SmartPhase

SmartPhase resolves haplotypes from sequencing reads and parental genotype data to identify and exclude non-causative compound heterozygous variant pairs for rare monogenic disease diagnosis.

Key Features:

• Efficient phasing algorithm: Leverages parental genotype information and sequencing reads (DNA or RNA) to construct accurate haplotypes for rare variants and distinguish potential disease-causing compound heterozygous pairs.
• Integration of haplotype information: Integrates existing haplotype data and applies logical rules to exclude variant combinations unlikely to cause recessive monogenic diseases.
• Confidence scoring system: Computes a confidence score for each phasing prediction to allow selection of high-confidence predictions.
• Flexible pairing strategy: Supports analysis of either all possible variant pairs within predefined genetic loci or a focused set of preselected variant pairs.
• Performance versus WhatsHap: On simulated data and a clinical cohort of 921 patients, resolved a higher percentage of variant pairs than WhatsHap and enabled exclusion of approximately 22% of input variant pairs in singleton patients and 44% in trio patients when parental genotypes were available.

Scientific Applications:

• Clinical genetic diagnosis: Reduces the number of candidate compound heterozygous variant pairs to improve identification of pathogenic variants in rare monogenic disease diagnosis.
• Research and cohort analysis: Prioritizes candidate variant pairs from genome and transcriptome sequencing datasets for follow-up in research studies and clinical cohorts.

Methodology:

Leverages parental genotypes and sequencing reads (DNA or RNA) to construct haplotypes; integrates existing haplotype data and applies logical exclusion rules for variant combinations; computes a confidence score for each prediction; analyzes either all variant pairs within predefined loci or preselected variant pairs.