genetics and reproductive options for sma families · kandel, jh schwartz, tm jessell , eds., 4....
TRANSCRIPT
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Genetics and Reproductive Options for SMA Families2018 Annual SMA ConferenceDallas, TexasFriday, June 15, 2017
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Part 1: SMA and GeneticsLouise R Simard, PhD
Part 2: SMA Carrier ScreeningMelissa Gibbons, MS CGC
Part 3: Reproductive Options for SMA Families
Harvey J Stern, MD, PhD
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Genetics and Reproductive Options for SMA Families
Part 1: SMA and Genetics
Louise R. Simard, PhDUniversity of Manitoba, Faculty of Medicine
Dept. Biochemistry & Medical GeneticsWinnipeg, MB, Canada R3E 0J9
1987 - Ph.D. U Toronto – Medical Genetics. 1988-2006 – Ste. Justine Hospital Research Centre, U Montreal
Independent research program in SMADNA diagnostics Consultant, incl. SMA testing
2006-present – Professor, Department Head, U Manitoba
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Questions are welcome!
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Genetics and Reproductive Options for SMA Families
Outline• SMA
Lower Motor Neuron Disease With a wide range of clinical presentation (severity)
• SMA Gene SMN1 and SMN2 SMN1 Mutations SMA severity
• SMA Genetics Chromosomes as vehicles of the DNA genomic blueprint Autosomal Recessive Inheritance
• SMA Molecular Tests Diagnosis Carrier
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Part 1: SMA and Genetics
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Genetics and Reproductive Options for SMA Families
SMA is a lower motor neuron disease that recurs in families (inherited).
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Type 2Intermediate SMA
< 18 monthsNever stand unaided
Decreased life expectancy
Type 3Kugelberg-Welander
18 monthsStand alone but loss of mobility
Normal life expectancy
Type 4 Adult SMA≥21 years of age
Progressive muscle weaknessNormal life expectancy
Type 1Werdnig-Hoffman
< 6 monthsNever sit unaided
Death before 2 years
Type 0Prenatal SMA
In uteroRespiratory support
Death before 1 month
Disease Severity
01
23
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Wide ClinicalPresentation!
Image adapted from from“Principles of Neural Science”, ER Kandel, JH Schwartz, TM Jessell,
eds., 4th Ed. McGraw Hill.
Loss of MN cells leads to Muscle Atrophy
Part 1: SMA and Genetics
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Genetics and Reproductive Options for SMA Families
Identifying the SMA gene 1 gene 5 SMA types
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Nature (1990) 345:823-825Nature (1990) 540-541
Nature (1990) 344:767-768 Lancet (1990) 336:271-273
Lefebvre et al., (Melki laboratory, INSERM Institut Necker)
Part 1: SMA and Genetics
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Genetics and Reproductive Options for SMA Families
Genetic Code = Blueprint of life~20,000 genes in the human genome
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DNA = four nucleic acids (C, G, T, A)Different sequence of A-C-T-G = geneC (cytosine) pairs with G (guanine)T (thymine) pairs with A (adenine)
CGT
AT A
A
TCG GC
CG
GC
AT TA
www.photoresearchers.com
1953
Part 1: SMA and Genetics
Geno
me
Deco
ratio
n Pa
ge/N
CBI
https://autisable.com/
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Genetics and Reproductive Options for SMA Families
SMN1 vs. SMN2 gene Chr 5q13
1 2 3 4 5 6 7 8Promoter
CSTOP
1 2 3 4 5 6 7 8Promoter
TSTOP
1 2 3 4 5 6 8
STOP
Start
STOP
1 2 3 4 5 6 7 8
Start
DNA (a)
RNA (b)
mRNA (c)
proteinunfunctionalprotein
functionalprotein
~10% Full-length transcripts
~90% Nonfunctional SMN protein
100% Full-length transcripts
Functional Wild Type SMN protein
> 99 % identical
SMN2 SMN17T
7
C
8
http://www.bbc.com/news/science-environment-27592655
Mutations in SMN1Cause 5q-SMA
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Genetics and Reproductive Options for SMA Families
Deletions (missing DNA) is a common mutation in SMA
SMN1 7 8
Very large deletions are often associated with type I and type II
SMA. Type I SMAs most often cannot make ANY SMN.
