Genetics, Reproduction and Family Planning https://www.youtube.com/watch?v=5GPPt0kftfE Many identified in disorders

Haemophilia A B

Semin Thromb Hemost 2019; 45(07): 695-707 DOI: 10.1055/s-0039-1687889 Questions about bleeding disorders https://www.forbes.com/sites/work-in- progress/2019/07/08/if-you-want-to-look-smart-ask- these-questions/#59ddc2db1448 • How did this happen? • Could other family members/ future children have a similar bleeding disorder ? • 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? Genetic counselling session https://www.massgeneral.org/tsc/patient-ed/comprehensive- care-genetic.aspx

“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 Questions about bleeding disorders

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

Greenwood Genetic Centre. 6th Ed. Counseling Aids Alteration in gene can affect production of

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

• F8 gene instruction is responsible for…

Important for blood Factor VIII production clotting

• If there is an alteration in the F8 gene…

Problem with production of normal Factor VIII Haemophilia A levels

• F9 gene instruction is responsible for…

Important for blood Factor IX production clotting

• If there is an alteration in the F9 gene…

Problem with production of normal Factor IX Haemophilia B levels von Willebrand disease

• VWF gene instruction is responsible for…

Important for adhesion of plug and blood production clotting

• If there is an alteration in the VWF gene…

Problem with production of normal von Willebrand von Willebrand disease factor ? Family history

• New genetic change • Inherited (from one or both parents) Questions about bleeding disorders

https://www.forbes.com/sites/work-in- progress/2019/07/08/if-you-want-to-look-smart-ask- these-questions/#59ddc2db1448 • 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? Genes are packaged into chromosomes

Greenwood Genetic Centre. 6th Ed. Counseling Aids The F8 and F9 gene are both found on the Genetics of Haemophilia

• Haemophilia A and Haemophilia B – Men with gene affected by condition – Women with gene mutation usually milder bleeding disorder or unaffected (carrier of haemophilia) How can girls have haemophilia? X chromosome inactivation non functioning gene XX Very early cell division XX XX Random inactivation of XX XX XX XX one X in each cell

Usually switch off roughly ‘half-half’ - many females have mild bleeding tendency But rarely a female will have moderate to severe bleeding non functioning ‘Skewed’ X chromosome inactivation gene XX

XX XX Inactivation can sometimes be randomly .X X. X. X. ‘skewed’ one way or the other 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 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

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

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

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 Gene testing

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

https://www.forbes.com/sites/work-in- progress/2019/07/08/if-you-want-to-look-smart-ask- these-questions/#59ddc2db1448 • 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? 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 http://pathcarelifesciences.com/nipt/ mothers blood – Checks sex of baby but doesn’t check for altered gene – Small chance of incorrect sex determination – U/S follow up 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 on 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

https://www.forbes.com/sites/work-in- progress/2019/07/08/if-you-want-to-look-smart-ask- these-questions/#59ddc2db1448 • 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? Preimplantation genetic diagnosis (PGD)

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

www.artreproductivecenter.com https://www.youtube.com/watch?v=LGjFAcijiEA Chances of success for a couple

Depends on Co-existing fertility maternal age 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 http://pathcarelifesciences.com/nipt/ – 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 Resources