Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers

Area of Science:

• Genomics
• Medical Genetics
• Bioinformatics

Background:

• Clinical exome sequencing (CES) is often nondiagnostic for patients with suspected Mendelian disorders, leaving a significant diagnostic gap.
• Approximately 75% of individuals undergoing CES for rare genetic conditions do not receive a diagnosis from the initial analysis.

Purpose of the Study:

• To investigate the diagnostic utility of systematic reevaluation of previously nondiagnostic clinical exome data.
• To determine if updated analysis can identify causative variants missed in initial assessments.

Main Methods:

• Exome and phenotypic data from 40 individuals with prior nondiagnostic CES were reanalyzed.
• Current bioinformatics software and updated scientific literature were utilized for the reanalysis.

Main Results:

• A definitive diagnosis was achieved for 4 out of 40 participants (10%) through reanalysis.
• Causative variants were de novo and located in autosomal-dominant disease genes, with supporting literature emerging 1-3 years after the initial report.

Conclusions:

• The continuous discovery of gene-disease and variant-disease associations necessitates regular reevaluation of exome data.
• Systematic reanalysis, requiring automation and updated databases, can improve the diagnostic yield of exome sequencing.
• Healthcare providers should consider periodic reanalysis of nondiagnostic exomes and factor reanalysis policies into laboratory selection.