and Family Planning https://www.youtube.com/watch?v=5GPPt0kftfE - - PowerPoint PPT Presentation

Genetics, Reproduction and Family Planning

https://www.youtube.com/watch?v=5GPPt0kftfE

Many genes identified in bleeding disorders

Semin Thromb Hemost 2019; 45(07): 695-707 DOI: 10.1055/s-0039-1687889

Haemophilia A Haemophilia B Von Willebrand disease

Questions about bleeding disorders

• How did this happen?
• Could other family members/ future children

have a similar bleeding disorder ?

• Gene testing other family members?
• Can we test for the bleeding disorder during a

pregnancy?

• Is there are way to avoid having a pregnancy

with the bleeding disorder?

https://www.forbes.com/sites/work-in- progress/2019/07/08/if-you-want-to-look-smart-ask- these-questions/#59ddc2db1448

Genetic counselling session

“Genetic counselling is a communication process, which aims to help individuals, couples and families understand and adapt to the medical, psychological, familial and reproductive implications of the genetic contribution to specific health conditions”

Resta et al, (2006) A new definition of genetic counelling: NSGC task force report, J Gen Couns

https://www.massgeneral.org/tsc/patient-ed/comprehensive- care-genetic.aspx

Questions about bleeding disorders

• How did this happen?
• Could other family members/ future children have

a similar bleeding disorder ?

• Gene testing other family members?
• Can we test for the bleeding disorder during a

pregnancy?

• Is there are way to avoid having a pregnancy with

the bleeding disorder?

https://www.forbes.com/sites/work-in- progress/2019/07/08/if-you-want-to-look-smart-ask- these-questions/#59ddc2db1448

Genes encode for proteins

Greenwood Genetic Centre. 6th Ed. Counseling Aids

Alteration in gene can affect production of protein

https://cdn.prod-carehubs.net/n2/71b34990bba71dfd/uploads/2018/07/genemutations-aid.png

Haemophilia A

Factor VIII production Important for blood clotting Problem with production

• f normal Factor VIII

levels Haemophilia A

• F8 gene instruction is responsible for…
• If there is an alteration in the F8 gene…

Haemophilia B

Factor IX production Important for blood clotting Problem with production

• f normal Factor IX

levels Haemophilia B

• F9 gene instruction is responsible for…
• If there is an alteration in the F9 gene…

von Willebrand disease

von Willebrand Factor production Important for adhesion of platelet plug and blood clotting Problem with production

• f normal von Willebrand

factor von Willebrand disease

• VWF gene instruction is responsible for…
• If there is an alteration in the VWF gene…

? Family history

• New genetic change
• Inherited (from one or both parents)

Questions about bleeding disorders

• How did this happen?
• Could other family members/ future children have

a similar bleeding disorder ?

• Gene testing other family members?
• Can we test for the bleeding disorder during

pregnancy?

• Is there are way to avoid having a pregnancy with

the bleeding disorder?

https://www.forbes.com/sites/work-in- progress/2019/07/08/if-you-want-to-look-smart-ask- these-questions/#59ddc2db1448

Genes are packaged into chromosomes

Greenwood Genetic Centre. 6th Ed. Counseling Aids

The F8 and F9 gene are both found on the X chromosome

Genetics of Haemophilia

• Haemophilia A and Haemophilia B

– Men with gene mutation affected by condition – Women with gene mutation usually milder bleeding disorder or unaffected (carrier of haemophilia)

How can girls have haemophilia?

Random inactivation of

• ne X in each cell

XX XX XX

XX

XX

XX

XX

Very early cell division Usually switch off roughly ‘half-half’ - many females have mild bleeding tendency

X chromosome inactivation

non functioning gene

But rarely a female will have moderate to severe bleeding

Inactivation can sometimes be randomly ‘skewed’ one way or the

• ther

XX XX XX .X X. X. X.

Can have almost no cells with a functioning FVIII or FIX gene – very low factor levels and moderate to severe bleeding – similar to that seen in males

‘Skewed’ X chromosome inactivation

non functioning gene

X X X/X

Inheritance of Haemophilia

Inheritance of Haemophilia

https://ghr.nlm.nih.gov/primer/illustrations/xlinkrecessive.jpg

The VWF gene is located on chromosome 12

Genetics of von Willebrand disease

• von Willebrand disease can equally affect men

and women

• Different types of von Willebrand disease

which can be inherited in different ways and can be complex

Inheritance of von Willebrand disease

Inheritance of von Willebrand disease

Other Genetic bleeding disorders

Dorgalaleh and Rad, Congenital Bleeding Disorders at https://scholar.google.com/citations?user=75MCVGgAAAAJ&hl=en&oi=sra

Questions about bleeding disorders

• How did this happen?
• Could other family members/ future children have

a similar bleeding disorder ?

• Gene testing other family members?
• Can we test for the bleeding disorder during a

pregnancy?

