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69 Cards in this Set
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Why would we offer prenatal diagnosis? What are the benefits?
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-Reassurance to at-risk families
-Preparation for birth of an affected baby support group, alert family, no surprises at delivery -->25% of couples with a child with down syndrome choose to prenatal diagnosis in a subsequent pregnancy, not to have an abortion, just to be prepared for the birth of another affected child -Preparation for timing/mode of delivery of a fetus affected with a disease -->Eg. if the fetus will require surgery immediately at birth you can prepare to have the delivery at a tertiary care center with the pediatric surgeons present -Providing risk information to couples for whom pregnancy termination is an option -In the near future: allow treatment in utero for genetic disorders amenable to correction via stem cell therapy -->Eg. Hurler syndrome -->Eg. monogenic disorders amenable to gene therapy like beta thalassemia, epidermolysis bullosa *Trials are already under way for this (Flip card for more details on these diseases, just in case you care to know!) |
Hurler syndrome is a rare, inherited disease of metabolism in which a person cannot break down long chains of sugar molecules called glycosaminoglycans (formerly called mucopolysaccharides).
Epidermolysis bullosa is a group of inherited disorders in which skin blisters develop in response to minor injury. |
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What is the difference between screening tests and diagnostic tests? What are you looking for in terms of sensitivity/specificity with each test?
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Screening
-Examination of asymptomatic individuals to detect those with a high probability of having a given disease -typically inexpensive and non-invasive tests -A test that you apply to the general population to identify a narrower group that is at high risk for a specific condition -Want high SENSITIVITY Diagnosis -Determination of the presence of a disease -Aimed at making a diagnosis -Often are invasive -May be painful -Usually more expensive -Want high SPECIFICTY |
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What is an indication?
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In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. The opposite of indication is contraindication.
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What are the indications for prenatal diagnosis?
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1. Maternal Age
2. Presence of structural chromosome abnormality in one of the parents (eg. translocation) 3. Previous child with de novo chromosomal aneuploidy 4. Genetic disorder amenable to prenatal diagnosis by biochemical or DNA analysis 5. Sex determination 6. Neural tube defect (NTD) |
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When would you want to take maternal age into consideration?
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1. Maternal Age
-“The generally accepted criterion for eligibility for prenatal diagnosis..is that the risk for fetal abnormality is > or = the risk of miscarriage or other complication from the procedure itself” -If you propose to a patient to do an amniocentesis that carries a 0.3% risk of losing the pregnancy, you would like to have a risk of a genetic condition being 0.3% or greater Maternal age and risk for down syndrome Y axis: risk of down syndrome per 1000 live births X axis: maternal age *Risk of down syndrome increases very little until age 35, and then there is a sudden exponential increase in risk* Age 35 is the arbitrary threshold to offer the diagnostic test -New recommendations: Diagnostic procedures should be offered to all women together with screening options independently from their age -It is not fair for the doctor to make a decision as to an arbitrary cutoff of risk above which we offer prenatal diagnostic test and below which we do not offer them. The decision should be left to the couple Eg. 38 year old woman, risk of 1/800 for down syndrome, had 3 children, had 2x higher risk of losing healthy pregnancy than having child with down syndrome. But she wanted it regardless |
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How might a parent find out that they have a structural chromosome abnormality?
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Presence of structural chromosome abnormality in one of the parents (eg. translocation)
-These are usually young couples who have a previous child affected with unbalanced translocation so they did testing on themselves and found out that one of the two is a carrier of a balanced type of the translocation and there is a risk of recurrence of the translocation -The risk of chromosome anomaly in the fetus depends on the type of anomaly/translocation and parent of origin |
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If a parent has already had a child with a de novo chromosomal aneuploidy, should they have diagnostic testing? That is, are their future children at risk?
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Previous child with de novo chromosomal aneuploidy
(Typically down syndrome) -Risk of recurrence for any chromosomal abnormality is 1/100 -May want to know for a future pregnancy to have an abortion or to be prepared .. Others don’t want to know |
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If a parent has a previously affected child with an autosomal recessive condition, what should you do? What is the risk for future children?
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-Genetic disorder amenable to prenatal diagnosis by biochemical or DNA analysis
-Risk based on family history Eg. If you have a previously affected child with an autosomal recessive condition -->Risk based on results of screening tests eg. CF; Ashkenazi Jewish panel; some skeletal dysplasias **If both parents are carriers for the same condition, then they have a 25% risk of an affected child and a diagnostic test can be offered ** |
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Why might you want to find out the sex of the child?
