MaryAnn Labant

Preconception Carrier Screening Offers Parents Insight on their Child’s Potential Health Risks

Earlier this year, the Obama Administration launched the Precision Medicine Initiative with a $215 million investment in the President’s 2016 Budget. Heralded as a bold new research effort to revolutionize how we improve health and treat disease, the Precision Medicine Initiative is intended to pioneer a new model of patient-powered research to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies.

Supporting the concept of precision medicine, preconception carrier screening predicts the chances of having a child with specific genetic disorders while diagnostic testing determines the cause of pediatric-onset and other genetic disorders.

Families can be started in both traditional and nontraditional ways; preconception carrier screening provides the information needed for prospective parents to figure out their preferred direction before conception. Counsyl provides screening for diseases where advanced knowledge makes a difference in health outcomes, whether it is changing a behavior, pursuing preventive measures, or simply preparing for what lies ahead.

MaryAnn Labant is a freelance science writer and a frequent contributor to GEN and Clinical OMICs.

A physician’s approval is required for screens, and the company has gained in-network status with major insurers. Challenges arise when medical guidelines and insurance coverage are out of sync; for example, a woman might request a Counsyl Family Prep Screen, but her physician might overturn the request because certain diseases, like spinal muscular atrophy or fragile X syndrome, are not yet part of universal screening guidelines. 

“Our goal is to have the Family Prep Screen become an essential part of pre-pregnancy planning. Women get ultrasounds to check on the development of their babies and usually the results are reassuring. To learn genetic carrier information even before conception seems like a no-brainer. But many people are not aware that carrier screening for over a hundred genetic diseases exists,” explained Shivani Nazareth, Director of Women’s Health, Counsyl.

Counsyl pairs its screening technology with a high-touch approach to delivering test results. Over 35 board-certified genetic counselors are employed and an on-demand counseling session can be scheduled within five minutes of receiving results. Last year, over 11,000 sessions were completed.

As more information about genetic makeup becomes accessible, the way individuals think about personal health susceptibilities will change, leading to better health outcomes and treatment.

“As a genetic counselor, for years I talked to patients who faced health hardships that could have been avoided had they known their genetic makeup. I felt we were not doing right by patients, but, of course, from a public-health perspective, it was too expensive to proactively offer screening to everyone. It is exhilarating to be at the forefront of this trend in preventative medicine,” concluded Nazareth.

Counsyl integrates sophisticated technology with custom automation in its CLIA-certified, CAP-accredited, and NYS CLEP-permitted laboratory. The company uses custom-built robots, which process blood and saliva samples while working alongside a team of scientists to simultaneously analyze thousands of DNA samples with precision, accuracy, and efficiency.

Next-Generation Sequencing

Next-generation sequencing (NGS) research aimed at discovering genes associated with severe, recessive and de novo pediatric-onset genetic diseases continues to yield relevant results. Identifying causal variants linked to disease reduces overall time to obtain clinically actionable results compared to current iterative-testing approaches.

Targeted NGS panels have enabled quicker and more cost-effective testing for larger numbers of genes. If specific diseases appear to run in the family, often a comprehensive screening approach yields greater peace of mind.

Published research provides good evidence of the genetic origins of disease for a number of severe recessive Mendelian disorders, such as cystic fibrosis and spinal muscular atrophies. However, often multiple genes can be associated with a particular disease phenotype, and the relationship between genes and the disease might not be clearly understood. 

 According to Douglas McCannel, Senior Product Manager, Reproductive and Genetic Health, Illumina, many of the severe, recessive, pediatric-onset Mendelian disorders are due to pathogenic mutations found in coding exons and intro-exon boundaries. 

The Illumina TruSight Inherited Diseases Sequencing Panel provides predesigned, ready to use oligos targeting 552 genes in these specific regions. The sequencing panel is compatible with TruSight Rapid Capture Kits that offer a single, integrated library preparation and enrichment workflow that can be completed in just 1.5 days. High-quality data are delivered from low sample input (50 ng) allowing retention of material for future analyses. 

Panel content was developed in collaboration with key opinion leaders to assure data are clinically relevant and actionable. Research and technology development will likely continue to move toward improving whole exome (WES) and whole genome sequencing (WGS) along with software tools to make extraction and filtration of actionable results from the vast amount of sequencing data generated easier.

Saving Babies

Genetic disorders and congenital anomalies are the leading causes of infant mortality; diagnosis is not sufficiently timely to guide acute clinical management.

