Most experts support newborn DNA sequencing for AADC deficiency

Early diagnosis can help 'improve healthcare disparities for affected children'

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Most rare disease experts are in favor of using DNA sequencing to screen newborns for AADC deficiency and other genetic disorders that are not covered by current screening programs, according to a survey.

“Early identification of infants who are at risk for genetic disorders can be lifesaving and screening has the potential to improve healthcare disparities for affected children,” Nina Gold, MD, the study’s first author and a medical geneticist at Massachusetts General Hospital for Children, a member of Mass General Brigham (MGB), said in a MGB press release.

“Medical experts are now calling for more conditions to be included in newborn screening that can only be identified through DNA sequencing,” Gold added.

Survey results were published in a study, “Perspectives of Rare Disease Experts on Newborn Genome Sequencing,” in JAMA Network Open.

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Newborn screening is a process that involves testing babies for genetic diseases within the first few days after birth. A positive test may prompt early treatment to slow disease progression and/or manage symptoms or close monitoring for symptom development and the need for future treatment.

With the increasing number of approved treatments, namely gene and cell therapies, for several genetic conditions, newborn screening for some of these diseases has become widespread.

However, screening for AADC deficiency, an ultra-rare childhood-onset metabolic condition caused by mutations in the DDC gene, is not currently commonplace.

Last year, Upstaza (eladocagene exuparvovec) became the first disease-modifying therapy approved for AADC deficiency in the European Union and the U.K. The gene therapy’s developer, PTC Therapeutics, is planning to apply for U.S. approval in the coming months.

While a range of technologies may be used in newborn screening for different diseases, in recent years there has been interest in newborn genome sequencing, or NBSeq — looking for disease-causing mutations by determining the sequence of a patient’s entire genetic code.

In theory, NBSeq could be used to screen for thousands of conditions at the same time. However, concerns have been raised about the cost and feasibility of using this technology, and there has been debate about which genes to include in such tests.

“It has been a longstanding dream to someday offer DNA sequencing to all newborns in order to detect their risk of disease,” said Robert Green, MD, the study’s senior author and a physician-scientist at MGB’s Brigham and Women’s Hospital.

“With the recent explosion of gene and cell therapies, some of which can fully prevent or cure a condition before symptoms appear, it is urgent that we move forward to provide this option to families who are interested,” he added.

Medical experts are now calling for more conditions to be included in newborn screening that can only be identified through DNA sequencing.

238 rare disease experts completed the survey

In the study, a team led by researchers at MGB asked 386 rare disease experts, including all 144 directors of accredited genetics training programs in the U.S., to complete a survey to assess their views on NBSeq.

The survey, conducted from February to September 2022, was answered by 238 experts (61.7%) across a wide range of specialties. Experts were first asked six questions about their overall opinions on NBSeq.

Results showed that most of them — 87.9% — “agree” or “strongly agree” that NBSeq should be available for treatable monogenic disorders that are currently not included in newborn screening programs. Monogenic disorders, such as AADC deficiency, are diseases caused by mutations in a single gene.

About two-thirds of the experts agreed that NBSeq should be available for monogenic disorders that are currently not treatable, but have established guidelines for monitoring and management. However, less than a third (27.9%) “agreed that NBSeq should include screening for conditions with no established therapies or management guidelines,” the team wrote.

Also, more than one-third (37.2%) agreed that newborns should be tested for adult-onset conditions with therapeutic or preventive interventions available to facilitate testing in parents, who might also be affected.

Younger experts were significantly more likely to support the use of NBSeq than their older peers, “suggesting that clinical experts who trained more recently are more open to the use of molecular screening tools in apparently healthy newborns,” the team wrote.

In the second portion of the survey, respondents had the option to review up to 649 genes associated with potentially treatable monogenic conditions currently excluded from newborn screening and to state whether each gene should be included in such testing.

Results showed high levels of agreement for many of these genes, with 432 of them being endorsed by at least half of the respondents and 42 genes being supported for inclusion by 80% or more of the experts.

“In our survey, [the experts] reached a striking consensus about the highest priority conditions to include,” Gold said.

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Notably, 71.7% of the experts were in favor of including the AADC deficiencyassociated DDC gene in NBSeq, while 11.7% were against and 16.7% were unsure.

“Concordance was highest among metabolic and [hormonal] disorders, clinical areas that are already well represented in current newborn screening,” the researchers wrote, adding that “experts also showed high concordance regarding the inclusion of disorders with newly developed and emerging pharmacologic therapies.”

These findings suggest that “rare disease experts support expanding the number of genetic disorders included in newborn screening through NBSeq,” the team wrote.

“NBSeq could be used as a tool to further the long-standing goals of newborn screening by identifying infants at risk for additional severe, treatable, childhood-onset disorders in clinical areas that have already been deemed appropriate for screening but are not amenable to detection by current methodologies,” the researchers added.

“Future studies will be needed to determine whether NBSeq is cost-effective and positively contributes to short- and long-term outcomes,” they concluded.