SFARI hosts workshop on newborn screening

Image of baby getting blood taken


As the number of genetic findings related to autism and neurodevelopmental disorders (NDDs) has risen and the cost of genome sequencing has fallen, the possibility of screening newborns for a subset of genetic conditions has come into view. On September 27, 2021, the Simons Foundation Autism Research Initiative (SFARI) convened a one-day virtual workshop to explore and discuss opportunities and challenges for early detection of NDDs through genomic sequencing. Spearheaded by Wendy Chung, SFARI director of clinical research and Kennedy Family Professor of Pediatrics in Medicine at Columbia University; SFARI John Spiro; and SFARI consultant Mike Hu, the workshop gathered over 50 participants from a variety of backgrounds, including parent advocates and specialists in NDDs and newborn screening.

“The promise of newborn screening has been recognized since the first draft of the human genome,” said Kelsey Martin, director of SFARI and the Simons Foundation Neuroscience Collaborations. “SFARI is interested in bringing the potential benefits of this genomic information to everyone.”

In the United States, newborns are currently screened for a number of conditions, mostly metabolic disorders. These are flagged by metabolites in blood samples collected at birth, as detected by mass spectrometry. Like metabolic disorders, NDDs are not apparent at birth, and so early detection through genome sequencing could alert families and clinicians to these often severe and lifelong conditions at a stage with minimum accumulative damages and maximum treatment efficacy.

“My wife and I have experienced firsthand how earlier diagnosis and treatment have helped our younger son to achieve much more than his elder brother, both born with MPS II, a severe condition with progressive physical and neurodevelopmental impacts,” Hu said. “With the painfully slow pace that can take five or more years to add a single condition to newborn screening, I believe bringing genomics to newborn screening will quickly bring real, tangible benefits to families.”

Many at the workshop agreed that the time was right for a pilot study of newborn screening for NDDs through genome sequencing. Discussions centered on study design, such as which NDDs to screen for; the genetic results that should be returned to families; the possibilities for long-term follow-up of screened newborns; the benefits and harms of screening for NDDs that have no cure; how to store and curate genome sequence data; and the ethical, legal and social implications of such a project.

Chung, who moderated the discussion, asked the group to think creatively and responsibly about the project and consider issues of equity and equality. “We want every newborn to get the same and equal chance for screening,” she said.

Motivating newborn screening for NDDs

For NDDs without cures, a case can still be made for screening for them in newborns — particularly the highly penetrant, single-gene conditions that could be detected genomically with high sensitivity and specificity. Don Bailey of RTI International argued for a broad view of benefits of newborn screening for NDDs such as fragile X syndrome (FXS); early detection could reduce secondary complications like seizures, access educational services earlier, avoid a prolonged ‘diagnostic odyssey’ that often accompanies NDDs and provide anticipatory support for parents.

Mustafa Sahin of Boston Children’s Hospital noted that early (before or at the time of birth) detection of tuberous sclerosis complex (TSC) has contributed to a detailed understanding of how the disorder unfolds (‘natural history’), which is key for therapeutic trials. Early detection of TSC also allows for early treatment of seizures, which could protect brain development (e.g., PREVeNT trial). Huda Zoghbi of Baylor College of Medicine spoke of Rett syndrome and its window of seemingly typical development during the first year of life before regression begins. Early detection could provide an opportunity for training to enhance skill acquisition during this period, which might lessen symptom severity, as suggested by preclinical studies in animal models.

Even for genetic diseases already included in newborn screening panels, however, there are complications. Elliot Sherr of the University of California, San Francisco reported that only half of babies that screen positive for X-linked adrenoleukodystrophy develop neurological impairments. This, combined with its invasive treatment, means that some clinicians currently wait for signs of neurological regression before treating.

Pilot study considerations

To understand the issues that come up in pilot studies of genome sequencing in newborn screens, the workshop featured experts involved in such trials in the past. Michele Lloyd-Puryear of the American College of Medical Genetics and Genomics described the pilot for Duchenne muscular dystrophy (DMD) and the importance of remaining focused on screening for DMD specifically, carefully choosing outcomes and parent participation through an informed consent process.

Amy Brower of the Newborn Screening Translational Research Network (NBSTRN, nbstrn.org) said that a pilot study should keep in mind the requirements for nominating a condition onto the recommended uniform screening panel (RUSP). This involves a multistep review by the federal Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) and the secretary of health and human services. Terri Klein of the National MPS Society described the essential roles advocacy groups play in this process: they can help educate a diverse cross-section of parents about study participation, and their input can bolster support of a condition’s nomination to a screening panel.

One consideration in choosing which NDDs to pursue in a pilot study is their degree of ‘clinical actionability,’ which reflects a combination of symptom severity, penetrance and treatment effectiveness1,2Jonathan Berg, from the University of North Carolina at Chapel Hill, described a method developed by the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) research team, which examined the potential use of exome sequencing as an adjunct to traditional newborn screening.  In weighing the ideal screening pilot, Berg suggested using the concept of ‘number needed to screen’ to effectively intervene for one person. This approach would take into account both the prevalence of the conditions and the effectiveness of interventions to prevent certain outcomes, in order to estimate the size of a pilot that would be required to demonstrate clinical utility.

Test, analysis, clinical follow-up challenges

Genome sequencing has become an increasingly important diagnostic tool, but its methods will have to be adapted for screening, which looks for a rare affected person among a large unaffected population. Bob Currier, formerly of the California Department of Public Health, said that ideally, a test must have high specificity (low rate of false positives) so as to avoid needlessly worrying families.