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Sex determination
-Family history of a boy affected by an X-linked disorder with no DNA analysis available for prenatal diagnosis -This is unusual |
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What do you do if mom has a family history of neural tube defect? How do you test if the baby is at risk?
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Family history of a NTD
-Positive screening by maternal serum alpha-fetoprotein then you can do amniocentesis -Amniocentesis goes into amniotic fluid and quantifies the amount of alpha-fetoprotein that leaks out from an open neural tube defect -If you have high levels then you suspect that there is a neural tube defect -However: ultrasonography has higher detection rate (95% vs 80%) and specificity (96% vs 5%) for prenatal diagnosis of NTD compared with MSAFP -We have moved away from amniocentesis for this indication |
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If we have one of the indications, what methods of prenatal diagnosis are available?
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1. Amniocentesis
2. Chorionic villus sampling (CVS) – sampling a piece of the placenta 3. Ultrasonography 4. Fetal blood sampling (FBS) 5. Preimplantation genetic diagnosis (PGD) – in cases of in vitro fertilization |
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Tell me all about the technique for amniocentesis!
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1. prep the abdomen with betadine (Betadine is a brand name for a range of povidone-iodine (PVPI) topical antiseptics )
2. insert the needle inside the amniotic fluid surrounding the fetus under ultrasound guidance, making sure to avoid the area of placental insertion and fetus 3. Take out whatever amniotic fluid you need, usually 1-2 syringe-fulls are enough 4. Remove the needle 5. Watch for bleeding and check FHR 6. The AF is spun in a centrifuge: a. Fetal cells sent for cytogenetic studies, FISH, CGH or other diagnostic tests b. Supernatant sent for alpha-fetoprotein (AF-AFP) regardless of indication for amniocentesis |
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What could high alpha-fetoprotein indicate?
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High AF-AFP seen in:
a. Neural Tube Defects (99% sensitive for open NTD) b. Fetal blood contamination c. Fetal abnormalities e.g. omphalocele d. Placental disorders eg. if a placenta is not implanted normally it can lead to a leakage of AFP in the amniotic fluid (flip for more info on omphalocele) |
An omphalocele is a birth defect in which the infant's intestine or other abdominal organs stick out of the belly button (navel). In babies with an omphalocele, the intestines are covered only by a thin layer of tissue and can be easily seen. |
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What is the risk of miscarriage with amniocentesis?
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-Not well quantified
-Thompson & Thomson: “risk of miscarriage of 1/1600 over the baseline risk” -->1/1600 comes from one, poorly done study that looked at the risk of amniocentesis, but the women who had amniocentesis were compared with controls in which they didn’t know the genetic makeup of the fetus. They were comparing apples and oranges. On one side they had pregnancies continuing with a healthy fetus with normal chromosomes, and on the other side there were pregnancies continuing with unknown chromosomes so some of the losses in the control group were probably due to chromosomal abnormalities so that’s why the comparison was not appropriate -Meta-analysis of comparison studies: Amnio 1.9% Total fetal losses Controls 1.3% Total fetal losses -->If you compare studies in which they do amniocentesis and they look at controls where the karyotype is established at birth, then there is a risk of 0.6%, much higher than 1/1600 Bottom line: Commonly quoted risk: 1/300 – 1/500, and that is the number that the counselors use when they counsel about the risks of amniocentesis |
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Besides miscarriage, what are other risks of amniocentesis?
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1. Feto-maternal hemorrhage
–> if you go through the placenta you create a hole that disrupts some of the villi, so some of the fetal blood may pass into the maternal blood 2. Leakage of amniotic fluid if the hole is made in the sac. 3.Infection –> if you don’t prepare the skin carefully you can carry an infection from the skin inside to the uterus OR if there is some bowel present between the skin and the uterus and you go with a needle through the bowel you carry all the e.coli and germs and anaerobes from the bowel straight into the amniotic sac and cause infection 4. Fetal trauma -->rare.. Was more common when people didn’t use ultrasound guidance 5.Respiratory distress at birth –> depends on how much fluid you take out and how early in the pregnancy you do the amniocentesis. 6.Hepatitis B carriers and HIV+ individuals -->Possible increased risk of vertical transmission in HbeAg+ and those with viral load detectable |
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What is early amniocentesis? Is it common?