In Type II & III SMA, the mutation is often confined to SMN1 exon 7.
% p
atie
nts
Simard et al., (1997) Am J Med Genet 72:51-58
0
10
20
30
40
50
60
70
80
90
100
type I type II type III
SMN null SMN E7
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Part 1: SMA and Genetics
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Genetics and Reproductive Options for SMA Families
SMA locus is very variable
But…also find:
SMN2 SMN1
SMN2 SMN1On average:
SMN1
SMN2 SMN1SMN2
SMN1SMN1No apparent Clinical effect
SMN2
SMN2 SMN1 SMN2SMA causing
Chromosomes
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Part 1: SMA and Genetics
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Genetics and Reproductive Options for SMA Families
SMN2 is a major modifier geneSMN2 copy number decreases with increasing severity
0
10
20
30
40
50
60
70
80
90
1 2 3 4
type I
type II
type III
% p
atie
nts
# SMN2 copies
n=188n=110n=77
Taken from Feldkotter et al., (2002) Am J Hum Genet 70:358-368
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Part 1: SMA and Genetics
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Genetics and Reproductive Options for SMA Families
SMA is inherited as an Autosomal Recessive Disorder
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The fundamental unit of inheritance is DNA.Each cell has over 5 feet of DNA! It must be compacted to fit inside a cell in the form of chromosomes.
We have 23 pairs of chromosomes; each set is inherited from our biological parents.
www.sciencemuseum.org.uk
SMA autosomal recessivemode of inheritance
********************************************There must be a mutation (error) in both copies of a gene (maternal and paternal) for the genetic disorder to be passed onto a child.
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https://www.biography.com/.image/t_share/MTIwNjA4NjMzNTA5MDg2NzMy/gregor-mendel-39282-1-402.jpg
Part 1: SMA and Genetics
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Genetics and Reproductive Options for SMA Families
SMA is inherited as an Autosomal Recessive Disorder
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• Affected individuals have mutations in both copies of a recessive gene.
• Carriers have a mutation in only one copy of a recessive gene and is asymptomatic.
• Males and females can be carriers.
• Males and females can be affected.
• If both parents are carriers, the risk of having a child with the disease is 25%.
Part 1: SMA and Genetics
Having an affected child is a surprise because carrier parents are
asymptomatic. From this point onwards – genetic
counseling becomes possible.
1 in 4 Chance25%
1 in 4 Chance25%
1 in 2 Chance (50%)
Taken from ghr.nlm.nih.gov
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Genetics and Reproductive Options for SMA Families
>95% of patients have deleterious mutations in the SMN1 gene(deletions, gene conversions, point mutations)
SMN1 7SMN27T C
X
point mutation
deletion
gene conversion SMN1 SMN2SMN27T T
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Part 1: SMA and Genetics
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Genetics and Reproductive Options for SMA Families
Molecular Diagnostic Tests
• Detection of homozygous mutations presence/absence of SMN1 Ex7 = diagnosis
• Detection of heterozygotes Number of copies of exon 7 = carrier testing
• Analysis of point mutations = diagnosis Not yet routine, specialized labs only
SMN2 SMN17T
7
C
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Part 1: SMA and Genetics
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Genetics and Reproductive Options for SMA Families
(164 pb)SMN2(187 pb)SMN1
Van der Steege et al. (1996) Am J Hum Genet 58:834-838.
All or None test!
