Expanded Carrier Screening IDs Rare Variants in Diverse Populations

Expanded next-generation sequencing-based carrier screening improves detection of rare and novel pathogenic variants even in a pan-ethnic population, according to a study published May 10 in the American Journal of Human Genetics. Despite patient interest, given the remaining challenges of classifying the significance of novel variants, the authors say that making expanded carrier screening available to everyone will require further enhancement in interpretation.

Traditionally, carrier screening focused on targeted disorders for certain ethnic populations, but there has been rapid expansion in the breadth of genes that can be screened for with NGS technology. Experts caution, though, that the utility of using this technology in routine care among healthy populations remains unclear, as does the downstream impact of clinical application.

As part of the NextGen study, researchers used NGS to analyze a pre-selected list of 728 genes known to be associated with disorders (autosomal-recessive and X-linked conditions), plus 148 genes for medically actionable conditions, among 131 women and their partners (n = 71) who were planning a pregnancy. Only pathogenic and likely pathogenic variants were confirmed and reported.

The researchers found that an average of 1.5 variants per individual, for a total of 304 variants. More than three-quarters of participants (78 percent) were carriers for at least one of the 700 tested-for conditions. Twelve carrier couples were identified as carrier for common conditions, including eight for hereditary hemochromatosis. Among the novel variants identified, one was reported in F8, known to be associated with hemophilia A. Prenatal testing showed that the male fetus harbored this variant and the neonate suffered a life-threatening hemorrhage, which was anticipated and appropriately managed. Just under half of all variants (48 percent) were missense. Additionally, 3 percent of participants had variants that were medically actionable.

The vast majority of the participants (93 percent) wanted to receive information for all categories of carrier results, whether the disorder was mild, severe, adult-onset, or unpredictable. Seven percent did not want to know their carrier status for unpredictable or adult-onset onset conditions, but nearly every participant (99 percent) requested the return of medically actionable findings.

“The 2015 American College of Medical Genetics and Genomics variant interpretation guideline is a powerful tool for systematic and organized classification for rare and novel variants that are detected by genomic sequencing,” write the authors led by Sumit Punj, from Oregon Health & Science University in Portland. “In our experience, the ability to accurately classify variants and predict outcomes is more challenging in a healthy population than in an affected individual and is less robust than in individuals presenting with an adverse phenotype.”

Takeaway: While NGS-enabled expanded carrier screening detects more rare variants than traditional screening, the ongoing challenges of classifying the significance of novel variants remains a barrier to routine clinical use of expanded carrier screening.