The Evolution and Practical Application of Genetic Testing

Genetic testing had its origins in the 1950s when scientists discovered that an additional copy of chromosome 21 causes Trisomy 21, also known as Down syndrome. Methods for staining chromosomes were used to sort and count chromosomes, a process called karyotyping. That process, combined with the ability to collect fetal cells from a pregnant woman’s amniotic fluid, provided scientists the ability to conduct genetic prenatal screening. Such testing revealed DNA-based diagnoses of genetic disorders caused by biologic irregularities such as too many chromosomes, too few, or clusters of chromosomes in the wrong places. As genetic testing became widespread, scientists began researching the substance of DNA, the chemical structure deciphered in 1953 by Rosalind Franklin, James Watson, and Francis Crick. Over the next several decades, it was discovered that helix-shaped patterns of paired chemical bases — adenine, thymine, cytosine, and guanine — provided a code that cells would decode into amino acids, the building blocks of protein. Scientists also discovered through research into the human genome that approximately 98% of DNA doesn’t actually code for proteins, and was seen as “junk DNA.”

APPLICATION IN OBSTETRICS

As science around genetics developed, the application and use in obstetrics medicine also expanded. Many diseases that affect humans have a genetic component. Some disorders are passed from parents to their children at conception. A change in DNA sequence away from the normal sequence can result in a genetic disorder. Such genetic disorders can arise through mutation in one gene (monogenic disorder), mutations in multiple genes (multifactorial inheritance disorder), a combination of gene mutations and environmental factors, or by damage to chromosomes (changes in the number or structure of entire chromosomes, the structures that carry genes).

Advances in genetic mapping and technology have increased the accessibility and affordability of preconception carrier screening for couples considering pregnancy. Given the advanced reproductive technologies now available, preconception carrier screening allows a woman and her reproductive partner to make informed reproductive decisions.

Systemic genetic screening has been available in the United States since the 1960s, when Dr. Robert Guthrie developed the newborn screening test for phenylketonuria, a metabolic disorder also known as PKU. Since 1964, the Minnesota Department of Health has coordinated the screening of all newborns for more than 50 inherited or congenital disorders via a blood draw between 24 and 48 hours of birth. In 2010, the Recommended Uniform Screening Panel (RUSP) was adopted as a national standard for newborn screening, consisting of five main categories: (1) hemoglobinopathies, (2) organic acid disorders, (3) amino acid disorders, (4) fatty acid oxidation disorders, and (5) miscellaneous disorders, such as cystic fibrosis and hypothyroidism. The newborn screening program is the largest genetic screening program, with approximately 4 million infants tested annually. While the advances in newborn genetic screening programs have improved the detection and early intervention for treatable genetic conditions, newborn testing cannot replace preconception or early prenatal carrier screening of the parents.

Beginning in 2017, obstetricians were advised to expand genetic screening offerings to their patients. Two committee opinions from the American College of Obstetricians and Gynecologists (ACOG), published in the March 2017 issue of Obstetrics & Gynecology, expanded guidelines on carrier screening for genetic disorders. These committee opinions were issued in response to the availability and affordability of expanded genetic testing that could screen for hundreds of conditions in one test, as well as in response to dilution of ethnic population concentrations that had previously guided genetic screening recommendations. ACOG Committee Opinion 690, “Carrier Screening in the Age of Genomic Medicine,” includes general guidelines; and Committee Opinion 691, “Carrier Screening for Genetic Conditions,” addresses testing for specific diseases.

The committee opinions distinguish three scopes of genetic screening:

• ethnic-specific, such as for Tay-Sachs disease among people of Ashkenazi Jewish descent;
• panethnic (for everyone), such as a test for cystic fibrosis, spinal muscular atrophy, and fragile X syndrome offered to all patients; and
• expanded carrier screening, which analyzes up to hundreds of conditions.

The general recommendation advises individual health care providers to “establish a standard approach” they offer consistently to patients, including counseling and informed consent. Counseling should include discussion of “residual risk” resulting from de novo mutations and mutations not included in test panels. At a minimum, the committee opinions advised that all patients should be offered screening for cystic fibrosis, spinal muscular atrophy, and hemoglobinopathies, because these are the more common recessive inherited conditions.

Advances in genetic science has led to the availability of preconception screening, offering couples seeking to become pregnant the opportunity to test for genetic changes that have little or no impact on their own health but can cause significant health problems for their children. ACOG defines carrier screening as “genetic testing performed on an asymptomatic individual to determine whether that person has a mutation or abnormal allele within a gene that is associated with a particular disorder.” Genetic changes carried by both partners can cause a health condition if both copies of the genetic change are inherited by a child. These are known as autosomal recessive conditions. Genetic changes that are carried by the female partner and cause a health condition when a male child inherits the genetic change are known as X-linked conditions.

Carrier testing is particularly valuable for consanguineous couples, whose offspring are at elevated risk of inheriting recessive mutations from shared ancestors. Prenatal carrier testing provides information for diagnostic testing of the fetus or newborn, for termination, or for arranging care.

Ideally, carrier screening should occur prior to pregnancy. If both partners are carriers for the same genetic condition, genetic counselling is recommended to help couples understand the meaning of the test results and the available reproductive options, such as in vitro fertilization (IVF) with prenatal diagnosis and preimplantation genetic testing of embryos, or the use of donor gametes.

Current guidelines by ACOG are that women’s health care providers offer carrier screening to all individuals who express an interest in becoming pregnant, regardless of ethnicity or family history. Recent progress in genetic testing technology with next- generation sequencing makes expanded carrier screening readily accessible for most couples. Where couples present themselves for preconception health evaluations, a provider has a duty to inform of the availability and offer carrier screening. When genetic screening isn’t offered to individuals seeking preconception evaluation, it is a deviation from accepted standards of care and could give rise under certain circumstances to a claim for wrongful conception.

With the added scientific knowledge gained through the National Institutes of Health Human Genome Project and spin-off research, we can expect to see continual expansion in applications for genetic science.