Improved Diagnostic Yield in Recessive Intellectual Disability Utilizing Systematic Whole Exome Sequencing Data...

Area of Science:

• Genetics
• Bioinformatics
• Medical Genetics

Background:

• Whole exome sequencing (WES) is a primary genetic diagnostic tool, but limitations leave many intellectual disability (ID) cases undiagnosed.
• Reanalysis of existing WES data is crucial for improving diagnostic yield in genetic disorders.

Purpose of the Study:

• To reanalyze WES data from Iranian families with recessively inherited ID using updated bioinformatics pipelines.
• To identify novel candidate genes associated with ID and increase the diagnostic rate.

Main Methods:

• Clinical re-evaluation of 159 families with recessively inherited ID.
• Two-phase WES data reanalysis using BWA-GATK/ANNOVAR and Illumina DRAGEN/Ilyome pipelines.
• Bioinformatics functional annotation and segregation analysis for variant prioritization.

Main Results:

• The initial analysis identified causative variants in 17 families (10.6%), including six novel candidate ID genes.
• The second phase reanalysis identified variants in two additional families, increasing the total diagnostic yield to 11.9%.
• Novel candidate genes (MAZ, ACTR5, AKTIP, MIX23, SERPINB12, CDC25B) were identified and supported by functional data.

Conclusions:

• WES reanalysis with updated bioinformatics tools and phenotypic re-evaluation significantly improves diagnostic outcomes for recessively inherited ID.
• This systematic approach can uncover new gene-disease associations and reduce the need for more expensive tests like whole genome sequencing.