Children’s Mercy Kansas City is part of NIH-funded NSIGHT (Newborn Sequencing in Genomic Medicine and Public Health). NSIGHT’s purpose is to explore, in a limited but deliberate manner, the implications, challenges, and opportunities associated with the possible use of genomic-sequence information in the newborn period. 

“We focus on critically ill babies in our hospital’s level IV, neonatal ICU (NICU) that are thought to have a genetic disorder. Unlike cancer, which can come back in a mutated manner if you can treat a genetic disorder you are done. WGS is performed using a rapid, sensitive NGS test, STAT-Seq, to look for a known cause of the babies’ symptoms. Initially we looked at 15 infants, our follow-up results looking at a larger group was just published in Lancet Respiratory Medicine,” discussed Stephen Kingsmore,  DSc, Dee Lyons/Missouri Endowed Chair in Pediatric Genomic Medicine, Children’s Mercy Kansas City.

The NICU is an expensive hospital stay; babies are very ill and shaving days or weeks off a diagnosis can make a difference. Thirty-five infants and their parents were enrolled in the Lancet Respiratory Medicine study. All infants were less than four months of age with an acute illness of suspected genetic cause. Fifty-seven percent of the enrollees got a diagnosis using STAT-Seq compared with nine percent by conventional testing.

Both infants and parents are sequenced to allow identification of de novo mutations, which is emerging as the most common inheritance pattern. In de novo mutation, the mutation arises either in the egg or the sperm, and is not inherited in a recessive/dominant manner.

Outcomes were followed for 120 days to determine if the diagnosis made a difference. In 65% of the cases the physician or medical record reported it did. Four treatments profoundly changed, and six babies were started on palliative care.

A STAT-Seq diagnosis in five days resulted in a hypoglycemic baby medically unresponsive to treatment receiving a partial pancreatectomy, which cured the disease. Conventional test results would typically have taken 4-6 weeks and during that time the baby’s brain would have recurrently been exposed to the low blood sugar.

Another baby with acute liver failure was diagnosed with a life-threatening but treatable immune disease, hemophagocytic lymphohistiocytosis. With treatment the baby’s liver recovered, and the child is now almost two years old and doing well.

Despite some successes, overall mortality was high; 57% of the babies who received a genetic diagnosis died within 120 days. Many genetic conditions are ultra-rare, and even with a rapid diagnosis medical teams must figure out if and how to treat the condition.

Dr. Stephen Kingsmore, Children’s Mercy Kansas City, evaluates NGS-based STAT-Seq results, to help end a family’s diagnostic odyssey. There are approximately 5,400 known genetic diseases. Some affect babies, and others affect adults. Many are rare or ultra-rare, with only a handful of worldwide cases.

Challenges in the Quest for Knowledge

Parents with a sick child quest for knowledge, disease diagnosis and prognosis. The diagnostic laboratory GeneDx focuses on identifying the cause of rare and ultra-rare inherited diseases in which the treating physician believes the cause is genetic. WES is predominantly performed for pediatric patients who have complex phenotypes to search for any pathogenic disease-causing variants in any of the genes on the panel.

“When you perform WES or WGS, sometimes secondary findings are found that are not directly related to the reason the patient is being tested. The patient or guardians need to know this type of information could come out, and must decide how to deal with it. Genetic counseling is recommended prior to testing and when results come back. Information once given cannot be taken back,” said Sherri Bale, Ph.D., Managing Director, GeneDx.

The National Center for Bioinformatics and the NIH support a publicly-accessible database, ClinVar (clinical variation), which aggregates information about genomic variation and its relationship to human health. Diagnostics laboratories can add newly identified variants in genes associated with a phenotype into ClinVar with the supporting evidence of pathogenic or benign change.

Reimbursement for tests can be a struggle; druggable mutations tend to be more reimbursable. The CPT code system and associated reimbursement rates are changing yet lag behind the science. Diagnostic laboratories look for the most efficient, cost-effective, and sensitive approach to answer the question, and as new information continually comes out, tests are updated and validated. New tests are challenging to the reimbursement system, often introduced before the system knows how to handle them.

Regulatory oversight may also be in flux. Previously, CMS has regulated diagnostic laboratories under CLIA. Just recently, the FDA has put out guidances to regulate clinical laboratories and laboratory-developed tests. If approved diagnostic laboratories will have to be responsive to two regulatory agencies, the FDA and CMS, and may need to submit test modifications and revalidations for FDA approval, slowing down their ability to provide state-of-art services.

MaryAnn Labant ([email protected]) is a freelance science writer and a frequent contributor to GEN and Clinical OMICs.

This article was originally published in the June 2015 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to

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