Whole genome sequencing better than standard targeted test for diagnosing suspected genetic disorder in infants: JAMA
USA: A recent study has revealed a higher molecular diagnostic yield for genomic sequencing compared to a targeted neonatal gene-sequencing test in 400 hospitalized infants suspected of having a genetic disorder. However, the time to return of routine results was slower.
Researchers found that whole genome sequencing captured almost twice as many genetic abnormalities that may be responsible for disease in infants, compared with a standard targeted test.
"For genome sequencing, the median time to result was 6.1 days and 4.2 days for the targeted gene-sequencing test," the researchers reported in In the Genomic Medicine for Ill Neonates and Infants (GEMINI) study published in the JAMA (Journal of the American Medical Association). "Molecular diagnostic yield of genome sequencing was 49% versus 27% with the targeted gene-sequencing test. 19% of the participants were affected by the changes in clinical interventions."
Genomic testing in infancy guides medical decisions and can improve health outomes. However, there is no clarity on whether enomic sequencing or a targeted neonatal gene-sequencing test provides comparable time of return of results and molecular diagnostic yields. Therefore, Jill L. Maron, Women and Infants Hospital of Rhode Island, Providence, and colleagues aimed to compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test.
The researchers enrolled 400 hospitalized infants younger than 1 year of age susoected of having a genetic disorder at 6 U.S. hospitals from 2019 to 2021 in their prospective, multicenter study. Their parents were also included when available, totaling 388 mothers and 318 fathers.
They received simultaneous testing with whole genome sequencing and the more targeted genetic panel. Whole genome sequencing was done by Rady Children's Institute for Genomic Medicine in San Diego, and the commercially available NewbornDx test was conducted by Quest/Athena Diagnostics, which looks at 1,722 genes associated with disorders that typically present early in life.
The study's primary end points were molecular diagnostic yield (participants with ≥1 pathogenic variant or variant of unknown significance), clinical utility (changes in patient care), and time to return of results.
The study led to the following findings:
- A molecular diagnostic variant was identified in 51% of participants (n = 204; 297 variants identified with 134 being novel).
- Molecular diagnostic yield of genomic sequencing was 49% versus 27% with the targeted gene-sequencing test.
- Genomic sequencing did not report 19 variants found by the targeted neonatal gene-sequencing test; the targeted gene-sequencing test did not report 164 variants identified by genomic sequencing as diagnostic.
- Variants unidentified by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar odds ratio, 8.6).
- Variant interpretation by laboratories differed by 43%.
- Median time to return of results was 6.1 days for genomic sequencing and 4.2 days for the targeted genomic-sequencing test; for urgent cases (n = 107) the time was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test.
- Changes in clinical care affected 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in clinical decision-making, irrespective of a diagnosis.
To conclude, for genomic sequencing, the molecular diagnostic yield was higher than a targeted neonatal gene-sequencing test, but the time to return of routine results was slower.
"Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management," the researchers wrote.
Reference:
Maron JL, Kingsmore S, Gelb BD, et al. Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder. JAMA. 2023;330(2):161–169. doi:10.1001/jama.2023.9350
