Download Objectives Case 1 - Precision Medicine Pathway

9/30/15 Objectives
•  Understand Preconcep4on and Post-­‐concep4on op4ons for gene4c tes4ng •  Pre-­‐Concep4on •  Review current guidelines for gene4c carrier screening (Amie) •  Review the in vitro fer4liza4on process (Kenan) •  Highlight the difference between preimplanta4on gene4c diagnos4c tes4ng and preimplanta4on gene4c screening •  Review the different stages of embryo development •  Post-­‐Concep4on •  Chorionic villous sampling, amniocentesis •  Aneuploidy screening •  Diagnos4c gene4c tes4ng Case 1
36 yo G0 who is interested in star4ng family. She has not family history of any medical problems, but notes that her ancestors are of Ashkenazi Jewish descent. Her husband 28 year old and is of Northern European descent and notes a family history of Hun4ngton’s disease in both his father and his paternal grandfather. He does not know whether he carries the Hun4ngton gene and would prefer not to know. What Preconcep4on carrier screening tes4ng is recommended? What addi4onal counseling does the woman’s age necessitate? What is their chance of having a child with Hun4ngton’s Disease given that the husband’s status is unknown? 1 9/30/15 Current Guidelines for Carrier Screening •  Professional guidelines (ACOG/ACMG/NSGC) •  Cys4c fibrosis •  2001 -­‐ offer to all Caucasian and Ashkenazi Jewish pa4ents •  2005 -­‐ offer pan-­‐ethnically •  Spinal Muscular Atrophy •  2008 – ACMG recommended offer pan-­‐ethnically •  ACOG recommends based on family history •  Screening offered based on stated ethnicity •  Hemoglobinopathies •  Thalassemias •  Ashkenazi Jewish carrier tes4ng •  Screening offered based on personal or family history •  Fragile X syndrome •  No society is recommending expanded carrier screening Current Guidelines for Ashkenazi Jewish Carrier Screening
ACOG (2004/2009/2014)   Offer to all: Cys4c Fibrosis, Canavan disease, Familial Dysautonomia and Tay Sachs   Make informa4on available on other tests so that pa4ent can make informed decision regarding addi4onal tes4ng ACMG (2008/2013)   Offer to all: Cys4c Fibrosis, Canavan disease, Familial dysautonomia, Tay Sachs AND Fanconi Anemia type C, Niemann Pick type A, Bloom syndrome, mucolipidosis type IV and Gaucher disease   Screening for addi4onal condi4ons as follows:   natural history of the condi4on is well understood and it carries a poten4al for significant morbidity and/or mortality   >90% detec4on rate OR allele frequency >1% in the Ashkenazi Jewish popula4on 2 9/30/15 Progenity Ashkenazi Panel
Limita4ons of Current Guidelines •  Inadequacy of ethnicity-­‐based screening: •  2010 US Census data – 32% increase in individuals repor4ng mul4ple races •  Preference against using racial and ethnic categoriza4on in medicine •  Possible unknown or unreported ancestry •  Lack of family history, limited knowledge, adop4on •  Family history based screening may not be helpful: •  Recessive nature of many condi4ons 3 9/30/15 Why not just test “everything”?