An offshoot of the large data set accumulated from these screens is the emergence of new variants of unknown significance (VUSs). Andreas Rohrwasser of the Utah Public Health Laboratory stressed the importance of establishing phenotype-genotype relationships, the importance of fully cataloguing variants of unknown significance and variant database integration and described a feasible exome-sequencing pipeline3. Establishing a system to curate genotype-phenotype- relationships constitutes a minimum requirement to link population screening with clinical variant knowledge and lays the foundation for truly scalable newborn screening solutions. Steven Brenner of the University of California, Berkeley described the NBSeq project, which evaluated whole exome sequencing for inborn errors of metabolism in California infants and found that it had less sensitivity and specificity than standard mass spectrometry4. This might be due to VUSs that have not yet been classified or undetected causal variants within the noncoding regions of the genome.

Michele Caggana of the New York State Department of Health detailed the need for an automated pipeline to interpret exome-sequencing results from newborn screening. Next generation sequencing work done with other single-gene genetic disorders such as cystic fibrosis could provide a model for tracking frequency and interpreting new variants that are detected when using these methods in newborn screening laboratories. Amy Gaviglio, a public health genetics and genomics consultant, described her involvement in a project with the Centers for Disease Control and Prevention (CDC) to build a national newborn screening data platform, which will include genetic, biochemical and clinical data components.

Genetic screening faces ethical, legal and social implication (ELSI) issues5. Jeff Brosco of the University of Miami Miller School of Medicine noted a tension between a public health approach that mandates screening (and thus reaches a more diverse population) versus an informed consent approach in a pilot study. For a population-level pilot study, the usual informed consent processes can be difficult to work into a busy maternity ward. Jeff Botkin of the University of Utah described two alternatives: a waiver of signed consent, which allows verbal consent, or automatic opt-in. Focus groups of prospective parents in Utah and Colorado were positive about automatic opt-in consent for a study of newborn screening, but ultimately this was rejected by the states. Colleen Olson of the DHPS Foundation offered that a screening conversation in the third trimester of pregnancy felt appropriate and that care must be taken in how results are delivered to parents.

Existing frameworks for embedding the study of ELSI issues into larger studies may also prove useful6,7. Toward this end, Kyle Brothers of Norton Children’s Research Institute and the University of Louisville suggested aiming for a sample with representative demographics, including outcomes that include ‘process measures’ like time to access services and surveying those who decide to participate in the screen and those who decline8.

Policy, system and the next steps for newborn screening

In the final panel, R. Rodney Howell of the University of Miami Miller School of Medicine said that genome sequencing at the newborn stage is important for spreading this technology equitably because this is the one time most people interact with the health care system. Though screening with sequencing may seem costly, Walter Kowtoniuk of Third Rock Ventures reminded the group that diagnosis is also very costly. Max Muenke of the American College of Medical Genetics and Genomics outlined other approaches to bolster equity, including diversifying the workforce, getting geneticists onto telehealth platforms and supporting research to clarify the interpretation of genetic variants for people with diverse ancestries. Michael Watson, former executive director of the American College of Medical Genetics and Genomics, noted that the fragmented nature of the U.S. health care system challenges the ability to implement screening efforts equitably but that public-private partnerships could help, particularly in funding population-level pilot studies of rare diseases. Others suggested a multi-agency effort within the Department of Health and Human Services (HHS).

The massive amounts of genetic data that will result from a population screen will tempt researchers to look at a large number of conditions simultaneously. But Joseph Bocchini of Tulane University warned that too broad a scope in a pilot may make it difficult to identify relevant outcomes by the end of the study. A more targeted approach may be more fruitful. He also emphasized that the ACHDNC will need to consider ways to modify its current one-at-a-time approach for reviewing conditions nominated for the RUSP, so that the advisory committee may expeditiously handle the quicker pace of discovery that is expected with genomic screening and rapidly advancing therapeutic developments9.

Melissa Parisi of the National Institute of Child Health and Human Development suggested an approach to data collection that is focused enough to inform the question of whether a specific condition can be added to a uniform screening panel yet wide enough to suggest NDDs that warrant study in the future. She also highlighted the fruits of the Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT) program, which includes the NBSeq and NC NEXUS projects, as well as one that screens for genetic conditions in neonatal intensive care units10.

Overall, the workshop marked a productive brainstorm on how to incorporate NDDs into new genomic approaches for newborn screening. Many participants are currently collaborating on a journal article to outline these issues.

“This was a very productive workshop. SFARI is now actively following up on many of the fascinating discussions that were sparked by the meeting and considering options of how to help move this forward,” Spiro said.

In closing, Chung said, “SFARI is convinced that genomic data will eventually help medical decision-making and is committed to helping this happen in an equitable way.”


  1. Milko L.V. et al. J. Pediatr. 209, 68-76 (2019) PubMed
  2. Lewis M.A. et al. Pediatrics 137, S16-23 (2016) PubMed
  3. Ruiz-Schultz N. et al. Genet. Med. 23, 767-776 (2021) PubMed
  4. Adhikari A.N. et al. Nat. Med. 26, 1392-1397 (2020) PubMed
  5. Lloyd-Puryear M.A. et al. Int. J. Neonatal Screen. 4, 6 (2018) PubMed
  6. Goldenberg A.J. et al. Genet. Med. 21, 525-533 (2019) PubMed
  7. https://nbstrn.org/data-tools/elsi-advantage?tab=about
  8. Pereira S. et al. JAMA Pediatr. 175, 1132-1141 (2021) PubMed
  9. https://www.hrsa.gov/sites/default/files/hrsa/advisory-committees/heritable-disorders/meetings/20210812/committee-process-review-report.pdf
  10. French C.E. et al. Intensive Care Med. 45, 627-636 (2019) PubMed
Recent Workshop and Meeting Reports