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6th EUROPEAN SYMPOSIUM ON RARE ANAEMIAS 1st Dutch-Belgian meeting for patients and health professionals
21st - 22nd November 2015
Amsterdam - The Netherlands
Will your child be sick as well? Testing before pregnancy
B. Gulbis, M.D., PhD
Université Libre de Bruxelles
Brussels, Belgium
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals
Disclosures Company name Research
support Employee
Consultant Stockholder Speakers bureau Advisory board Other
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals
This talk is applicable for:
Definite Probable
Thalassemia’s X
Sickle cell disease X
Membrane disorders (e.g. sferocytosis)
Enzym defects (e.g. PKD, G6PD) X
PNH
Other forms of hemolytic disease X
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 4
Plan
• Preconception – prenatal diagnosis: the procedures
– Invasive
– Non-invasive
– Future?
• How to provide those diagnostic procedures?
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals
Will our child be sick as well?
Genetic counselling
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 6
Invasive procedures Prenatal diagnosis
Prenatal diagnosis (Antenatal screening)
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 7
Invasive procedures Prenatal diagnosis
Prenatal diagnosis (Antenatal screening)
Amniocentesis
Fetal
Blood
Sampling
Chorionic
Villous
Sampling
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 8
Invasive procedures Prenatal diagnosis: 10 – 12 weeks
Prenatal diagnosis (Antenatal screening)
Amniocentesis
Fetal
Blood
Sampling
Chorionic
Villous
Sampling For Prenatal Diagnosis (1983: Rodeck et al; Simonini et al; Ward et al).
Safety
• Ultrasound guidance
• Fetal medicine specialists
• Not before 10 weeks of gestation
(see limb disruption defects)
• Post-procedure loss 1%
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 9
Invasive procedures Prenatal diagnosis: after 15 weeks Prenatal diagnosis (Antenatal screening)
Amniocentesis
Fetal
Blood
Sampling
Chorionic
Villous
Sampling
Safety • Ultrasound guidance • Fetal medicine specialists • Not before 15 weeks of gestation (see direct fetal injury, amniotic membrane damage, high rate of culture failure) • Post-procedure loss 0.5%
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 10
Hôpital Erasme experience Prenatal diagnosis
CVS = 40% (107/268)
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals
CVS - Amniocentesis
CVS Amniocentesis
Timing (weeks) 10 – 11 15 -
Chance of successful sampling
99% (contamination)
99%
Miscarriage risk ± 1% ± 0.5 %
Time required for diagnosis
3 – 7 days 3 to 7 days Culture: 2 to 3 weeks
11
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 12
Preimplantation Genetic Diagnosis (PGD)
Diagnosis on day 4
Transfer on day 5
In vitro fertilisation
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 13
Preimplantation Genetic Diagnosis (PGD)
• PGD-PCR
– For monogenic diseases
– For HLA typing
– …
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 14
Preimplantation Genetic Diagnosis (PGD)
• PGD for whom?
– Infertile couples
– Previous history of termination of pregnancy
– Objection to termination of pregnancy
– Thinking of a saviour baby
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 15
Preimplantation Genetic Diagnosis (PGD)
• PGD with HLA-typing
– 1/4 HLA matched embryos
– Risk of no transferable embryo
– Future of non-HLA matched embryos but without the disease?
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 16
Preimplantation Genetic Diagnosis (PGD)
• Most frequent indications
– Cystic fibrosis (CF)
– Myotonic dystrophy (DM1)
– Huntington disease (HD)
– Haemoglobinopathies (HBB)
– Fragile-X syndrome (FraX)
– Spinal muscular atrophy (SMA)
– + HLA typing (HBB + HLA; HLA)
The ESHRE PGD Consortium: 10 years
of data collection Harper J et al. Hum. Reprod. Update 2012;humupd.dmr052
Number of cycles
DMD, Duchenne muscular dystrophy; NF1, neurofibromatosis type 1; HaemA, haemophilia A; HLA, human leukocyte antigen for acquired diseases; APC, familial adenomatous polyposis; CMT1, Charcot-Marie-Tooth disease type 1; FAP, familial amyloidotic polyneuropathy; MS, Marfan syndrome; TS, tuberous sclerosis; VHL, Von Hippel Lindau.