•  Several expanded carrier panels are being marketed   Typically screen for ~400 muta4ons in ~100 autosomal recessive disorders   The “long tail of Mendelian disease” Does everyone need to know what they are carriers for? Srinivasan BS et al, RBMO, 2010
Experience with Expanded Carrier
Screening
•  3,738 couples tested with Inheritest or Counsyl •  25.1% had ≥1 posi4ve result •  Only 7 couples (0.19%) had findings that impacted subsequent clinical management •  3 of these were CF and would have been captured on rou4ne screening Franasiak, ASRM 2014 4 9/30/15 Huntington disease
•  Autosomal dominant disorder caused by an expansion of a CAG trinucleo4de tract in the HTT gene •  Progressive disorder of motor, cogni4ve, and psychiatric condi4ons •  Mean age of onset is 35-­‐44 years of age F / B A / E ? A / B C / D 5 9/30/15 F / B A / E AT RISK NOT AT RISK ? A / B A / D B / C C / D A / C B / D B / C CASE 1
•  Carrier screening nega4ve for both. Couple would like to proceed with preimplanta4on gene4c diagnosis (PGD) to reduce risk of having child with Hun4ngton's disease 6 9/30/15 PGD for Single Gene Disorders
Putative Advantages
• Safer than elec4ve termina4on • More ethically and psychologically acceptable than termina4on for many couples • Provides the couple with more op4ons than: • Adop4on, steriliza4on, donor eggs or sperm Preimplantation Genetic Testing
• Preimplanta4on Gene4c Diagnosis (PGD) •  Done in individuals with KNOWN GENETIC DISORDERS (o0en fer5le) •  Different test for all individuals •  Even those with the same gene4c disorder •  Even those with the same muta4ons •  The analy4cal plaporm chosen may depend on the nature of the specific disorder 7 9/30/15 Single Gene Disorders
•  Are typically the result of a single mutated gene • 
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Muta4ons Trinucleo4de repeat expansions (HD) Dele4ons Duplica4ons •  > 6000 human diseases due to single gene disorders; occur in ~1 in 200 births •  Inheritence parerns: • 
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Autosomal dominant Autosomal recessive X-­‐linked dominant X-­‐linked recessive Y-­‐linked recessive Mitochondrial Single Gene Disorders
•  Autosomal Recessive Disorders •  β-­‐thalassemia and/or sickle cell syndromes •  Cys4c fibrosis •  Spinal muscular atrophy •  Autosomal Dominant Disorders •  Hun4ngton Disease •  Myotonic distrophy type I •  Charcot Marie-­‐Tooth •  Sex Linked Disorders •  Fragile X syndrome •  Duchenne and Becker muscular dystrophy •  Hemophilia A and B •  HLA Matching (Saviour Siblings) •  β-­‐thalassemia and/or sickle cell syndromes •  Fanconi anemia 8 9/30/15 Differences
Origins obetween
f Carrier
PGD WfTesting:
or SPGD/PGS
ingle Gene Rand
Expanded
Concerns
Iden4fy P
a4ents ith I
ncreased isk Genetic Carrier
Screening
Prenatal/Antenatal
Testing
Disorders •  5 Couples with X linked disorders •  Adrenoleukodystrophy •  X linked mental retarda4on 1990 •  Day 3 biopsy •  DNA amplifica4on with PCR •  Y chromosome specific sequence iden4fied •  Only female embryos transferred Handyside, et al. Nature 1990;244:768–70. PGD is a 3 step process
•  In vitro fer4liza4on (embryo crea4on) •  S4mula4on •  Egg retrieval •  Insemina4on/fer4liza4on •  Embryo culture •  Biopsy and test the DNA from the embryo (embryo tes4ng) •  Place the embryo’s back into the uterus (embryo transfer) 9 9/30/15 IVF (Stimulation process)
IVF (egg retrieval process)
10 9/30/15 IVF (insemination and fertilization)
IVF (embryo culture and biopsy)
11 9/30/15 Day of Biopsy:
•  Polar Body •  Blastomere (day 3) •  Trophectoderm (day 5-­‐6) Testing the DNA: PGD
methodologies
Types of analyses
•  Short tandem repeat (PCR fragment size analysis) •  DNA sequencing •  Mul4plexing •  Nested PCR •  Whole genome amplifica4on 12 9/30/15 IVF (embryo transfer)
Preimplantation Genetic Screening
•  Controversy •  False posi4ve rates •  Which pa4ents •  Scaleability •  Which plaporm 13 9/30/15 “PGS for aneuploidy does not improve IVF success
rates and may be detrimental”
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