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Counsyl Researchers Report Validation of Expanded Carrier Screen

NEW YORK (GenomeWeb) – Researchers from the genetic screening firm Counsyl have reported in a new study that their expanded carrier screen is highly accurate.

The company recently updated its Foresight Carrier Screen to test prospective parents for more than 175 heritable conditions compared to 94 conditions for a previous version.

Researchers from the company examined how well the expanded carrier screen performed on nearly 37,000 samples. As they reported this week in Clinical Chemistry, they found the screen to have more than 99 percent analytical sensitivity and specificity. The researchers further reported that folding in panel-wide deletion and certain duplication analyses improved their ability to detect couples at risk of affected pregnancies.

"[B]y using limited carrier screening or low-sensitivity expanded carrier screens, providers are missing at-risk couples," James Goldberg, the chief medical officer at Counsyl, said in a statement. "It is clear that by using a high-sensitivity assay, clinicians can provide patients with more clinically relevant and actionable information than in the past when only high-risk patients were screened for the most common disorders."

The firm's expanded carrier screening test contains a panel of 235 genes linked to 220 autosomal and 14 X-linked conditions, including Bloom syndrome, fragile X syndrome, and familial Mediterranean fever. This panel includes a "universal" sub-panel that covers 176 diseases as well as an opt-in panel of 234 diseases for high-risk populations.

The panel relies on next-generation sequencing to identify SNVs, indels, CNVs, and other variants. For some tricky genes, the test uses a combination of targeted genotyping and read-depth-based copy number analysis or PCR amplification and capillary electrophoresis.

To assess the screen, researchers led by Counsyl's Dale Muzzey compared their expanded carrier screen results for a reference sample from the Genome in a Bottle Consortium to the consortium's data. They tested the sample across five batches and in duplicate in three batches, which they said yielded an accuracy of more than 99.9 percent.

They also evaluated the screen's ability to pick up different types of variants. When they used their screen to evaluate indels within reference samples from the 1000 Genomes Project, they reported 36,032 true-positive calls and 212,139 true-negative calls, or more than 99.9 percent accuracy, analytical specificity, and sensitivity.

But some variants are more difficult to call than others. Large indels — bigger than five basepairs — can affect sensitivity, the researchers noted. But in their cohort of 52 patient samples with 49 large inserts, deletions, or complex indels in 42 different genes, they reported observing the expected calls for all 52 samples.

Likewise, when they tested its CNV calling performance using Coriell cell lines, the researchers reported their screen could detect all 44 CNVs across 13 genes. They added that it also performed well on a set of in silico simulated CNVs and on 1000 Genomes Project reference samples.

Muzzey and his colleagues also reported that the screen performed well on calling variants within technically challenging genes like CYP21A2, HBA1/2, GBA, and SMN1. It was also able, they said, to correctly classify CGG repeats in the fragile X syndrome genes FMR1 with 39 Coriell samples.

He and his colleagues also estimated how many at-risk pregnancies their screen would capture. Of 7,498 couples who underwent screening, 335 were found to be at risk of one of the conditions included on the universal panel. This, they said, underscores the clinical importance of the test.

They further estimated that 1 in 300 pregnancies in the US are expected to be affected by one of the conditions included on their panel, higher than the 1-in-500 rate of the previous version of the screen.

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