Genome sequencing in persistently unsolved white matter disorders

Area of Science:

• Genetics
• Neurology
• Genomic Medicine

Background:

• Genetic white matter disorders present diverse causes and symptoms, complicating diagnosis.
• Previous exome sequencing efforts left many cases unresolved.
• Identifying the genetic basis is crucial for understanding and managing these rare neurological conditions.

Purpose of the Study:

• To evaluate the diagnostic effectiveness of genome sequencing in previously unsolved genetic white matter disorder cases.
• To determine if genome sequencing offers advantages over exome sequencing for complex genetic variants.
• To assess the overall diagnostic yield of genome sequencing in a historical cohort.

Main Methods:

• Performed genome sequencing on 41 unsolved cases with prior exome sequencing.
• Reanalyzed an additional 191 cases using updated genetic information and variant annotation.
• Included analysis of copy number variants (CNVs) and variants in difficult-to-sequence genomic regions.

Main Results:

• Reanalysis resolved 64% of previously undiagnosed cases by incorporating novel genes and improved variant interpretation.
• Genome sequencing directly identified diagnoses in remaining cases, including those with complex structural variations (CNVs).
• The combined approach achieved an 85% diagnostic yield in the retrospective cohort.

Conclusions:

• Genome sequencing is highly effective for diagnosing genetic white matter disorders, particularly when prior exome sequencing was inconclusive.
• This method successfully identifies a wider range of genetic variants, including structural and deep intronic mutations.
• Genome sequencing represents a critical advancement in diagnosing rare neurological diseases, improving patient outcomes.