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Early amniocentesis
-Thompson & Thompson: “can be performed at 10-14 weeks; 3-fold increased risk of miscarriage compared with midtrimester amniocentesis” – do NOT need to know this outdated number -In reality: Early amniocentesis is associated with an unacceptable rate of miscarriage (as high as 5%) and should not be offered, since a safer alternative (CVS) exists *Makes no sense to do a procedure that carries higher risk when you have alternatives* |
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What is chorionic villus sampling?
When do you do it? What kinds are there? |
Chorionic villous sampling
-Biopsy of chorion frondosum -The placenta represents the genetic makeup of the fetus 99% of the time -Between 10-12 weeks -Transcervical vs transabdominal a. Transabdominally: prepare the skin and go in through the skin b. Transvaginally: prepare the vagina and go in through the vagina, through the CERVIX -->There are always some germs present in the vagina and cervix, so taking the lower route has a higher risk of fetal loss, perhaps because you have higher risk of infection |
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How close are the placenta and fetus in terms of genetic makeup?
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The placenta represents the genetic makeup of the fetus 99% of the time
__ Ambiguous results in about 2% of cases due to chromosomal mosaicism – need for amniocentesis What is chromosomal mosaicism? |
Chromosomal mosaicism: discordancy between the placental genetic makeup and the fetal genetic makeup
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What are the advantages and disadvantages of chorionic villous sampling?
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Advantages:
-Allows results at an early stage of pregnancy – as early as 10-11 weeks Disadvantages -Does not allow AFP determination -Ambiguous results in about 2% of cases due to chromosomal mosaicism – need for amniocentesis |
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What is the risk of miscarriage with chorionic villous sampling?
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-Thomson & Thompson: risk of 1/100 of inducing miscarriage over the baseline risk (p. 447)
-Meta-analysis of comparison studies: Total fetal losses - CVS vs Amnio: Difference = 2.4% -Commonly quoted risk by genetic counselors: 1%-1.5% *higher than amniocentesis |
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What are the complications of chorionic villous sampling?
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1. Bleeding and sub-chorionic hematoma (4%)
2. PROM (0.3%) – rupture of the membranes 3. Rh-sensitization – passage of blood from fetus to mother 4. Fetal abnormalities (OR = 15) – not after 10 weeks with experienced operators -->Happens because you’re disrupting the placenta at a time when the fetus is still developing organs -->Limb abnormalities (eg. short finger?) -->Oro-mandibular hypogenesis (eg. chin abnormalities) |
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What is the most important tool for prenatal diagnosis of major anomalies?
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Ultrasonography is the most important tool for prenatal diagnosis of major anomalies:
-major fetal anomalies: 3%-5% *Ultrasonography detects 50% *Amniocentesis detects 5% same due to aneuploidies: 0.4% *Ultrasonography detects 50%* *Amniocentesis detects 100% If you take 100 pregnant women and you let them continue their pregnancy, what % will have some major fetal anomaly? How many of these are due to aneuploidy? What does this mean for ultrasonography? |
3-5% will have some major fetal anomaly
Major means an anomaly that has an impact on the life of the baby or requires surgery to be fixed Of these, only 0.4% are due to aneuploidies *Thus, ultrasonography is much more powerful that amniocentesis or other invasive procedures for prenatal diagnosis |
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What can you look for with ultrasonography? How early can these things be detected?
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Rate of cardiac anomalies by expert echocardiographers detected after 20-24 weeks: 50-80%
Structural anomalies detected at 16-20 weeks: 15%-50% Why is there a range? What does the detection of anomalies depend on? |
* It depends on the type of malformation
–> if it’s straightforward and jumps at you you can see it very easily. -->If it’s more subtle, like cleft palate, you may miss it. -Cardiac diseases may also be difficult to identify, particularly very early in pregnancy. Detection of anomalies depends on: 1. type of malformation 2. expertise of the operator |
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Can you be 100% certain you're going to have a "perfect" baby after testing?
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His summary for couples who want the perfect baby, who want all the tests..
