Phenotype-Driven In Silico Proficiency Testing Represents a Viable Approach for Undiagnosed Disorders by Exome...

Area of Science:

• Genomics
• Bioinformatics
• Medical Diagnostics

Background:

• In silico mutagenesis can introduce variants into next-generation sequencing data.
• This method is promising for proficiency testing, enabling the modeling of rare or novel variants absent in current materials.

Purpose of the Study:

• To evaluate in silico mutagenesis as a proficiency testing methodology for exome sequencing in undiagnosed disorders.

Main Methods:

• Laboratories performed exome sequencing on reference samples.
• Raw sequence data underwent in silico mutagenesis to add specific variants.
• Mutagenized files were processed through bioinformatic pipelines for variant interpretation.

Main Results:

• Seven educational proficiency testing challenges were conducted from 2018-2021 with an average of 47 participating laboratories.
• Participating laboratories returned an average of 94.3% of intended response variants.
• The percentage of laboratories correctly identifying all intended variants ranged from 70.0% to 96.7%.

Conclusions:

• In silico mutagenesis is a suitable approach for proficiency testing in exome sequencing.
• This method allows for graded, intended response-based testing.
• It enables laboratories to assess both analytical and interpretative aspects of genetic testing.