Diagnostic Tests: SMN1 mutationsDiagnosis of SMA patients
Compared to EMG & muscle biopsy, the DNA test is:• non-invasive• sensitive, detects >95% of all SMAs• accurate, all lacking SMN1 exon 7 have SMA• ideal for newborn screening
Limitation: Some SMA individuals have a point mutation in the SMN1 gene. Such mutations are not detected by the deletion or quantitative PCR assay.
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Part 1: SMA and Genetics
Taken from Passon et al. (2010) Mol Cell Probes 24:310
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Genetics and Reproductive Options for SMA Families
Diagnostic Tests: Carrier Detection2 vs. 1 copy of SMN1 exon 7 test (dosage)
• 95% of SMA patients are lacking SMN1 exon 7
• Because SMA is an autosomal recessive disorder, most SMA carriers should have only 1 copy of SMN1 exon 7
SMN1
SMN2SMN1:SMN2 copies
2:1 2:21:31:20:4 0:4 0:3
McAndrew et al. (1997) Am J Hum Genet 60:1411-1422 Rochette et al., (1997) Neurogenetics 1:141-147.
Detection of heterozygotesSMN quantitative test
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Part 1: SMA and Genetics
Taken from Passon et al. (2010) Mol Cell Probes 24:310
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Genetics and Reproductive Options for SMA Families
Diagnostic Challenges Rarely able to give a 100% Yes or No result.
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Part 1: SMA and Genetics
These tests do not detect small mutations in the SMN1 gene.
Taken from Alías et al. (2009) Human Genetics 125:29
2 to 5% of individuals have both SMN1 genes on the same chromosome
(2+0 genotype) - so are carriers
On average:SMN2 SMN1
SMN2 SMN1
SMN2
SMN2 SMN1 SMN1
But….
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Genetics and Reproductive Options for SMA Families
A Genetic Counselor is a valuable resource to help you understand the genetics of SMA, opportunities for testing (diagnosis, carrier status, prenatal) and how to interpret test
results.
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Part 2: SMA Carrier ScreeningMelissa Gibbons, MS CGCCertified Genetic Counselor
Neuromuscular Clinic Children’s Hospital Colorado
Assistant ProfessorUniversity Colorado School of Medicine
MemberCure SMA Medical Advisory Committee
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Genetics and Reproductive Options for SMA Families
Genetic Counselors are:
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• Master’s-trained health care professionals who combine their knowledge of: ―Basic science―Medical genetics―Epidemiological principles―Counseling theory
• With their skills in: ―Genetic risk assessment―Education―Interpersonal communication and counseling
• To provide services to clients and their families for a diverse set of genetic or genomic indications
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Genetics and Reproductive Options for SMA Families
Genetic Counselors work in:
• Clinical Setting―Preconception―Prenatal―Pediatric―Adult―Cancer
• Genetic Testing Laboratory• Pharmaceutical Companies
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Genetics and Reproductive Options for SMA Families
Genetic Counselor can:
• Explain your/your child’s results• Discuss different genetic testing options• Assist with coordinating carrier testing for
―You―Extended Family
• Provide family education • Discuss treatment options• Discuss reproductive options
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Genetics and Reproductive Options for SMA Families
Understanding Your Results
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http://www.curesma.org/documents/support--care-documents/genetics-of-sma.pdf
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Genetics and Reproductive Options for SMA Families
Understanding Your Results
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Positive Deletion Results:
Inconclusive Deletion Results:
Additional Types of Sequencing Results:
Sequencing Results:
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Carrier Testing Affected Individual has
2 SMN1 Deletions
Parents and Extended Family can be tested by
Deletion Studies
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Affected Individual has1 SMN1 Deletion &
1 SMN1 Point Mutation
Parents should be tested first to determine
targeted testing for the extended family
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Genetics and Reproductive Options for SMA Families
Different Types of Carriers“1 + 0”
“2 + 0”
5q
5q
SMN1
5q
5q
SMN1SMN1
5q
5q
SMN1 SMN1
5q
5q
SMN1SMN1
SMN1
*“2 + 0*”
*Point mutation or microdeletion.Adapted from PMCID: PMC3234503
“1 + 1*”*
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Genetics and Reproductive Options for SMA Families
What does negative mean?