That’s impossible because the tests aren’t perfect: Here’s the revised risk of major fetal anomalies after prenatal diagnosis: 1. Background risk of major anomalies: 3-5% 2. Residual risk after ultrasound (50% detection rate): 1.5-2.5% 3. Residual risk after invasive genetic test for chromosome anomalies (0.4%): 1.1-2.1% These residual risks either: A. can’t be detected with ultrasound B. can’t be detected with amniocentesis or invasive testing Give an example or two of a residual risk! What's the take home? |
Eg. anal atresia (The anus is either not present or it is in the wrong place.). This cannot be detected by ultrasound or amniocentesis
Eg. skin abnormalities like hemangioma (A hemangioma is an abnormal buildup of blood vessels in the skin or internal organs. Symptoms: A red to reddish-purple, raised sore (lesion) on the skin; A massive, raised tumor with blood vessels.) Take home: can’t be 100% certain |
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When can you do ultrasonography? What types are there?
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-Can do it starting in the 1st trimester
-Can also do it in the 2nd trimester -This is a profile of the fetus at 12 weeks -Can do 2D or 3D ultrasound How does 3D ultrasound work ? What might you use it for? |
3D: A reconstruction by the computer of 2D images
This is good for looking at things like finger abnormalities, cleft lift, other surface abnormalities |
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What types of anomalies can be detected with ultrasonography?
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Anomalies detected with ultrasonography can be:
1. Isolated (most commonly) Eg. renal anomaly – for instance, has a kidney missing Eg. cardiac anomaly – for instance, has a hole in the heart Eg. extra finger Eg. cleft palate 2. Associated with aneuploidies (usually multiple anomalies or markers) Eg. Trisomy 13 Eg. Neural tube defects Eg. Cardiac anomaly Eg. cleft lip / cleft palate 3. Associated with single-gene disorders e.g. some skeletal dysplasias are autosomal dominant Eg. Infantile polycystic kidney disease (IPKD) is autosomal recessive 4.Associated with multifactorial disorders Eg. neural tube defects Eg. cardiac anomalies Eg. cleft lip / cleft palate In this case, the risk of recurrence is 3-5% |
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If you see an abnormality using ultrasonography, what do you do?
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Following US detection of a fetal anomaly:
Careful examination searching for associated anomalies --look for other anomalies! If you see more than one type then you start wondering whether there is an underlying genetic condition If you suspect an underlying genetic condition, you can consider invasive testing to label the condition more precisely -->Consultation with geneticist |
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What is the technique for fetal blood sampling?
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1. Go in with a 20-22 G needle into a vessel in the umbilical chord – usually the umbilical vein – and take a sample of fetal blood
2. 2-3 cc’s is enough to do the test 3. Cordocentesis vs intrahepatic vein vs cardiocentesis 4. Option of fetal paralysis 5. Quality control |
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What are the indications for fetal blood sampling?
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Fetal Blood Sampling: Indications
1. Cytogenetic diagnosis --> Quick results --> Impending fetal death -->Mosaicism -- for instance, if amniocentesis and chorionic villous sampling show that there are different genetic makeups in the different tissues in the fetus, then you may want to sample an additional tissue (the blood) to see how diffuse the mosaicism is 2. Congenital infections 3. Congential immunodeficiencies 4.Coagulopathies |
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What are the complications for fetal blood sampling?
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-Fetal losses: 2.8%
Depends on: a. Indications b. Operator experience c. Technique d. Gestational age -Hemorrhage/Hematoma -Bradycardia -Fetomaternal hemorrhage **this is NOT done that often New techniques available with amniotic fluid allow one to run a ton of genetic tests on amniotic fluid without having to take fetal blood |
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What is preimplantation genetic diagnosis?
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Preimplantation Genetic Diagnosis
-Requires in vitro fertilization (IVF) -Performed on polar body or single cell biopsy from 6-8 cell bastomere -Take one cell from the blastomere 8 cell embryo and run all the tests in that one cell |
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What are the indications for preimplantation genetic diagnosis?
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Indications:
1. couples at risk for a specific genetic disorder who are averse to termination of pregnancy 2. screening in infertility cases requiring IVF Expansion of indications has occurred rapidly -PCR for single gene disorders or FISH probes (e.g. karyotype) |
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What are the limitations of Preimplantation Genetic Diagnosis?
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-Increased number of probes increases the technical risk and rates of false positive / false negative diagnoses
-For any indication, constraints of limited sample material (1-2 cells --- The cell that you’re sampling is not necessarily reflective of all the other cells of the embryo), wide prevalence of embryo mosaicism (up to 50%), cost, and a narrow window of testing have greatly reduced its request -Effects of biopsy: to date, no increase in obstetric complications or congenital anomalies |
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What are the methods for prenatal screening?