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 17
Preimplantation Genetic Diagnosis (PGD)
• Neonatal follow-up of 995 born children
– PGD= No extra risk
• Mean term
• Prematurity
• Mean birthweight
• Perinatal death
• Major malformations
• Neonatal hospitalizations
• Congenital anomalies
Desmyttere S. et al Hum. Reprod. 2012; 27:288-93.
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 18
Preimplantation Genetic Diagnosis (PGD)
• Up to 4 attempts per family to achieve a suitable donor sibling
• ~20% embryos diagnosed as suitable for transfer
• ~10% embryos diagnosed as suitable for transfer if + HLA-typing
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 19
PGD experience Hôpital Erasme – Fertility Clinic
• First PGD for haemoglobinopathy in 2006
• Records treated: n= 70 • 64 for sickle cell disease (3 HbSthal.; 6 HbSC)
• 6 for thal. major
• Records rejected: 9/70 - without follow-up: 16/70
• 63 cycles for 29 couples (Mean 2.2 cycle by couple)
– PGD performed on 34 cycles (54%) all for SCD
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 20
PGD experience Hôpital Erasme
• PGD failure (biopsy not obtained): n= 29 cycles
– Failure of stimulation (not enough oocytes) 48%
– To few embryos 21%
– No fecundation 14%
– Low quality of the embryos 7%
– Spontaneous pregnancy 7%
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 21
PGD experience Hôpital Erasme
Diagnosis on day 4: 151 embryos
Affected embryos N= 33
Unaffected embryos N= 107 (71%)
?
11
Unaffected, “good quality” embryos transferred
N= 54 (50%)
Cryopreservation N= 20 (19%)
Unaffected, “poor quality” embryos
Transfer not possible N= 20 (31%)
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 22
PGD experience Hôpital Erasme
Diagnosis on day 4: n= 151
Transfer on day 5: n= 54
Pregnancies: n= 18/54 (33%)
Failure: n= 10
16.5%
Baby n= 9 (1 twins)
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals
Prenatal/Preimplantation genetic diagnosis
Prenatal diagnosis PGD
Accuracy of genetic analysis
99% 99%
Risks Miscarriage, fetal injury No greater risk than conventional procedures
Major drawbacks Decision of abortion for affected embryos
Technically challenging Risk of IVF Low pregnancy and birth rates Costly
23
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 24
From the technique to the patient
•Detection of couple at risk
•Genetic counselling
•Fertility team
•If failure of stimulation or no fecundation…
•Molecular diagnosis •If failure of pregnancy or transferable embryo… •If failure of HLA matching embryo…
Couples should be clearly counselled before embarking on this reproductive option
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 25
Other options?
• Non-invasive prenatal testing with cell-free DNA
– … an accurate diagnosis of the presence or absence of the paternal mutation in the fetus was not possible in all cases to make it clinically applicable.
• D'Souza E et al J Postgrad Med. 2013 Jan-Mar;59(1):15-20. doi: 10.4103/0022-3859.109483. Detection of fetal mutations causing hemoglobinopathies by non-invasive prenatal diagnosis from maternal plasma.
– … provided that a previously born child is available for testing to determine the linkage to the paternal SNPs.
• Phylipsen M Prenat Diagn. 2012 Jun;32(6):578-87. doi: 10.1002/pd.3864. Epub 2012 Apr 20.
Non-invasive prenatal diagnosis of beta-thalassemia and sickle-cell disease using pyrophosphorolysis-activated polymerization and melting curve analysis.
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 26
Other options? • Gene therapy
–Ongoing clinical trials
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 27 Training Course on Haemoglobin Disorders 2011
Other options?
• New regulators of foetal haemoglobin ?
– two SNPs - BCL11A region rs4671393 and rs11886868
– three SNPs - HBS1L-MYB region rs28384513, rs9399137 and rs4895441
Nguyen TK et al Blood Cells Mol Dis. 2010 Aug 15;45(2):124-7.
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 28
Take home message
• Availability of relatively safe procedures
– Invasive or “non-invasive”
• New trends
• Complex procedures and not only “technical”
6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 29
Thank you very much for your attention