIC DISEASE PEDIGREE

Less pattern – more scattered

CANCER FAMILIES

“Doc – I’ve got cancer in the family

Should I be worried?”

Beware of the elephant in the room….

CASE HISTORY 2

Breast cancerBreast cancer

4646

KayKay

6565

7676

4949 5151 5353 5555

7070

BREAST CANCER GENES

BRCA1, BRCA2 possible BRCA3?Tumour supressor genes, generate protein involved in

DNA repair, destroys cell if DNA cannot be repairedSeveral hundred mutations have been identified,

varying effect on gene function Racial variation – Ashkenazi JewsThe 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%

BREAST/ OVARY CANCER

Ignore “one cancer only, age over 40y”. Everything else – check guidelines

CASE HISTORY 2


4646

KayKay

6565

7676

4949 5151 5353 5555

7070

Low risk

Manage in primary care

Older age of onsetOlder age of onset

Different sides of the Different sides of the familyfamily

Reassure and explain population risk, advise on symptom awareness and to report any changes in family history

CASE HISTORY 3

3535

3232

JanetJanet

48 breast cancer 48 breast cancer 56 ovarian cancer56 ovarian cancer

4242


Ovarian cancerOvarian cancer

Refer –high risk

Breast and ovarian cancer

Multiple tumours in one individual

Young age onset

Different generations

Equal transmission through men

FAMILIAL COLORECTAL CANCER

Colorectal cancer common – 1 in 25

5-10% - strong genetic contributionThe most important of these are:

- familial adenomatous polyposis (FAP)

- hereditary non-polyposis colorectal cancer (HNPCC)

Most are autosomal dominant – not all!

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

Case History 4

73

32Peter

75

60’s

78

73

4377

35 died in war

68

Colorectal cancer

Refer –moderate risk

Two close relatives average age under 70 yrs

Case History 5

80 75

6955

784842George

49

Colorectal cancer

4230Martin

39Polyps

Endometrial cancer

Refer –high risk

Young age of onset

Endometrial cancer with bowel family history (other related cancers: ovarian, ureteric, renal pelvis, gastric)

Two generations

Polyps

ASSESSING CANCER RISKStop and think …..

young age of onset, pattern of similar tumours in a familymultiple primaries in one individual

Remember:Related tumours Ethnicity matters Ashkenazi Jewish ancestry

Use national/local guidelinese.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

RESOURCES

GP Curriculum Map:

InnovAiT 1;8Websites

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

MACMILLAN - CANCER GENETICShttp://www.macmillan.org.uk/Cancerinformation/Causesriskfactors/Genetics/Cancergenetics/Cancergenetics.aspx

UNIVERSITY OF TEXAS – TEACHING CASES

http://genes-r-us.uthscsa.edu/resources/genetics/primary_care.htm

A good series of case reports to work throughExplore various aspects of genetics in primary care

American flavor but still useful!

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

activityReading on National MacMillan/ Australian

website

University of Texas case reports

Number of close relatives affected by breast cancer

Family History of breast cancer

Age of cancer diagnosis Refer to combined FH clinic

(Breast Unit)

1 (first degree)

≤ 40 > 40 X

(bilateral) < 50

(2nd primary can be over 50)

(male) Any age

2 (one 1st degree)

Average age under 60

3 (or more)

Any age

OVARIAN CANCER FAMILIES BREAST & OVARIAN CANCER FAMILIES Number of close relatives affected by ovarian cancer

Action Number of close relatives affected by either breast or

ovarian cancer Refer to FH clinic

1 No screening required

1 both breast and ovarian cancer

2 or more Refer to FH clinic

1 male breast cancer and 1 ovarian cancer Key

1 breast and 1 ovarian cancer (one 1st degree) Green is low risk No action

required

3 or more breast and/or ovarian cancer at any age Orange is moderate or high risk Refer to FH clinic

What to do if a patient has a family history of Breast/Ovarian Cancer

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.

The family history should be of affected blood relatives through either the maternal or paternal side of the family. If there is Jewish ancestry in the family, the history may be more significant – seek advice from the Clinical Genetics service. Refer affected patients and close female relatives. For enquiries about a patient’s family history, or if there is a history of unusual cancers, please contact the Clinical Genetics

Service on : 0114 2717025.

Key Green is low risk Orange is moderate risk Pink is moderate to high risk Red is high risk

Number of close relatives with bowel cancer

Age of cancer diagnosis Refer to FH clinic

1(1st degree) <45

>45 x

1 (1st degree) Separate or multiple tumours at any age

1 (1st degree-polyps only) More than one significant (>10mm) polyp under 50yrs Average age < 70

2 (same side or both parents) >70 x

2 (same side)* Average age <50

3 or more (same side)* Any age

Polyposis Coli Positive family history

*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.

What to do if a patient has a family history of bowel and related cancers.

A close relative is any first or second degree relative (parent, brother, sister, child, aunt, uncle, grandparent). The family history should be of affected blood relatives through either the maternal or paternal side of the family. For enquiries about a patient’s family history, or if there is a history of unusual cancers, please contact the Clinical Genetics

Service on :0114 2717025.

The End

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