Prenatal Diagnosis Flashcards
Describe the basic principles behind and techniques deployed during prenatal diagnosis.
There are 4 main domains being investigated with prenatal screening diagnostics: genetic, chromosomal, anatomic and growth. Currently, over 100 conditions can be diagnosed prenatally. The cornerstone of prenatal diagnosis is the personal and family history of the parents. Prenatal testing attempts to do as much testing on the parents as possible in order to avoid direct testing of the fetus. Thus, non-invasive maternal serum analytes are used to test alpha fetoprotein, estriol and HCG.
Ultrasound is another non-invasive method of visualizing the fetus. Ultrasound must be done trans-vaginally early in the pregnancy, but can be done trans-abdominally later. If the history or results of non-invasive testing suggest risk to the fetus, amniocentesis or chorionic villus (CVS) sampling can be done, though these have an increased risk to the fetus. Both amniocentesis and CVS give access to fetal cells which can be analyzed for DNA or chromosomal abnormalities.
Differentiate between targeted and population based screening for prenatal diagnosis
Population based offered to general population for common disorders, such as Sown Syndrome and neural tube defects.
Targeted screening for families with hx of known, specific disorders. It can also be done on a population level for groups at risk for clustered disorders such as thalassemia, Tay Sachs, and CF.
Describe screening programs for single gene defects of Tay Sachs,
Tay-Sachs is an autosomal recessive lysosomal storage disease caused by deficient hexosaminidase A, leading to accumulation of gangliosides and CNS deterioration. People of Ashkenazi Jewish descent are at an increased risk of Tay-Sachs as well as several other diseases and are thus screened more aggressively than other population subgroups. There are a very small number of mutations responsible for the majority of cases of Tay-Sachs. Thus, molecular DNA studies are performed. Molecular testing detects 94% of heterozygotes (this to me indicates they can just test the parents…but the notes don’t really say…). Additionally, analysis of the ratio of hexosamindase A to total hexosaminidase can detect 98% of cases. Fetal samples of DNA can be evaluated from amniocentesis or CVS.
- Explain the importance of knowing the correct gestational age in the context of prenatal diagnosis.
Knowing how old the fetus is determines what prenatal testing can be done and what should be expected in the results. For example, normal analytes of the integrated screen require knowing the gestational age as the levels change over the pregnancy and can be misinterpreted. Additionally, the earlier the results are delivered to the mother the better for pregnancy management; if the mother decides to terminate the pregnancy, it is better for her health to do so as early as possible
List the ultrasound findings used to estimate gestational age and fetal weight.
In order to estimate age an ultrasound should be performed. The earlier the ultrasound is performed, the more accurate it is as early in the pregnancy development is more prescribed compared to later when there is more variability in growth of the baby. In the first trimester crown-rump length is used to estimate gestational age while in the 2nd trimester biparietal diameter, abdominal circumference and femur length are used.
Describe current screening programs for Down syndrome.
Down Syndrome is a combination of congenital malformations caused by a Trisomy of chromosome 21. It causes intellectual disability, increased incidence of early Alzheimer’s, heart disease and increased incidence of pneumonia. The most common cause of Trisomy 21is due to nondisjunction of the chromosomes in the oocyte during meiosis I. Most of these cases are related to maternal age.
Down Syndrome is detected using an integrated screen which measures maternal serum α fetoprotein (MS-AFP), hCG, unconjugated estriol (uE3), inhibin A and pregnancy-associated placental protein (PAPP-A). The levels of these analytes are reported as Multiples of the median (MoM) for singleton fetuses at the same gestational age. This screen is also used assess risk of Trisomy 13 and Trisomy 18. Nuchal translucency testing is also done whereby the thickness of the skin on the back of the neck is measured via ultrasound between 10 and 14 weeks of gestation. Increased thickness of the back of the neck is caused by problems in lymphatic drainage.
Women are not routinely screened for Trisomy 21 until they reach 35 years of age. That is the age at which the risks of performing amniocentesis or CVS are less than the risk of identifying a chromosomal abnormality.
Describe current screening programs for neural tube defects.
Neural tube defects include anencephaly and spina bifida and are caused by failure of portions of the neural tube to close. This allows increased amounts of AFP to escape into the amniotic fluid and then into the maternal serum.
Describe screening program for cystic fibrosis.
Cystic Fibrosis (CF) is an autosomal recessive disease that causes lung and pancreatic disease and that can be detected prenatally or in the newborn period. There are a large number of mutations that can occur to give rise to CF. The most common mutation in Caucasians of non-Askenazi descent is the deletion of an entire codon at position 508, resulting in a loss of a phenylalanine. About 50% of couples at risk for having a child with CF can be identified by screening the parents for DF508. Detecting other causes of CF is difficult. There is a panel of 23 mutations that includes pan-ethnic mutations to help detect other cases. Not all alleles are tested for thus, a negative test result indicates reduced risk, not a risk of zero. Screening starts with testing the pregnant woman. If the woman’s test is positive, her partner is tested. If both are positive, then amniocentesis or CVS can be done.
Describe the screening program for Sickle Cell Disease
Sickle cell anemia screening first checks for an MCV
Describe the screening program for Thalassemia
Thalassemias can be assessed by an MCV: greater than 80% excludes heterozygosity for α or β thalassemia. Most cases of an MCV less than 80% are cases of iron deficiency anemia. If Fe deficiency is not found, hemoglobin electrophoresis should be undertaken. Elevated hemoglobin A2 and hemoglobin F confirms β thalassemia. α thalassemia requires DNA testing to detect α globin gene mutations.
Amniocentesis
Needle passed through mom’s lower abdomen into amniotic cavity to get amniotic fluid/fetal cells in there. Enough present at about 14 weeks so usually done between 14 and 20 weeks. Can grow fetal cells in culture.
Risks uncommon but include fetal loss. Contamination of fluid by maternal cells highly unlikely
Chorionic Villus Sampling
Catheter is passed into placenta under US guidance. Trophoblast cells from chorionic villi obtained. Can safely be performed from 9.5-12.5 weeks gestation with risk of fetal loss about 0.5-1% higher than amniocentesis. Maternal blood cells can confound chromosome analysis.
Can get genetic mosaicism– individual has 2 cell lines with different karyotypes. In this case have to analyze multiple cells.
Maternal serum beta-HCG
about a week post conception, trophoblast produces enough beta-HCG to diagnose pregnancy. Later in pregnancy, elevated HCG coupled with decreased MS-AFP suggests Down syndrome.
Maternal serum Estriol
Esteriol in mom’s serum dependent on viable fetus and properly functioning placenta. Substrate for Estriol (DHEA-S) from fetal adrenal and converted to 16-OH DHEAS by fetal liver. This is metabolized in the placenta to estriol which enters maternal circulation.
-Estriol tends to be lower in Down syndrome
Maternal serum alpha-fetoprotein (MS-AFP)
Fetus has 2 major blood proteins – albumin and AFP. Fetal AFP produced in fetal liver. Adults usually only have albumin, so MS-AFP reflects AFP from fetus that has crossed into mom’s circulation. Ordinarily little fetal AFP gains access to amniotic fluid and crosses placenta
MS-AFP reported in multiples of Median at each gestational age (MoM). Can detect most cases of neural tube defects
