Sequencing the genome to address pediatric abnormalities and disease

At Children’s Wisconsin, medical geneticists bring cutting-edge prenatal screening to families throughout the Midwest

It’s been 18 years since scientists announced they had sequenced the entire human genome. Since then, the field of genetics and genomics has exploded, with new technology and lower costs bringing genetic diagnosis into the clinical setting. Today, genetic screening and testing is rapidly becoming the standard of care, ushering in the age of personalized medicine.

This is particularly true in obstetrics. “We have advocated for a long time that women have prenatal screening of some sort,” says Donald G. Basel, MD, who directs the Genetics Center at the Children’s Wisconsin. Twenty-five years ago, that meant ultrasound screening. Then came biochemical tests such as the quad screen and other first-trimester screenings, with women who have abnormal results given the option of diagnostic testing through chorionic villus sampling (CVS) or amniocentesis — both invasive procedures with some risk to the mother and fetus.

An improved screening option became available in 2011 with the release of the first commercial assay capable of sequencing fragments of DNA found in maternal serum. Called non-invasive prenatal testing (NIPT), or cell-free testing, this test is now routinely offered to all pregnant women to screen for fetal aneuploidy. It can be performed as early as nine weeks into the pregnancy up until delivery, with results available within seven to 10 days.

“The DNA is thought to be derived from trophoblastic and placental cells released into the maternal circulation,” Dr. Basel explains. It offers a “reasonably good” representation of the baby’s DNA. The test has a more than 99 percent specificity and sensitivity for trisomy 18 and 21, with a more than 99 percent specificity for trisomy 13 and sex chromosome abnormalities. The sensitivity for those conditions, however, is between 80 and 90 percent.¹

The test can also screen for some microdeletion syndromes, as well as trisomies 16 and 22, which are common causes of early miscarriage. However, Dr. Basel says, “the positive predictive value is not always that great for these conditions, and there are still a fairly high number of false positives.”

Specificity and sensitivity are different but equally important measures screening efficacy. Specificity is the percentage of persons without the disease who are correctly excluded by the test. Sensitivity is the percentage of persons with the disease that the test correctly identified. Ideally, a test should provide a high specificity and sensitivity. Both continue to improve for NIPT, Dr. Basel says.

It’s important to remember that the NIPT is not diagnostic, he says. Thus, a positive screen triggers a confirmatory CVS or amniocentesis. However, “in the five to six years after the release of this testing, the frequency of amniocentesis or CVS has dropped dramatically in most academic centers,” he adds.

Also, because the fragmented fetal DNA is identical to the mother’s, the test has the potential to find other sources of fragmented DNA, including malignancies in the mother, something clinicians need to be aware of.

Counseling Is Critical

Dr. Basel notes that it is critically important that women undergoing NIPT meet with a genetic counselor if they have abnormal screening results — something that may not always be possible in the community setting.

Another testing option routinely offered to expectant couples is carrier screening. It assesses a couple’s risk of having a child affected with genetic conditions such as cystic fibrosis, spinal muscular atrophy and sickle cell disease, among others. Large multigene, low-cost carrier screening panels for these and other conditions are available today.

Screening can take the form of carrier testing to determine if either parent is a carrier of more common genetic disorders, those that affect less than one in 100,000. “Unfortunately, a lot of these tests are ordered with very limited counseling,” Dr. Basel says.

Preparing Parents

All prenatal genetic testing, whether carrier screening, NIPT screening or diagnostic testing from amniotic fluid, are designed to help parents and their physicians make informed decisions about a pregnancy.

“It helps us know how to plan for the birth, what to expect,” Dr. Basel says. “Obviously, some of these genetic disorders carry a more severe prognosis, and having this knowledge ahead of time can help the family prepare for the fact that the baby may not survive, rather than finding out at the time of delivery.”

Diagnostic screening at the Genetics and Genomics Program at Children’s Wisconsin can also help identify potentially treatable diseases prenatally, such as spinal muscular atrophy - the second most common fatal autosomal recessive disorder after cystic fibrosis - allowing for immediate treatment after birth.

Dynamic Research Environment

Dr. Basel and his colleagues throughout the hospital are involved in numerous research initiatives in the genetics arena, including:

•  Identifying genes that predict the development of type 1 and type 2 diabetes in at-risk individuals to enable early interventions
• Participating with the National Institute of Health’s Pharmacogenetics Research Network to choose medications based on a child’s genetic makeup
• Using pre-implantation genetic diagnosis coupled with in-vitro fertilization to prevent the genetic transmission of unique single-gene disorders
• Manipulating gene delivery systems to develop gene therapy protocols to treat children with bleeding disorders
• Conducting genome-wide association studies to identify complex causative and modifying genes in childhood inflammatory bowel disease, hemangiomas, congenital heart disease, eye malformations and other childhood disorders

One area of interest is identifying the genetic abnormalities in babies born with multiple congenital abnormalities. “When we see a pattern that is not diagnosable prenatally, we attempt to coordinate genomic sequencing on the baby to try and offer an answer for the parents,” he says. This can be particularly important if they want to have other children. So far, the team has sequenced DNA from six families, providing a diagnosis and “helping them come to terms with what’s going on,” he says.

The future aspect of prenatal genetic diagnosis lies in the fetal red blood cells that remain in the mother’s circulation for years, he says. “Some research groups are trying to isolate those cells, then take the DNA and amplify it and do whole-genome sequencing looking for potential causes of abnormalities rather than having to obtain the tissue through an invasive procedure.”

Looking forward, Dr. Basel sees a world in which we embrace precision health care and utilize genomic data to guide the various health interventions along the course of that person’s lifetime. For example, we could know before a baby is born if they are predisposed to hypertension or other diseases 40 or 50 years down the road. “Then you can modify the environment early on to try and alter the epigenetic influences to improve health and wellness"

1American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine. Committee Opinion: Cell-free DNA Screening for Fetal Aneuploidy. Reaffirmed 2017.