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1. History and ethnicity
2. Maternal serum 3. Ultrasonography |
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What is detection rate?
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Detection rate: ratio of affected fetuses detected by the screen over the total of affected fetuses (synonym: sensitivity) (a/a+b)
Eg. mammogram – of women with breast cancer, how many can be detected with mammogram Eg. down syndrome – how many fetuses with down syndrome are detected with that test? |
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What is the false positive ratio?
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False positive rate: ratio of normal fetuses falsely identified as affected (c/c+d)
How many of the normal fetuses would be wrongly diagnoses or suspected to be affected? |
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How does maternal age work as a screening test?
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Maternal age as screening test
-“high risk” because of advanced maternal age (traditionally considered ≥35 years) -New recommendations: do not use the terms "high risk" and "low risk," but rather present the parents with the actual numerical risk value. -Screening can work both ways: --> Screening tests can be applied to younger women and if the results come back as abnormal or high risk then you may offer invasive testing OR you can use it in older women – if they have reassuring results from the screening test they may choose not to do any invasive tests |
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What is the most important determinant of uptake of genetic screening?
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Patient attitude towards prenatal diagnosis is the most important determinant of uptake of genetic screen
A – B – C A: Type Anxious (high anxiety): desires testing irrespective of risk – want the perfect baby B: Type Balance (weighs risks): wants assessment of risk before considering invasive diagnostic testing – best candidate for screening tests since screening tests provide information without jeopardizing the pregnancy by looking at markers in the blood of the mother or at markers in ultrasound. The mother is given a probability of genetic problems and she can decide based on the risk whether to pursue diagnostic testing – most common type of patient C: Type Content: refuses prenatal diagnosis or screening tests – don’t need to offer any further testing Factors that are important in shaping mom’s opinion: -Religious beliefs -Social pressure |
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The risk based on maternal age can be modified using which screening methods?
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Risk based on maternal age can be modified using screening methods:
-maternal serum screening -ultrasound screening |
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Name 6 things that can be used as a screening tool
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1. maternal age
2. family histories 3. universal screening 4. screening for fragile X 5. screening for down syndrome 6. screening for neural tube defects (NTDs) |
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What are the various recommendations made by the ACMG and ACOG about what to do with genetic testing based on ethnicity?
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-there are overlaps for certain conditions (ex: cystic fibrosis)
-tay-sachs and many other diseases on this chart are more prevalent in ashkenazi jews than other ethnicities -sickle cell anemia is more prevalent among african americans -beta-thalassemia is offered to mediterraneans -alpha-thalassemia is offered more to southeast asians |
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According to the ACMG and ACOG, what disease is offered as a screening test to anyone independent of ethnicity?
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-cystic fibrosis
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What is the problem with offering tests based on ethnicity?
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-ethnicity is NOT clear cut
-in white caucasians and ashkenazi jews, the detection rate for CF is very HIGH, but in other ethnicities it is very LOW bc there are more MUTATIONS -the detection test using specific mutations may NOT detect the condition in ethnicities where you have RARER mutations *It was found that in 45% of the mutations that were found to be more prevalent in ashkenazi jews were ALSO found in people that did not report any jewish ancestry (carriers for this specific mutation that are more common in jewish individuals) What is the rationale behind using ethnicity as a screening tool? |
-the detection rate of certain diseases is affected by ethnicity
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What are some situations where ethnicity is NOT clear cut?
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1. marriages b/w ethnicities (1 in 7 marriages)
2. many do not know the ancestry of all 4 of their grandparents (~40%) 3. multiracial children increased 50% since 2000 |
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Since it is becoming difficult to assign a specific ethnicity to affected individuals, what is offered instead?
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-universal prenatal screening
What are the advantages? |
-for the same cost (~$349) you can offer screening for over 100 different single gene disorders (so in general, it is less expensive per disease)
-more comprehensive -can you saliva or blood from both parents -universally applicable to both genders and all ethnic groups |
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What is the most common genetic condition found with universal screening? What is the 5th most common?
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-most common = alpha-1-antitrypsin
-5th most common = sickle cell *to learn more about alpha-1-antitrypsin, click again! |
-protease inhibitor
-without it, elastin is broken down, particularly in the lungs leading to respiratory problems like emphysema and cirrhosis |
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Is the pickup of a condition fairly common using the universal screening technique?
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NO!
-less than 1% of the couples are BOTH carriers for the same condition making it fairly rare |
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Is universal screening currently being recommended?
