A Framework for Variant Filtering to Improve Diagnostic Outcomes in Genome Sequencing

SMART filtering of genome sequencing in 153 previously undiagnosed cases found pathogenic or likely pathogenic variants in 4.6% of cases, plus strong VUS in 1.3%.

• Why it matters: Many rare genetic disorders remain unresolved even after exome and genome sequencing, especially when non-coding and regulatory variants are missed by standard pipelines.
• What they did: The authors retrospectively applied SMART filtering as a pre-annotation step, using conservation metrics, allele frequency thresholds, and splicing prediction scores, then used phenotype-based prioritization and manual review.
• The result: The framework also yielded additional candidate variants in 5.2% of cases, and confirmed several deep-intronic variants with RNA studies and segregation analyses, improving non-coding variant prioritization.

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