• Is there are way to avoid having a pregnancy with

the bleeding disorder?

https://www.forbes.com/sites/work-in- progress/2019/07/08/if-you-want-to-look-smart-ask- these-questions/#59ddc2db1448

Gene testing

For affected person gene testing may

– Confirm diagnosis – Add to understanding of likely prognosis/management – Allow or make simpler testing in other family members – Identify mutation for reproductive planning

https://www.bellairetpp.org/columnseditorials/2019/05/23/ genetic-testing-our-future/

Gene testing

• Detection rate targeted diagnostic testing

– 95% for haemophilia A – Greater than 95% for haemophilia B – VWD

• 65% -85% depending on severity Type 1
• >90% Type 2
• 80-90% Type 3
• Beware – reproductive carrier screening panels

https://www.bellairetpp.org/columnseditorials/2019/05/23/ genetic-testing-our-future/

Carrier testing in healthy individuals

• Can’t rely on factor levels alone
• Genetic carrier testing can clarify chance of having

an affected child & may inform pregnancy management

• Inform whether need for genetic testing in other

family members (cascade testing)

• Genetic carrier testing for obligate carriers

Timing of carrier testing

• Before / as part of family planning
• Understand information and competent to

consent to testing

• Chance of altered self image
• Open communication prior to carrier testing can

make a difference

Communication of carrier status

• Different for everybody
• Privacy vs need/desire to share information
• When to discuss with partner?
• Fears about how person may respond
• Delaying too long can sometimes result in

mistrust/resentment

• Preparing for conversations can help
• Resources - Haemophilia Foundation

Questions about bleeding disorders

• How did this happen?
• Could other family members/ future children

have a similar bleeding disorder ?

• Gene testing other family members?
• Can we test for the bleeding disorder during a

pregnancy?

• Is there are way to avoid having a pregnancy

with the bleeding disorder?

https://www.forbes.com/sites/work-in- progress/2019/07/08/if-you-want-to-look-smart-ask- these-questions/#59ddc2db1448

Genetic testing in pregnancy

• Decision to test or not to test is very personal

– To inform precautions at time of delivery and neonatal period – For psychological preparation – For consideration of termination of pregnancy

Non invasive prenatal screening to determine sex of baby

• Non-invasive prenatal testing

(NIPT)

– No risk to pregnancy – Usually performed from 10 weeks – Detects cell free DNA from fetus in mothers blood – Checks sex of baby but doesn’t check for altered gene – Small chance of incorrect sex determination – U/S follow up

http://pathcarelifesciences.com/nipt/

Chorionic villus sampling (CVS)

• 11-12 weeks of pregnancy
• Sample of chorionic villi

(placenta)

• Less than 0.5% (1 in 200)

chance of miscarriage from procedure

http://pathcarelifesciences.com/nipt/

• Genetic testing for familial mutation performed
• n specimen

Amniocentesis

• 15 weeks onwards
• Sample of amniotic fluid
• Less than 0.5% (1 in 200)

chance of miscarriage from procedure

http://pathcarelifesciences.com/nipt/

• Genetic testing for familial mutation

performed on specimen

Questions about bleeding disorders

• How did this happen?
• Could other family members/ future children have

a similar bleeding disorder ?

• Gene testing other family members?
• Can we test for the bleeding disorder during a

pregnancy?

• Is there are way to avoid having a pregnancy

affected with the bleeding disorder?

https://www.forbes.com/sites/work-in- progress/2019/07/08/if-you-want-to-look-smart-ask- these-questions/#59ddc2db1448

Preimplantation genetic diagnosis (PGD)

Possible for almost all disorders/scenarios that can be diagnosed prenatally Analysis of DNA from a few cells only More technically challenging than prenatal tests Expensive, not currently funded in public system in NSW

Conditions for which couples have requested PGD

Indication # workups 1 Cystic fibrosis 111 2 Translocation 111 3 Huntington disease (direct and exclusion) 73 4 Fragile X 42 5 HLA Match 37 6 Beta thalassemia 33 7 Myotonic muscular dystrophy 31 8 Facioscapulohumeral muscular dystrophy 26 9 Haemophilia (A and B) 25 10 Neurofibromatosis type 1 23 11 Charcot Marie Tooth 1A 18 12 connexin 26 17 13 AD PKD1 16 14 BRCA1 breast cancer 16 15 Duchenne muscular dystrophy 16 16 marfan syndrome 16 17 alpha thalassaemia 14 18 Microduplication/deletion 13 19 spinal muscular atrophy I 13 20 Familial adenomatous polyposis (FAP) 12

PGD process

Fertilisation using ICSI (Intracytoplasmic sperm injection) Embryo development (Day 1 – Day 5/6) Biopsy hatching blastocyst

www.artreproductivecenter.com

Biopsy of the hatching blastocyst

https://www.youtube.com/watch?v=LGjFAcijiEA

Chances of success for a couple

Depends on maternal age Co-existing fertility problems Genetics of their condition

Balancing the pros and cons

Balancing the pros and cons

Psychosocial aspects of reproductive decision making

• May be influenced by

– Experience and perception of bleeding disorder – Religious/ moral beliefs – Feelings of guilt/responsibility – Consideration of impact/views of partner/other family members – Reproductive history – Economic / practical considerations

http://pathcarelifesciences.com/nipt/

Resources