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NEGATORY
-they are unclear about its true cost effectiveness (ex: how many couples need to be screened to prevent just one case?) -the value on the ability of parents to prepare for the birth of an affected child to avoid lengthy diagnostic tests, or to plan future child bearing has NOT yet been quantified |
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What is the most common form of INHERITED mental retardation AND the most common single gene disorder associated with autism?
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-Fragile X
-1/157 women are carriers -it is a repeated expansion of a triple repeat in the 5' non-coding (promoter) region FMR1 gene on the X chromosome -loss of function mutation with extinguished gene expression at >200 repeats Who is this screening currently offered to? |
-women who are infertile
-fragile X carriers have premature death of their eggs and end up with premature infertility and ovarian failure -also offered to women if there is an unexplained family history of mental retardation, developed mental disabilities, or autism |
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What is the most common cause of mental retardation?
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-down syndrome
-what are 2 ways we can screen for it? |
1. serum markers
2. sonographic markers |
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Describe a serum marker in regards to down syndrome.
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-proteins produced by the fetus or placenta
-always produced in normal gestation BUT when a pregnancy is affected with an aneuploidy, there are DIFFERENT levels of these proteins produced -the graph shows that the unaffected bell-shaped curve average for AFP is 1 BUT DS patients produce less of this protein and their average AFP level is less than 1 **SO, the lower the level of AFP = higher risk of DS AND the more AFP = the lower risk of DS SO, we can adjust the risk of DS quite well by looking at multiple proteins in this way |
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Here are pictures showing the detection rate and false positive rate within the DS bell curves
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-detection rate and false positive rate bell curves
-the false positive rate is the part of the triangle ONLY under the unaffected curve |
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Describe a sonographic marker in regards to DS.
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-the most typical one is the thickness of skin behind the neck between the skin and occipital bone
-in the ultrasound the black area in the neck is lymphatic fluid -in DS fetuses there is more accumulation of this lymphatic fluid |
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There are currently 5 screening tests available for DS. What are they and what are their detection rates?
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1. maternal age: 30%
2. 1st trimester screen (combines blood and ultrasound markers): 87% 3. 2nd trimester screen: 80% 4. ultrasound only in 2nd trimester: 60% 5. combine everything: 95% |
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How do screening tests modify risk?
*this point was emphasized by Ghidini |
-they can be proposed to a low risk woman (22 yr. old, no family problems or risk factors) who decides to have invasive testing done bc of her modified high risk after screening OR it can be proposed to a high-risk woman (couple who had a child with DS, a women who is 42) but if the screen comes back reassuring she may decline diagnostic testing
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What is a new prenatal screening for DS and other common aneuploidies?
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-blood test in the mother with very HIGH accuracy to detect down syndrome in the fetus
-requires real time PCR -shorter fragments than maternal free DNA -every pregnant woman carries genome from her own cells that die and release DNA into her blood -she ALSO carriers a tiny amount of free fetal DNA from fetal cells: these are cells form the placenta that die from apoptosis and release genetic material into the maternal circulation and are present from the beginning of pregnancy (as early as 32 days post-conception) until delivery and then they disappear -10% of the DNA fragments are from the fetus (small amt. in comparison to mother's amt of DNA fragments) -not only can we distinguish which fragments are fetal and which are maternal but this new technique also allows us to identify which fragments come from which chromosomes -SO, if you have excess material coming from chromosome 21 for example, it signals the presence of trisomy 21 in the fetus -100% sensitivity for trisomy 21, 97% sensitivity for trisomy 18, and 79% sensitivity for trisomy 13 -false positive rates = VERY LOW What are its limitations? |
1. only been tested on twins (singletons)
2. does not pick up any other abnormalities except for those that you test for (12% of abnormal results at 1st trimester or quad screen signal the presence of anomalies other than T13, T18, or T21 ex. triploidy, sex chromosome anomalies, or fetal structural anomalies non-chromosomal) 3. small amount of samples sometimes do not contain enough free fetal DNA (1-3%) 4. only high risk women (2 trials on low risk women are underway) |
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What are 5 conditions that are associated with NTDs?
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1. high maternal serum alpha-fetoprotein (MSAFP)
2. intake of valproic acid 3. previous child with neural tube defect 4. patient herself has NTD 5. patient has uncontrolled diabetes: high levels of glucose in mother are teratogenic and can cause malformations in the fetus, in the heart and NTDs |
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Why should we screen for NTDs?
