Diagnostic value of partial exome sequencing in developmental disorders

Area of Science:

• Genetics
• Molecular Diagnostics
• Neurodevelopmental Disorders

Background:

• Intellectual disability necessitates genetic counseling, yet lacks standardized molecular diagnostic algorithms.
• Whole exome sequencing is common, but resource-intensive.
• Investigating targeted gene panels as an alternative is crucial.

Purpose of the Study:

• To evaluate partial exome sequencing as a cost-effective alternative to whole exome sequencing for intellectual disability.
• To determine the diagnostic yield of a targeted gene panel approach.
• To compare detection rates across different intellectual disability severities and clinical presentations.

Main Methods:

• Analyzed 106 patients with intellectual disability using partial exome sequencing (4,813 genes) after array-CGH for copy number variations.
• Applied ACMG guidelines for variant interpretation.
• Assessed diagnostic yield based on clinical features and intellectual disability severity.

Main Results:

• Achieved a molecular diagnosis in 34% of patients and identified candidate mutations in an additional 24%.
• Overall causative mutation detection rate exceeded 30%, comparable to whole exome sequencing.
• Detection rates were consistent across mild and severe intellectual disability, with a slight decrease in patients with seizures (23%).

Conclusions:

• Partial exome sequencing is a valid and efficient alternative to whole exome sequencing for diagnosing intellectual disability.
• The approach demonstrates high diagnostic utility for both syndromic and non-syndromic forms across all severity levels.
• This method provides significant diagnostic yield, supporting its integration into molecular testing workflows for intellectual disability.