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Genetics and Reproductive Options for SMA Families
What does negative mean?g.27134T>G
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Genetics and Reproductive Options for SMA Families
Options for Carrier Testing • Single gene testing
―Testing for one condition―Also referred to as known familial mutation testing
• Targeted carrier screening―Testing based on your ethnicity or family history―Also referred to as ethnic-based carrier screening
• Expanded carrier screening―Many disorders are screened for using a single sample―Test selection is done without regard to race or ethnicity―Each company determines the genes on their panel ―Screening panels usually focus on severe disorders that
affect a person’s quality of life from an early age
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Genetics and Reproductive Options for SMA Families
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Genetics and Reproductive Options for SMA Families
Carrier Testing
• Allows for more informative preconception counseling
− Reproductive risks for the couple− Discussion of preimplantation/prenatal testing options− Development of PGD for your family
• Provides information to family members− Who should be tested− What testing do they need
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Genetics and Reproductive Options for SMA Families
Resources
• Genetic Counselors on the Cure SMA Medical Advisory Board
− Jin Yun (Helen) Chen, Massachusetts General Hospital− Khalida Liaquat, Quest Diagnostics− Melissa Gibbons, Children’s Hospital Colorado
• National Society of Genetic Counselors―NSGC.org
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Part 3: Reproductive Options for SMA Families
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Harvey J. Stern MD, PhDDirector, Reproductive GeneticsGenetics & IVF Institute
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Genetics and Reproductive Options for SMA Families
Workshop GoalsWhat are the genetic aspects of SMA especially as they relate to
reproduction?
What are the reproductive choices for families at-risk for SMA?
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RECESSIVE DISEASE
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Genetics and Reproductive Options for SMA Families
Very difficult decisions about family building
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Reproductive Options for SMA Families
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Genetics and Reproductive Options for SMA Families
Reproductive Options for SMA Families
• Decisions regarding childbearing are personal and reflect our own ethical, moral and religious views. This is not a “one size fits all” type of issue.
• Couples who are at-risk for a genetic disorder should be allowed to make up their own minds after considering all their reproductive options.
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Genetics and Reproductive Options for SMA Families
Reproductive Options for SMA Families
• Decisions are influenced by the couple’s experience with SMA. Those who have had a child or sib affected will react differently from a couple identified to be at-risk by genetic screening.
• Decisions are also influenced by couple’s attitudes towards prenatal diagnosis and assisted reproduction (“playing God”)
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Genetics and Reproductive Options for SMA Families
Reproductive Options for SMA Families
Most families do not wish to bring another child with SMA into the world.
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Genetics and Reproductive Options for SMA Families
• Have no or no more children (Most Common Choice)
• Adoption• Use a gamete donor (pre-tested for SMA)
Reproductive Options for SMA Families
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Genetics and Reproductive Options for SMA Families
Reproductive Options for SMA Families
Natural conception with 1st or 2nd
trimester prenatal testing.Preimplantation Genetic Diagnosis
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Genetics and Reproductive Options for SMA Families
What is PGD?
• Involves the use of assisted reproduction technologies (IVF) to provide a method of prenatal diagnosis.
• Offers an alternative to traditional methods of prenatal diagnosis including chorionic villous sampling and amniocentesis, with the option of termination of affected pregnancies.
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Genetics and Reproductive Options for SMA Families
Development of PGD
• This year represents the 28th anniversary of the first application of PGD in humans.―(Handyside et al. Nature 244 1990)
• Since 1990, approximately 400,000 PGD cycles have been performed worldwide.
• This has resulted in over 100,000 PGD babies born after the procedure.
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Transfer unaffected embryos to the patient
affected affectedaffected
PGD for Genetic Disease
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In-Vitro Fertilization (IVF)
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Genetics and Reproductive Options for SMA Families
Questions About PGD
Why do I need to do IVF, I have no trouble getting pregnant?
