The greatest opportunity for reducing the morbidity and mortality associated with rare genetic diseases is through early detection. Since about half of rare genetic diseases manifest in childhood, genetic testing at the earliest point in life may provide the most benefit.
Genetic testing in the perinatal period, including carrier testing for recessive disorders, prenatal screening for chromosomal abnormalities and newborn screening for preventable genetic disorders has been around for decades. Perinatal genetic testing maximizes reproductive choices and affords an opportunity for early interventions and has led to a reduction in the incidence, morbidity and mortality associated with genetic disorders.
Scientific and technological advances continue to push the limits of genetic testing in the perinatal period, leading to more sensitive, robust and safer tests. Concurrently, the number and type of genetic disorders has grown, making the perinatal genetic testing space difficult to navigate.
In this post, I’ll first briefly describe the major technological developments that are impacting testing and then provide a roadmap for different testing options in the perinatal period.
Technological developments
Most genetic testing aims to directly measure genetic changes in the DNA of an individual. Accessing a DNA sample is relatively straightforward in a child and even a newborn but becomes increasingly more difficult as you go back in development to the fetal period, or embryonic period in the case of in vitro fertilization (IVF).
Preimplantation Genetic Testing (PGT) is a procedure available to couples at risk of conceiving a child with a genetic disorder. The procedure requires the couple to undergo IVF where mature eggs are collected from ovaries and fertilized by sperm in a lab. The resulting embryos are biopsied and genetic testing performed on the tissue. PGT is presently the only option available for avoiding conceiving a child affected with a genetic disease. It is an attractive means of preventing heritable genetic disease, thereby eliminating the dilemma of pregnancy termination following an unfavorable prenatal diagnosis.
Once a mother is pregnant, different methods are available to access fetal DNA. Amniocentesis (amniotic fluid) , chorionic villus sampling (CVS - placenta) and the less commonly used cordocentesis (fetal umbilical cord) are three invasive sampling techniques available for pregnant women but each possess a risk of harm to the fetus.
Fetal DNA makes up about 10% of the DNA found in the maternal blood stream during pregnancy. The use of non-invasive sampling of cell-free fetal DNA (cfDNA) in the maternal blood presents a safer option than invasive amnio/CVS. Because the fetus and mother have shared genetic identity (50% of genes) it’s not always possible to distinguish genetic variation in the mother from variation in the fetus. Non-invasive prenatal testing (NIPT) is currently limited to chromosomal abnormalities but is an area of active technological development for expanding its capabilities.
Landscape of genetic testing across the perinatal period
Genetic testing is available across the perinatal period, beginning pre-conception, through pregnancy and into the newborn period.
Disorders most commonly screened for during different periods
Tests in the pre-pregnancy period
The earliest time point for screening for genetic disorders is even before conception. Carrier testing does not analyze fetal DNA, but rather, testing is performed on the DNA of the parents. The test is used to determine if one or both parents are carriers of a single mutated gene for a recessive condition.
The conditions tested for have historically been limited and include common recessive disorders like Tay Sachs, Cystic Fibrosis and Sickle Cell Disease. Nowadays, expanded carrier testing panels exist that can test for hundreds of recessive disorders.
If both parents are carriers for a pathogenic mutation in the same gene, any child they have has a 25% chance of inheriting both mutations and developing the recessive disease. Thus, carrier testing is not diagnostic, but instead indicates whether parents are at greatly increased risk of having a child with a recessive genetic disorder.
At risk parents have an option to undergo IVF with PGT of the embryos in order to select one without risk of disease to implant. In this way, they can avoid having a child with a recessive genetic disease. This method can also be used when families are known to harbor other disease-causing variants for dominant or sex-linked disorders but is typically not used as a general screening test for single gene disorders. PGT is sometimes used to screen for chromosomal abnormalities in women with advanced maternal age, a history of recurrent pregnancy loss or IVF failures.
Tests in the prenatal period
In practice, most patients are using carrier testing in the prenatal period, after conception, probably due to a lack of awareness of the availability of pre-conception screening by healthcare providers. For carrier couples at risk of having a child with a recessive disorder, their options include invasive sampling using amniocentesis or CVS followed by genetic diagnostic testing of the fetus to determine whether they are affected. Amnio is usually is done between 15-20 weeks gestation while CVS can be done earlier between 10-13 weeks.
