Whole Genome Sequencing Facilitates Diagnosis of Rare Diseases in Infants

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The researchers found that whole-genome sequencing captured almost twice as many genetic abnormalities that could cause disease in infants compared to standard targeted testing.

In the Genomic Medicine for Sick Newborns and Infants (GEMINI) study, whole-genome sequencing had a diagnostic yield of 49%, compared with a diagnostic yield of 27% with NewbornDx, a standard targeted gene panel. said Jill Maron, M.D., MPH, of the Women’s and Infants Hospital. Dr. and her colleagues from Rhode Island, Providence reported. JAMA.

Whole-genome sequencing took an average of 6.1 days to provide results compared to 4.2 days for NewbornDx, although the most urgent cases actually took less time (3.3 Japan vs. 4th), the researchers said.

“Our study demonstrates the ability to understand the onset of these genetic disorders early in the life course, which was lacking,” Mallon said. Today’s Medpagepointed out that getting answers in rare diseases is often described as a “six-year diagnostic journey.”

“Some of the babies diagnosed in the neonatal period would have been diagnosed eventually. I hope there will be a lot of intervention,” she said.

As for how long it takes to get results back, Maron said, “If you believed that a baby was born with a serious illness, you would have got the whole genome faster than the panel, so it would take two days.” [difference] Probably irrelevant. “

The research was supported by a grant from the Clinical Translational Science Award (CTSA) Program at the NIH National Center for the Advancement of Translational Sciences (NCATS), according to NCATS Acting Director PJ Brooks, Ph.D. The goal of this program is to accelerate the translational research process and enhance collaboration between various research and clinical sites.

“This gives us a complete picture of rare disease diagnosis,” Brooks said. Today’s Medpagesaid that since this project was first funded five years ago, “a lot has changed in terms of the development of gene-targeted therapies. How these molecular diagnostics ultimately translate into therapeutic intervention is very important.” is interesting,” he pointed out.

While “diagnostic pain remains a challenge” for patients with rare diseases, Brooks said, NCATS has “several of our funded technologies that can incorporate genome sequencing and artificial intelligence approaches to speed it up.” There are different projects,” he said.

This prospective, multicenter study enrolled 400 infants younger than 1 year who were admitted to six U.S. hospitals from June 2019 to November 2021 with suspected genetic disorders. Parents were included where possible, for a total of 388 mothers and 318 fathers.

They underwent concurrent testing with whole-genome sequencing and a more targeted gene panel. Whole-genome sequencing was performed by Rady Children’s Institute for Genomic Medicine in San Diego, and Quest/Athena Diagnostics performed the commercially available NewbornDx test. The test looks at 1,722 genes associated with diseases that usually appear early in life.

Overall, 51% of infants had a molecular diagnostic mutation identified by testing that was considered causative (causative or probable pathogenic) or highly suspicious (variation of unknown significance). had at least one genetic mutation. [VUS]).

A total of 95 infants had a diagnosis identified by whole-genome sequencing rather than targeted testing (49% of 195 positive cases). Also, he had only 9 infants (8% of 195 positive cases) whose diagnosis was reached by targeted testing rather than by whole-genome sequencing. 109 positive people).

Maron and his colleagues also discovered 134 potentially novel variants that will be uploaded to ClinVar, the NIH’s database of genetic variants.

The researchers also noted that conflicting results are not uncommon. When both laboratories detected the same variant, interpretation and classification were found to differ 43% of the time, making the study from both laboratories not the first to report “discordant variant interpretation”. pointed out.

Mallon gave an example of how heredity affects interpretation. “He had a pathogenic hit from his mother and a hit from his father was a variant of unknown significance. You might say you need a hit. [one lab may] This is called VUS. But other labs would say, “I have the pathogenic allele and her VUS, and I think that’s what’s causing the problem.” I will call it a pathogenic variant. ”…it all has to do with human interpretation. “

Brooks said the divergence in interpretation “indicates the need for better standardization on how to interpret variants of unknown significance,” and in the future, it will facilitate data sharing. said that there is a need to promote greater agreement on how to interpret variants of unknown importance. Various efforts are being made. We’re moving towards it, but it seems like maybe more needs to be done. “

Ultimately, about one-fifth (19%) of patients changed clinical care based on test results, Maron et al. reported. They noted that 15 infants “transitioned from palliative care to either known treatment of disability or discontinuation of life support.”

“Most of the diseases we diagnose have no cure,” Maron said. “What we’re really trying to do is get answers to find out what this is, and many babies have genetic disorders, many of which were previously unrecognized. It is to contribute to a body of literature that says, hopefully, that it will help advance the field. “

In fact, 76% of clinicians reported finding genome sequencing useful or very useful, regardless of whether a diagnosis was provided.

This study was limited because no formal superiority test was conducted to assess whether one test was superior to the other. Researchers should also be careful about extrapolating data to real-world situations. Part of the reason is that “access to technology and well-developed research protocols may have affected the speed with which molecular diagnostics can be performed.”

Still, Mallon and co-authors concluded their study “supports the need to make such tests widely available and covered by Medicaid and commercial insurance.”

The cost of genetic testing has long been an issue for diagnosing rare diseases because not all insurance companies will pay for it, Maron said. She estimated that out-of-pocket whole-genome sequencing would cost “about $9,000 for each of the three mothers, fathers, and probands.”

In some cases, she says, the hospital will absorb the costs. “At the end of the day, having an actual diagnosis saves hospital money, rather than spending a day in the ICU not knowing what’s going on.”

Study co-author Jonathan Davis, M.D., director of neonatal medicine at Tufts Medical Center in Boston, said, “It can be frustrating to have all these tests — MRIs, blood tests, biopsies — but this yes,” he said. [genetic] They don’t cover the tests. “

This led his group to conduct a cost-effectiveness study, which will be published in the near future, he said.

Davis pointed out that genetic testing is also being used in medical malpractice cases that frequently occur in the field of obstetrics and gynecology.

“A lot of the time they’re yelling at obstetricians who should have had a C-section sooner, and we’d say ‘no, that’s something else’, but we can’t figure it out.” I can’t,” Davis said. “I hear over $200 million in malpractice claims paid out to one baby, and while it’s sometimes easy to blame obstetricians and hospitals, we’re looking at the array of these children. We’ll have to go and see if there’s anything else, and some courts are starting to allow it.”

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    Kristina Fiore leads MedPage’s enterprise and investigative reporting team. She has been working as a medical journalist for over 10 years and her work has been recognized by Barlett & Steele, AHCJ, SABEW and others. Send her story tips to k.fiore@medpagetoday.com. follow


This research was funded by a grant from the National Center for Advancement of Translational Sciences (NCATS).

The authors are Biomarin, 4D Therapeutics, PTC Pharmaceuticals, LogicBio, Kriya Pharmaceutical, Satellite Bio, Jaguar Gene Therapy, Horizon Therapeutics, Acer Therapeutics, Sanofi, Axcella Health, Agios Pharmaceuticals, Innara Health, Nicolette, Astarte Medical, Medela , and Ferring Pharmaceuticals, PPD, Thermo Fisher Scientific.

Primary information


See source: Maron JL, et al “Rapid Whole Genome Sequencing and Targeted Neonatal Gene Panels in Infants with Suspected Genetic Disorders” JAMA 2023; DOI: 10.1001/jama.2023.9350.

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