Moving towards ending the diagnostic odyssey: how Sema4 research benefits rare disease patients

Today we celebrate Rare Disease Day, an international day of awareness that shines a light on rare diseases and their impact on patients’ lives. The day’s theme this year is one fundamental to Sema4’s mission: research. More than 7,000 rare diseases have been identified to date, 80% of which are caused by known genetic factors and, collectively, these diseases affect 30 million Americans, half of whom are children. While on a worldwide population level these diseases may be rare, in some population groups they are dramatically enriched. Reports from rare disease communities, biotech companies focused on rare diseases, and rare disease researchers indicate that it takes most rare disease patients on average five to eight years to obtain an accurate diagnosis, during which time irreversible damage can occur to their health. How, then, can we reduce the duration of that diagnostic odyssey and improve health outcomes?

Diagnosis is typically made after symptoms have manifested, but for many patients, the answer lies in their DNA from birth. We built on our expertise in medical and pediatric genetics, as well as our roots in the Mount Sinai Health System, to create Sema4 Natalis, a supplemental newborn screen designed to detect the strongest genetic risk factors of rare diseases even before the onset of symptoms. Until now, families have been likely to be caught off-guard by these early-onset diseases, and prognosis is often poor by the time symptoms have manifested, a problem compounded by the long wait for an accurate diagnosis. Natalis was developed to help address this issue of undiagnosed pediatric illness by using next-generation DNA sequencing and analysis to supplement traditional newborn screening.

Natalis screens for 193 childhood-onset diseases or disorders — more than five times the number on most standard state-mandated newborn screening tests — and also includes a pharmacogenetic analysis of how a child is likely to respond to 38 medications commonly prescribed in childhood. Our goal when designing Natalis was simple: to identify babies at risk for these 193 diseases, and allow pediatricians to reach a diagnose and deliver interventions – sometimes as simple as vitamin supplements – in time to make a real difference in the life of a child. Rare diseases included in Natalis, but not in most state-mandated screens, include spinal muscular atrophy (for which a recently FDA-approved drug offers treatment), atypical epilepsy (for which vitamin B6 supplementation can reduce or prevent seizures), and mutations that lead to certain childhood cancers at exceptionally high rates (where knowledge of such high risk can lead to more frequent monitoring).

We designed Natalis to provide results that are both accurate and medically actionable, based on years of research and clinical experience in molecular diagnostics. It was essential that Natalis meet three strict criteria: analytical validity, clinical validity, and clinical utility. Testing takes places in our CLIA-certified laboratory, using advanced next-generation sequencing technology that is >95% accurate, guaranteeing analytical validity. All positive test results are confirmed with a second sequencing technology. To ensure clinical validity, we only included diseases with “high penetrance,” meaning that if a patient tests positive for a disease-associated variant, there is a high probability (>80-95%) that he or she will develop symptoms of that disease. Finally, clinical utility was achieved by only including diseases for which there is a medical intervention available.

Although ordering Natalis can be initiated online, it is distinct from direct to consumer (DTC) tests in that the order must be approved by one of our independent physicians to ensure it is medically appropriate for the child. Parents can also opt to order the test through their own physician. These features, along with the inclusion of genetic counseling, set Natalis apart from DTC tests. We are hopeful that Natalis will be embraced by patients and physicians in as positive a way as hereditary cancer testing, which is available in DTC form and has markedly improved outcomes for patients despite looking for disease-associated variants with far lower penetrance than those in Natalis.

To assess the attitudes of consumers toward genetic screening for newborns, Sema4 recently commissioned a Harris poll – just one component of our overall program to gain new insights into genomic health – which revealed that the majority of Americans are in favor of newborn genetic screening. 88% of Americans said that if they could find out just after their baby is born about their child’s genetic risk of getting a treatable early-onset disease, they would want to know. We are also in the process of launching a clinical study to explore the utility of supplemental newborn screening to both patients and physicians, including how individuals respond to this new type of actionable information, what actions they take as a result, and how this ultimately impacts health outcomes and healthcare utilization. Through our consumer research, clinical study, and Natalis itself, we seek to understand, in partnership with our patients and the scientific and medical communities, the benefits of obtaining supplemental genetic information at birth and whether DNA screening for treatable childhood disorders should become the standard of care.

As a parent, I understand all too well the emotions surrounding the birth of a child and the urge to keep them safe. When my first baby was born, I was consumed by fears, most of which I could allay through preventative measures: removing loose bedding, installing a baby gate, and keeping up to date with vaccinations. But, some things were out of my control: what if he would one day develop a genetic disease that not even I, an expert in genetics, could predict or fix? A test like Natalis back then would, I think, have provided tremendously empowering insights. Looking forward, I firmly believe Natalis will give other parents the advantage of early insight in support of the care of their children and am proud to be leading the way with Sema4 in this new age of genomic medicine.


Eric Schadt, Ph.D.
Founder and Chief Executive Officer