Amnio/CVS has historically been used among women who test positive for a serum-based screening test for fetal aneuploidies like Down Syndrome as well as neural tube defects (NTDs). Increasingly, amnio is being used to detect a range of genetic conditions in at-risk women. The indications for testing is usually an abnormal sonogram. Arrays, panels and even exome sequencing may be performed, although the American College of Medical Genetics cautions against the use of the latter.
NIPT has been widely adopted as an additional screening method for chromosomal abnormalities, especially as a second-line test among high risk women. The accuracy of this test is so high that it has drastically reduced the need for diagnostic amnio/CVS. For technical reasons, clinical use of NIPT is currently limited to aneuploidies. However, recent studies have demonstrated expanded application of NIPT for detecting large, de novo structural variants, and small de novo single nucleotide variants or dominant disorders that are paternally inherited.
Fetal diagnosis can provide prognostic information, and impact prenatal care, including planning for the delivery and subsequent neonatal care. It may also impact reproductive decision-making, including the option for pregnancy termination.
Testing in the newborn period
Mandatory newborn screening programs conducted by each state usually test all newborns in the first days of life for a standard panel of 34 genetic diseases, many of which are metabolic disorders. These conditions were selected based on their prevalence, severity and ability to prevent disease manifestations with early treatment. Examples include phenylketonuria, galactosemia, hearing loss and others. These programs have been successful in reducing the morbidity associated with these disorders.
Testing is typically done biochemically using tandem mass spectrometry (MS/MS). Most agree that despite sequencing being a cost-effective method of detection, biochemical methods remain more sensitive and economical on a population-screening level, especially for some conditions.
Recently, expanded newborn screening panels of several hundred rare disease genes have become commercially available directly to consumers. In addition, some groups have explored the feasibility and interest in population-wide sequencing at birth. Whether in a clinical or public health context, there are concerns about the limited usefulness of sequencing in asymptomatic populations (benefits of early detection), storage of results, resource utilization for follow-up care and autonomy of the newborn (the right to not know, especially for adult-onset conditions).
Newborn screening only detects a small fraction of the several thousand rare genetic diseases. For most other genetic diseases, a diagnosis is made only after the child exhibits clinical signs of disease. When a child presents with a rare disease with no obvious diagnosis, diagnostic sequencing may be offered. Diagnostic whole genome or exome sequencing has been used in the neonatal intensive care unit where rapid diagnosis has been shown to reduce the morbidity of genetic diseases.
What healthcare providers need to know
Genetic testing in the perinatal period is not for everyone. While population-based genetic screening is generally offered for a select group of disorders, most diagnostic testing is only done in at-risk individuals. Examples of indications include carrier-positive parents, abnormal ultrasound findings, positive serum screening tests, family history of genetic disease, or a history of recurrent pregnancy loss. This risk-based approach to testing considers the benefit and likelihood of diagnosis balanced against the possible risks to the embryo/fetus/child. Risks associated with testing include physical harm associated with invasive sampling, as well as the risk of unnecessary or dangerous procedures or follow-up of false positive results.
The exceptions are those disorders of great public health importance, like those tested in newborn screening programs where the potential benefits of diagnosis far outweigh the risks, even in the general population.
Technological advances will continue to push the boundaries of perinatal genetic testing with expanded testing menus and a move toward earlier and earlier diagnosis. Ultimately, a more integrated system that includes preconception, prenatal and newborn screening to get as much data at the right times based on parent preference and good science should be our goal. Knowing the capabilities and limits of current testing paradigms is key to successful implementation of perinatal genetic testing.
Learn More
To learn more about genetic testing and improve your genomic literacy, check out our online courses at precisionmedicineacademy.org.
Precision Medicine Advisors specializes in communicating precision medicine to lay professional audiences, providing scientifically sound, unbiased information to promote the responsible use of genomics in medicine.
Contact info: jeanette@pmedadvisors.com