Whole-genome sequencing continues to show promise for diagnosing genetic disorders in the clinic, according to a newly published study, which sifted through factors involved in reliably narrowing in on authentic disease-causing variants from genome sequences for individuals with Mendelian or immunological conditions.
As part of the WGS500 study, an international team led by investigators in the UK did clinical genome sequencing on more than 150 cases or families that appeared to be genetic in nature but could not be explained by prior screening tests. The approach led to new diagnoses in just over one-fifth of the cases, including more than one-third of the Mendelian disorders considered.
The researchers also found a few dozen alterations that had possible clinical importance but were in genes not related to the condition they were originally attempting to diagnose.
"Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges," corresponding author Gilean McVean, a researcher with the University of Oxford's Wellcome Trust Centre for Human Genetics, and colleagues wrote.
He and his colleagues considered 156 individuals or families affected by unexplained Mendelian or immunological conditions, sequencing each individual's genome to nearly 32-fold coverage, on average. More than 88 percent of protein-coding sequences were covered to average depths of at least 20-fold or more.
The team tracked down pathogenic variants in 33 of the individuals tested — just over 21 percent. The diagnostic yield was somewhat higher within the Mendelian cases, where genome sequences that led to disease-related variants were identified in 23 of the 68 cases, or nearly 34 percent of the time.
The researchers had even more success making diagnoses for individuals with de novo or recessively inherited conditions. There, they diagnosed 57 percent of cases when genome sequences from the affected individual and both parents were available.
When they delved into technical features that may impact successful diagnoses, the researchers determined that slight jumps or dips in sequence coverage across different portions of the genome did not seem to significantly impact their ability to track down disease-causing variants.
On the other hand, the team highlighted the importance of analytical approaches for calling variants and identifying those with ties to a given condition.
For instance, by combining a two-stage variant calling process with local database filtering and multiple algorithms for annotating the genome, the study's authors found that it was possible to identify variants more effectively dial, leading to more accurate diagnoses.
Although most of the disease culprits identified in the current study fell in protein-coding sequences that would have been interrogated by exome sequencing, they noted, the full genome sequences proved useful for finding potential non-coding contributors to disease and characterizing inheritance patterns for disease-related glitches within genes.
Still, the team cautioned that whole-genome sequencing may be unnecessarily time-consuming or complex when dealing with conditions inherited dominantly or when insufficient information on other family members, inheritance patterns, or clinical features are available.
"Ultimately, whole-genome sequencing will only be able to reliably assess the diagnostic and predictive value of ay specific variant if this variant, or another variant in the same gene, is identified in other individuals with the same disorder for whom detailed phenotypic and clinical data are available," McVean and co-authors concluded.