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Newborn Screening + Genome Sequencing: The Formula for Faster Rare Disease Diagnosis?

Now is the time for the entire industry to understand what newborn screening and newborn sequencing programs are, how they benefit the rare disease community, and how to maximize their benefits. 

The earlier diseases are diagnosed, the earlier they can be treated. Unfortunately, time is often of the essence for those with rare genetic disorders. For example, the few therapies that exist for infantile Krabbe disease, which is usually fatal by age two if left untreated, are most effective when done before symptoms appear. Indeed, some research suggests that one therapy is most successful when done within 30 days of birth.  

Such scenarios are the driving force behind newborn screening programs worldwide. These programs rely on the biochemical analysis of babies’ blood samples to detect severe disorders. Yet, despite being incredibly valuable, these screening methods have their limitations. Most notably, newborn screening is not intended to definitively diagnose disease, only to indicate when further diagnostic testing might be warranted.

One recent study suggests that adding genome sequencing to newborn screening programs might hasten and improve the diagnosis of serious and rare diseases. Thus, parents might be better equipped to pursue treatments for their infants faster—including enrollment in clinical trials for disorders with few treatment options. 

As genome sequencing science advances, it is not a matter of whether it will be leveraged as part of newborn screening but who will do it first. Still, even this promising prospect has its drawbacks, including increased demands on genetic counselors and other healthcare professionals. Therefore, now is the time for the entire industry to understand what newborn screening and newborn sequencing programs are, how they benefit the rare disease community, and how to maximize their benefits. 

Screening vs. sequencing

Newborn screening programs are public health initiatives that started in the 1960s to aid in the early detection of phenylketonuria (PKU), a rare but serious genetic disease. Today’s screening programs still test for PKU, but also a wide variety of other disorders. In the U.S., the diseases screened for vary by state. 

No matter the disorders screened for, the programs all take a similar approach. They involve pricking newborns’ heels and analyzing the biochemical makeup of the resulting blood spots. This is usually done soon after birth and is paid for with government funds. Parents who don’t want their babies screened typically must opt out.  

It is important to understand that newborn screening tests can only identify indicators of disease; any positive results require secondary testing to confirm a diagnosis. In addition, current screening tests are designed to err on the side of false positives since the goal is to catch as many babies as possible who might have a debilitating or rare disease. Consequently, some parents may be needlessly subjected to stress and worry while awaiting confirmatory testing results.

Newborn sequencing, on the other hand, is an emerging field that is not yet part of public health initiatives. Instead, sequencing programs are research studies conducted by various academic institutions. Parents must qualify, opt into, and consent to enroll their babies in a sequencing research study. Unlike screening programs, which tend to be uniform across specific geographies, each sequencing program looks for different diseases, looks for different genetic variants, has different requirements, etc. Examples of sequencing programs in the U.S. include BabySEQ, BeginNGS, and Early Check.

Like screening programs, most newborn sequencing research also uses babies’ blood samples from a heel stick. However, the subsequent analysis is quite different. Rather than look for disease indicators — such as high or low levels of specific chemical compounds — sequencing technologies examine the newborn’s actual DNA to uncover potential genetic health risks more accurately. 

Although every newborn sequencing program is unique, they all have one thing in common: They use genome sequencing at birth to enable earlier diagnosis of genetic disorders. 

Benefits, challenges, and call to action

Many genetic disorders do not manifest right away. In other words, a baby might appear perfectly normal at birth yet harbor a serious genetic disorder such as PKU, Krabbe disease, cystic fibrosis, or beta-thalassemia. Combining screening with sequencing can empower faster diagnosis and decision-making, buying valuable time for infants and their families to try to prevent disease through earlier treatment.

However, one key challenge is that screening and sequencing can create difficult emotional, ethical, and logistical choices for parents. Sequencing, especially, may unveil genetic insights with devastating short- or long-term implications. Very often, time- and resource-strapped providers may feel ill-equipped to have in-depth discussions with parents about specific genetic tests, test results, and their options. 

While genetic counselors may already be involved in newborn screening, they should also be involved in newborn sequencing  conversations to help maximize their benefits. Genetic counselors are well-situated to educate parents (and providers) about:  

  • differences between screening and sequencing.
  • potential benefits and drawbacks of screening and sequencing.
  • the “knowns” and “unknowns/limitations” of various genetic tests.
  • potential future ramifications for parents, their children, and their families.
  • applicable sequencing studies that might be available. Groups such as the International Consortium on Newborn Sequencing (ICoNS), which collates research programs globally, can help stakeholders keep their fingers on the global pulse of sequencing programs.
  • relevant clinical trial options. For many rare diseases, a clinical trial may offer the only available treatment option. 

Although genetic counselors bring unique knowledge and skills to the table, another looming challenge is the need for many more genetic counselors, lab staff, IT specialists, data analysts, and others to support the impending explosion sequencing opportunities. Currently, there are not even enough genetic counselors available to support a national-level sequencing program. In fact, before sequencing can become a truly complementary aspect of newborn screening, the industry will need to address numerous tactical and ethical questions, such as:

  • Should sequencing be a single federal initiative, or multiple state-by-state initiatives that leverage the same infrastructure as current screening programs?
  • Who should pay for sequencing?
  • Where will sequencing data be stored, and who will have access to it?
  • Which genetic variants should be pursued, why, and how are they reported to the parents / patients?

Is the industry prepared to leverage newborn sequencing fully? Not yet. While that’s fine for now, we must understand there is tremendous value in pairing newborn sequencing with newborn screening and involving genetic counselors at its various stages. For some rare genetic diseases, early diagnosis through newborn sequencing may be the best hope for improving outcomes for infants and their families. So, let’s roll up our sleeves and get ready to use it.  

Photo: Lisitsa, Getty Images

Derek Ansel, MS, LCGC, is the Executive Director and Therapeutic Strategy Lead for Rare Disease at Worldwide Clinical Trials and a board-certified and licensed genetic counselor. He has worked in clinical research for more than ten years, focusing almost exclusively on rare and pediatric diseases, including non-malignant hematology, autoimmune diseases, metabolic disorders, movement disorders, and other genetic conditions. At Worldwide, he leads and supports corporate initiatives within rare and pediatric diseases and maintains relationships with over 45 patient-focused advocacy organizations.

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