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-90% of NTDs occur in families with NO previous history or risk factors
-alpha-fetoprotein leaks out from the fetus into the amniotic fluid and then into the maternal blood -by sampling the maternal blood we can find out the risks for these defects in the fetus |
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What does the bell-shaped curve look like for NTDs?
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-average normal AFP in anaffected fetus is 1
-fetus with open spina bifida have a level of 5 in the blood -fetus with anencephaly (lack of formation of the skull) has a level of 10 **remember that DS has "down" (lower) levels of AFP and so therefore NTDs have higher levels of AFP -80% is detected for spina bifida -90% is detected for anencephaly -false positive rate of 3.5% What should you do if you get an elevated sample? |
-must test it again to confirm it is NOT a false positive
-ALSO! with ultrasonography getting better and better, we rely on it more now that these screening tests -detection rate for spina bifida: 92% -detection rate for anencephaly: 100% -false positive rate: 3% *reassuring ultrasound decreases risk of NTD by 12x |
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How ca you prevent NTD?
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-requires intake of folic acid for 2-3 months before conception and needs to be continued until 10 weeks
-optimal dosage = 1-4 mg/day -cuts down the risk of NTDs by 50% |
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What are the 2 laboratory tests that can be done after you have gone through the screening tools and diagnostic test samples?
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1. karyotyping or comparative genomic hybridization (CGH) and FISH studies
2. biochemical assays |
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What is the difference between a standard karyotype and CGH/ FISH?
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-with FISH and CGH you can increase the resolution of the karyotype
-FISH and CGH compare the genome of the fetus with a control that has normal results |
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What are the advantages of CGH?
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1. higher resolution
2. can avoid the need to culture cells present in the amniotic fluid/chorionic villi 3. does not require dividing cells so it is practical to determine fetal death 4. it is automated, so there is better quality control and faster turn around times What are the disadvantages? |
1. unable to detect balanced translocations, inversions, insertions or triploidy
2. detection of CNV of uncertain clinical significance (increases with density of arrays): 3%-8% |
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SO if the detection rate of CGH is so much higher than standard karyotype or high-resolution karyotype, why don't we send all our amniotic fluid for CGH?
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-a study found out that will all pregnancies you end up with 2.5% detection of some microdeletion or microduplication, which are tiny amounts of genome that are overrepresented or missing that can have clinical significance: copy number variances (CNV)
-they are genetic material that is not right but we don't know yet whether it has a clinical significance or not -many of us carry these copy number variances that have no clinical significance which is the reason that is holding us back from using CGH instead of karyotyping -bc there are so many of these, there is a need for a large database of both healthy and affected individuals *if you get all these uncertain clinical variances, you don't know how to counsel the couple since we are not even sure what these abnormal copy number variances mean clinically |
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What is CGH recommended for?
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1. fetuses with structural anomalies in normal karyotypes
2. fetal death with congenital anomalies |
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What are the biochemical assays for?
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-most mendelian metabolic disorders are AR
-if both parents are carriers for a genetic condition, prenatal diagnosis can be performed by DNA analysis or enzyme assays on chorionic villi or amniotic fluid cells What is the advantage? |
-can detect abnormalities caused by any mutant allele: important for disorders with allelic heterogeneity or new mutations
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How long do the results take for ultrasounds, karyotypes, FISH and CGH?
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-ultrasound: immediate
-amniocentesis or CVS: 2 weeks for karyotype, 3 days for FISH, 1 week for CGH |
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What is cell-free fetal DNA?
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-type of prenatal diagnosis/ screening for DS that has a high detection rate
Who is this currently recommended for? |
1. high-risk populations: populations in which screening tests have detected a high risk for aneuploidies
2. couples in their forties 3. couples with a screening test with a high risk for DS -test is provided in a cost-effective, timely and equitable manner -confirmatory tests required with invasive testing |
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What is a possible trend that could be seen in type A couple that want to have the perfect baby?
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1. couples coming in preconceptually or within the 1st trimester who want to be screened with the universal screening test that can screen for over 100 gene disorders and fragile X
2. THEN! if the couple wants to pursue additional screening tests you can offer non-invasive prenatal diagnosis for trisomy 21, 13, 18 in maternal blood 3. THEN!!!! if there is anything positive you can pursue invasive tests and sent the placental or fetal cells for CGH |
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