Preimplantation Genetic Testing (PGD) Prenatal Genetic Diagnosis
Preimplantation Genetic Testing (PGT) is a crucial step in the assisted reproductive technology process. Conducted prior to embryo implantation during in vitro fertilization (IVF), PGT allows for the genetic assessment of embryos. This testing can be performed using polar bodies, blastomeres from embryos, or a trophectoderm sample. There are several types of PGT, each targeting different genetic concerns.
Types of Prenatal Genetic Diagnosis (PGD)
- PGT-M focuses on single-gene (monogenic) abnormalities. This test is essential for identifying conditions like cystic fibrosis, ensuring that embryos free from such genetic disorders are selected for implantation.
- PGT-A assesses chromosomal aneuploidy, particularly useful for embryos from women of advanced maternal age. Although its routine use is debated, it helps in identifying chromosomal abnormalities before implantation.
- PGT-SR looks for structural rearrangements, such as unbalanced translocations, which could lead to genetic disorders. This test is crucial for identifying embryos with significant chromosomal rearrangements.
Chorionic Villus Sampling (CVS)
Chorionic Villus Sampling (CVS) is a prenatal genetic test that involves aspirating and culturing chorionic villi from the placenta. This procedure offers genetic and chromosomal information similar to amniocentesis but is performed earlier, between 10 weeks gestation and the end of the first trimester.
Advantages and Disadvantages
The primary advantage of CVS is its ability to provide earlier results, which can alleviate parental anxiety or allow for earlier pregnancy termination if needed. However, CVS does not measure alpha-fetoprotein, so women are advised to undergo serum alpha-fetoprotein screening between 16 and 18 weeks of gestation. CVS can be performed either trans-cervically or trans-abdominally, depending on the placental location. The risk of fetal loss is approximately 0.2%, and about 1% of specimens may exhibit confined placental mosaicism, which might necessitate further consultations or amniocentesis for additional clarification.
Amniocentesis
Amniocentesis involves inserting a needle into the amniotic sac to withdraw amniotic fluid and fetal cells for testing, typically after 14 weeks of gestation. Historically recommended for women over 35 due to their higher risk of chromosomal abnormalities, this test is now suggested for all pregnant women.
Risks and Considerations
The fetal loss rate for amniocentesis is about 0.1 to 0.2%, with rare complications including maternal morbidity and an increased risk of talipes equinovarus if performed before 14 weeks. Vaginal spotting or amniotic fluid leakage occurs in 1 to 2% of cases. Despite these risks, amniocentesis remains a valuable tool for detecting genetic disorders.
Percutaneous Umbilical Blood Sampling (PUBS)
Percutaneous Umbilical Blood Sampling (PUBS) involves obtaining fetal blood samples through a puncture of the umbilical cord vein, guided by ultrasound. The results of chromosome analysis can typically be completed within 48 to 72 hours. While historically used for rapid results, advancements in other testing methods, such as interphase fluorescent in situ hybridization (FISH) on amniotic fluid or chorionic villi, have reduced the frequency of PUBS for genetic testing.
Prenatal Genetic Counseling
Prenatal genetic counseling plays a vital role for prospective parents, ideally occurring before conception. This counseling assesses risk factors for genetic disorders and provides guidance on preventing other causes of birth defects, such as avoiding teratogens and managing chronic conditions. The counseling should be simple, non-directive, and jargon-free, ensuring that anxious parents understand the information provided. Patients are often given time to formulate questions, and additional resources, like those from the American College of Obstetricians and Gynecologists, may be recommended for further information.
Referral to Genetic Specialists
For prospective parents with known or suspected risk factors for genetic abnormalities, referral to genetic specialists is beneficial. These specialists provide information about potential outcomes and options for genetic evaluation. If a genetic disorder is identified, various reproductive options are discussed, including:
- Preconception Options: Donor sperm or oocytes may be considered if one partner is a carrier. In vitro fertilization (IVF) with preimplantation genetic testing (PGT) can help identify genetic defects in embryos before implantation.
- Postconception Options: Prenatal testing can detect congenital anomalies, and pregnancy termination might be considered if a genetic disorder is present. In some cases, transfer to a tertiary center with more extensive neonatal services might be necessary.
Risk Factors for Genetic Disorders
All pregnancies carry some risk of genetic abnormalities. The incidence rates among live births are as follows:
- Numeric or Structural Chromosomal Disorders: 0.5%
- Single-Gene (Mendelian) Disorders: 1%
- Multiple-Gene (Polygenic) Disorders: 1%
In spontaneous abortions or stillbirths, the rates are higher, reflecting the increased prevalence of genetic malformations. These often involve polygenic or multifactorial inheritance, which includes environmental factors.
Increased Risk Factors
Certain factors increase the risk of chromosomal disorders:
- Previous Chromosomal Disorder: Couples with a history of a chromosomal disorder may face an increased risk for future pregnancies, particularly for specific conditions like Down syndrome.
- Maternal Age: The risk of chromosomal abnormalities, such as trisomy 21, increases with maternal age. For women under 35, the risk of trisomy 21 is 1 in 591, whereas for women 35 and older, it increases to 1 in 100.
- Paternal Age: Advanced paternal age (35 to 50 years) can increase the risk of spontaneous dominant pathogenic gene variants, such as achondroplasia.
Submicroscopic Chromosomal Abnormalities
These abnormalities, which are clinically relevant copy number variants, are found in 1% of fetuses with normal karyotypes and 6% in those with structural abnormalities.
Autosomal Dominant and Recessive Disorders
- Autosomal Dominant Disorders: If one parent has an autosomal dominant disorder, there is a 50% risk of passing it to offspring.
- Autosomal Recessive Disorders: Both parents must be carriers for the disorder to be expressed. Carrier parents have a 25% chance of having an affected child, whereas one carrier parent has a 50% chance of having a carrier child.
X-Linked Recessive Disorders
These disorders are expressed in all males carrying the pathogenic gene variant. Carrier females have a 50% risk of having an affected son and a 50% chance of having a carrier daughter. Affected males do not transmit the gene to their sons but pass it to all their daughters, making them carriers.
prenatal genetic testing encompasses a range of methods and considerations, from early testing like PGT and CVS to later procedures such as amniocentesis and PUBS. Each test has its advantages and risks, and genetic counseling plays a critical role in guiding prospective parents through these complex decisions. Understanding the various genetic disorders and risk factors can help in making informed choices to ensure the health and well-being of both the parent and the child.
