avoiding transmission of genetic disease avoiding transmission of genetic disease professor peter...
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Avoiding Transmission of Genetic Disease
Professor Peter BraudeDivision of Women’s Health
Kings College, London
Centre for Preimplantation Genetic Diagnosis
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Avoiding Transmission of Genetic Disease
• The health legacy of genetic disorders• Reproductive options for couples with history of
recurrent genetic risk• For what conditions is PGD successful• Options when PGD is difficult, inappropriate, or
won’t work
Centre for Preimplantation Genetic Diagnosis
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Health legacy of genetic disorders
Sporadic early embryonic loss
Recurrent pregnancy loss
Anatomical abnormality
Mental disability
Neonatal and childhood death
Chronic disease and early demise
Late onset disease
Centre for Preimplantation Genetic Diagnosis
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Recurrent: As a result of inherited
disorders
Sporadic:
Random, often age related
Two kinds of genetic risk
Centre for Preimplantation Genetic Diagnosis
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Autosomal Recessive Genetic Disease
1:4 free of disease; 1:2 carriers – but asymptomatic; 1:4 will be affected
Cystic fibrosisSpinal muscular atrophy Sickle cell diseaseTay-Sachs disease Fanconi Anaemia
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z
SymptomlessCarriers
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Autosomal Dominant Genetic Disease
Huntington’s DiseaseAchondroplasiaMarfan SyndromeNeurofibromatosisRetinoblastoma
50:50 (1:2) chance of passing on disease
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Haemophilia
Genetic disease
Women are carriers but generally don't have symptoms; only males affected
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Chromosome RearrangementsInheritable but pattern random
ESHRE 2015
46,XX,t(12;17)(p13;p13)
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Reproductive options for those with serious recurrent genetic risk
Gamete donationAdoptionRemain childless
Reproductive roulette
Prenatal diagnosis and termination of pregnancy
Centre for Preimplantation Genetic Diagnosis
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Preimplantation Genetic Testing
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Preimplantation Genetic Testing
Detection of genetic information in an embryo made by examining a representative sample taken at a preimplantation stage of development
Centre for Preimplantation Genetic Diagnosis
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Early human development in vitro
Late Day 1 2-cellsDay 1 Fertilised egg Day 2 4-cells Day 3 8-cells
Day 4 Morula
Day 5 BlastocystDay 6 Hatching blastocystLate Day 6 Hatched blastocyst
ICM
ICM
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Tissues for Preimplantation Biopsy
Polar Body Blastomere Trophectoderm
egg cleavage stage blastocyst
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Recurrent: As a result of inherited
disorders
Sporadic:
Random, often age related
Two kinds of genetic riskTwo kinds of genetic test
PGD
To diagnose known genetic condition
PGS
To screen for random aneuploidy to improve infertility outcome
Centre for Preimplantation Genetic Diagnosis
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The principle of PGD
Select for transfer to the patient
affected affectedaffected unaffectedunaffected
Centre for Preimplantation Genetic Diagnosis
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Sporadic Genetic Risk & InfertilityTheory for use of PGS
To improve chances of conception through IVF for women of older age and for those with IVF failure or repeated miscarriage
by screening for random aneuploidies
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“The extent to which beliefs are based on evidence is very much less than what believers suppose.”
Bertrand Russell
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ESHRE PGD Consortium members by country
number of centres: 11
number of centres: 86
number of centres: 27
Total number of centres: 124
(June 2015)
ESHRE 2015
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Indications PGD & PGS
0
1000
2000
3000
4000
5000
6000
7000
PGS
social sexing
sexing for X-linked disorders
chromosomal abnormalities
monogenic disease
ESHRE 2015
54,589 cycles
ESHRE 2015 Coonen: Unpublished and still to be verified data
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Monogenics
Chromosomal
Sexing X linked
Aneuploidy
Social sexing33 741 (58.0%)
668 (1.1%)
12 885 (22.2%)
9 081 (15.6%)
1 749 (3.0%)
ESHRE 2015 Coonen: Unpublished and still to be verified data
REASONS FOR EMBRYO BIOPSYESHRE Consortium data I-XV
Based on 54,589 cycles
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Cleavage stage mosaicism
15, 490 - 491 (2009)
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48% of cells testednormal at blastocyst stage
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Ermanno Greco, M.D.Maria Giulia Minasi, M.Sc.Francesco Fiorentino, PhD.European Hospital & Genoma Molecular Genetics LaboratoryRome, Italy
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In the light of recent re-evaluations of the risk benefit ratio, it seems that PGS has been oversold
“Rather than improving outcome for childless couples,PGS encourages the waste of healthy embryos which are excluded from transfer to the uterus.”
“The procedure just appears to increase costs and complexities of IVF. Its utilization, at present, should therefore be acknowledged as highly experimental
and refuted in routine IVF care.”
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Number of PGS cycles reaching a plateau?
1997/1998
1998/1999
1999/2000
20012002
20032004
20052006
20072008
20092010
20112012
0
500
1000
1500
2000
2500
3000
3500
4000
4500
PGS cycles over time
ESHRE 2015ESHRE 2015 Coonen: Unpublished and still to be verified data
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Single Gene 1
161
Rearrangements
798
X-Linked
132
Aneuploidy
Social S
exing
Tota
l 2
0910
5
10
15
20
25
30
35
40
45
Per Egg CollectionPer Embryo Transfer
Results of 2091 cyclesin one PGD only centre (1998 -2014)
Centre for Preimplantation Genetic Diagnosis
Ongoing PregnancyRate
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Range of SGD Cases for 2014
Centre for Preimplantation Genetic Diagnosis
191 biopsy cases
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Maternal Inheritance with variable expressionGenetic disease due to mtDNA mutations
(maternally inherited – in the egg)
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PGD for Nuclear DNA is Different from testing
Mitochondrial DNA
affectedunaffected
Nuclear DNA
Bad gene present or not present
Mitochondrial DNA (mtDNA)
Mixture of mutated and normal mtDNA (heteroplasmy) in each cell
Less likely to be affected
More likely to be affected
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PGD for mtDNA mutations
Less likely to be affected
More likely to be affected
PGD can workin heteroplasmy
All childrenwill be affected
PGD inappropriatein homoplasmy
Unlikely <20% Variable 20-50%
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What happens when both parents are affected by
genetic disease?
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What happens when both parents are affected by
dominant disease?
X1:4 free of disease; 3:4 will be affected or lethal
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What happens when both parents are affected by
recessive disease?
Sickle cell disease, Cystic fibrosis, Spinal muscular atrophy, Fanconi Anaemia, Tay-Sachs disease
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?