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Panel Sequencing Leads to Pathogenic Mutations in Autoinflammatory Cases

NEW YORK (GenomeWeb) – A team from the UK has demonstrated the feasibility of finding pathogenic and likely pathogenic mutations in individuals with autoinflammation and vasculitis using custom, targeted gene panel sequencing.

Researchers from the University College London and elsewhere came up with two different vasculitis and inflammation panels, dubbed VIP1 and VIP2, to sequence more than 100 selected genes in 72 individuals with known or suspected monogenic autoinflammatory conditions.

The team's results, appearing online yesterday in PLOS One, suggest that gene panels can lead to firm or potential molecular diagnoses in nearly one-third of the 50 previously undiagnosed cases, while identifying known mutations with high sensitivity and specificity in the 22 cases with known genetic culprits.

"A significant diagnostic contribution was observed in 32 percent of patients with previously unclassified phenotypes," corresponding author Ebun Omoyinmi, a researcher at the UCL Great Ormond Street Institute of Child Health, and her co-authors wrote. "The level of diagnostic yield obtainable in a timely manner can have a profound impact on patient management, with improved use of targeted therapies, prognostication, and genetic counseling."

Mutations in a mounting collection of genes have been implicated in monogenic autoinflammatory conditions — a set of conditions characterized by intermittent or ongoing systemic inflammation that can cause symptoms such as vision or hearing loss, rashes, vasculitis, intestinal problems, infertility, and a range of other problems, depending on the tissue affected, the team explained.

Consequently, the authors noted, "[g]ene-by-gene sequencing is an increasingly outdated, expensive, and often futile diagnostic approach for patients with [autoinflammatory disease] because there is an ever-increasing number of monogenic diseases now known to cause autoinflammation, with increasingly overlapping phenotypes that now also include vasculitis and immunodeficiency."

With the help of Agilent SureDesign tools, the researchers established a VIP1 gene panel targeting 113 genes with potential ties to autoinflammation and vasculitis and a second panel, VIP2, which focused on sequences for 166 genes. They then used the Illumina MiSeq instrument to do multiplex sequencing on genes captured from 22 individuals with known autoinflammatory/vasculitis disease and 50 more suspected cases.

Using the 22 positive control samples, the team hammered out criteria for analyzing panel sequencing data to detect as many alterations as possible. From there, the group attempted to interpret results for the latter group of previously undiagnosed individuals, leading to one or more likely pathogenic mutations in 11 cases and clearly pathogenic mutations in half a dozen individuals. Another 31 individuals carried variants of unknown significance.

"VIP reliably detected different types of mutations, including rare and common [single nucleotide variants], insertion/deletions, splice-junction and variants in upstream promoter regions, and somatic mosaicism," the authors concluded.

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