PseudoRA: A Novel Pseudogene ReAligner for Detecting SBDS Variants in Shwachman-Diamond Syndrome.

SBDS

Read realignment and haplotype-based reassignment to resolve misalignment between SBDS and its pseudogene SBDSP1.

The pseudogene SBDSP1 disrupts read alignment for SBDS, the Shwachman-Diamond syndrome gene, leading to false-negative calls, particularly for low variant allele frequency (VAF) variants such as c.183_184delinsCT. The authors developed PseudoRA, an algorithm that resolves this misalignment through read realignment and haplotype-based reassignment. Applied retrospectively to targeted NGS alignment files from 846 patients with suspected haematological disorders, it detected SBDS variants in 10 patients (1.2%) versus 6 (0.7%) with conventional analysis, a 1.7-fold increase in diagnostic yield. All variants detected showed 100% concordance with Sanger sequencing. Sensitivity was comparable to HapICE, with detection extended across multiple exons.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Gene-pseudogene pairs are a known blind spot of short-read sequencing, and a tool that recovers mismapped low-VAF variants fills a concrete gap in SBDS diagnostics. The gain should be read with caution: it involves 4 additional patients, and the abstract does not explain how the "seven additional cases" it reports relate to the increase from 6 to 10 patients. Code availability is not stated, which will determine integration into other pipelines.

Analysis by Dr Thibaut Benquey