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Whole-Genome Sequencing Can Help Diagnose Adults With Rare Disease, Study Presented at NSGC Finds


NASHVILLE, Tennessee — Whole-genome sequencing can help diagnose and change clinical management of adult patients with rare disease, according to a new analysis presented here Saturday at the annual National Society of Genetic Counselors meeting.

For pediatric populations, whole-genome sequencing has increasingly been suggested as a first-tier test for children with suspected genetic disorders because it increases diagnostic yield and may bring down costs. Whole-genome sequencing for adults with undiagnosed disease, however, is often considered investigational or experimental, noted Kirsten Blanco, a genetic counselor at Children's Hospital Los Angeles, adding that insurers typically need more evidence of the clinical utility of genome sequencing in adults.

"Despite diagnostic benefits and recommendations for [genome sequencing] utilization in neonatal and pediatric populations, routine ordering for adult patients remains low," Blanco said during her presentation, which she delivered virtually. "A main reason is that current practice guidelines are only for pediatric patients, so there are no standards for clinical implementation in adults."

Blanco and her colleagues examined the diagnostic rate and clinical utility of genome sequencing among adults with rare, but undiagnosed disease. All the patients were eligible for sequencing through the Undiagnosed Diseases Network, a US National Institutes of Health Common Fund-backed effort that aims to improve the diagnosis rate of individuals with rare disease, which cumulatively affects about 25 million people in the US.

For their analysis, Blanco and her colleagues focused on undiagnosed participants who were over the age of 18 when they applied to the UDN between September 2015 and June 2021 and subsequently underwent clinical genome sequencing. By the end of September 2021, 409 adults had undergone genome sequencing as part of their evaluation for the UDN, or about 51 percent of the 801 adult patients.

This population was 48 percent male, 87 percent were white, and 58 percent had symptoms onset at or after the age of 18.

Within this population, sequencing analysis uncovered 159 pathogenic or likely pathogenic variants or variants of uncertain significance in 55 percent of participants. In particular, 44 percent of participants had negative results, 28 percent had a VUS only, and 28 percent had at least one potentially diagnostic pathogenic or likely pathogenic variant. Of the individuals with a VUS, 53 percent had previously undergone exome sequencing that was non-diagnostic, and of those with a pathogenic or likely pathogenic variant, 49 percent had undergone previous exome sequencing that was non-diagnostic.

In this cohort, the overall diagnostic rate was 7 percent, according to Blanco.

The diagnostic yield was highest among patients with neurological symptoms. Further, a diagnosis was reached for 18 percent of participants who previously underwent exome sequencing but did not receive a diagnosis from that testing.

Blanco and her colleagues further examined a number of different measures of clinical utility, including the effect of finding a pathogenic or likely pathogenic variants on diagnosis, additional clinical workups, and medical management and therapies, and surveyed clinicians regarding these measures.

They found that patients who received a diagnosis were more likely to avoid additional testing, as compared to those who did not receive a diagnosis, and medical management changes were more likely for those who received a diagnosis. The most common medical management change was a referral to a specialist to screen for comorbidities.

These findings, Blanco said, reflect an increased diagnostic yield, including among patients with previous uninformative genetic testing, and "supports the expansion of practice guidelines needed for widespread adoption and clinical implementation of [genome sequencing] in the adult population."

She noted that the study had a few limitations, including that it was enriched for patients with neurological phenotypes and for patients likely to have a genetic conditions due to the UDN recruitment strategy. The clinician response rate to the survey was also low.

Still, genome sequencing "is a valuable diagnostic tool in adult patients," Blanco said. "Demonstration of clinical utility can inform practice and clinical implementation guidelines to encourage more universal adoption of [genome sequencing] in the diagnosis and management of adult patients with undiagnosed condition."