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Genetics and Reproductive Options for SMA Families
Questions About PGD
• IVF is used to increase the odds of producing a healthy child.
• There is no change in the genetic material (egg or sperm).
• By creating multiple embryos, one increases the chance that good quality embryos which are not affected with SMA will be present and available to be returned to the uterus.
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IVF Procedure
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Genetics and Reproductive Options for SMA Families
IVF/PGD Procedure
Components of IVF/PGD Cycle:1. Down-regulation (preparation)2. Ovarian Stimulation - FSH3. Egg Retrieval4. Fertilization (ICSI)5. Embryo biopsy and testing6. Embryo transfer to uterus
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Genetics and Reproductive Options for SMA Families
Parts Of An IVF Cycle
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Genetics and Reproductive Options for SMA Families
Normal Ovulation
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Embryo DevelopmentDay 2Day 3Day 4Day 5
Fertilization
2 cell4 cell
8 cell
Morula
Blastocyst
Adapted from Moore and Persaud, Saunders, 1993
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IVF: Monitoring Visit
0
500
1000
1500
2000
2500
3000
0 2 4 6 8 10 12 14
Estradiol levels
Follicle measurement
Days of FSH Stimulation
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Genetics and Reproductive Options for SMA Families
Stimulated Ovary
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Egg Retrieval
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Egg Aspiration
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Egg Ready For Fertilization
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Fertilization by IntracytoplasmicSperm Injection
ICSI
ICSI60
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Embryo Development
2 cell
3 cell
4 cell
8 cell
61From: Veeck LL, An Atlas of Human Gametes and Conceptuses, Parthenon Publishing, 1999
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Embryo Development
Morula stageembryos
Blastocyst stage embryos
From: Veeck LL, An Atlas of Human Gametes and Conceptuses, Parthenon Publishing, 1999
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Embryo Transfer
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Genetics and Reproductive Options for SMA Families
PGD for Single Gene Disorders
• Analysis involves whole genome amplification with multiplex PCR amplification of the mutation along with 3-4 linked polymorphic markers which generate a chromosomal haplotype.
• At the same time, the embryos are also tested by a chromosomal microarray for abnormalities (ie. Down syndrome) which can lead to failed implantation or pregnancy loss.
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Genetics and Reproductive Options for SMA Families
PGD for SMA
EmbryoBiopsy
SMN gene
SMN 1 & 2 = unaffected
SMN 2 only = affected
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NO SMN1Affected
SMN1 PresentSMN 1 & 2
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Genetics and Reproductive Options for SMA Families 70
24 Chromosome Analysis by MicroarrayPerformed concurrently with SMA testing to identify the embryos with the best potential to make a baby as well as being free of SMA.
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Genetics and Reproductive Options for SMA Families
Accuracy of PGD
• Using the combination of mutational analysis and linked markers the accuracy of the test 98-99%.
• Contamination with external DNA is a major concern.
• Analyses done in surgical clothing in biohazard hood.
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Genetics and Reproductive Options for SMA Families
Specific Issues with IVF/PGD
• Patient Discomfort: Medications are given by injection (subQ).
• Abdominal distention and discomfort and some nausea are common.
• Egg retrieval done under anesthesia.
• Ovarian hyperstimulation syndrome 1-2%.
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Genetics and Reproductive Options for SMA Families
Questions about IVF/PGD
• Is IVF Safe?• What will I feel?• Does it increase cancer risk?• Are the babies born normal?• What are the costs?• What about insurance?
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Genetics and Reproductive Options for SMA Families
Questions About IVF/PGD
What is the success rate of IVF/PGD?• Varies, particularly with maternal age, but in
large series 50-60% of patients became pregnant per IVF/PGD cycle.
• Improved with concurrent testing for chromosome abnormalities.
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Thank you!!!
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