Novel Strategy for Structural Variant Genotyping by Short-Read Genomic Sequencing From Restriction-Circles: Experimental and Bioinformatics Proof-of-Concept.

DMD

BclI digestion, ligation of fragment ends and short-read WGS; linking pair-end reads (LPERs) carry long-distance haplotype information used to genotype structural variants.

The authors propose genotyping structural variants by short-read WGS of restriction-circles: BclI digestion of genomic DNA, ligation of fragment ends, then short-read sequencing. The pipeline relies on linking pair-end reads (LPERs) that carry long-distance haplotype information, each structural variant matching a specific LPER pattern. Applied to one patient with Duchenne muscular dystrophy, the approach recovers the previously characterised genotype (deletion of DMD exons 45-54 and duplication of exons 38-43). It also detects two novel structural variants in Xq28, verified by direct molecular investigation: a 1.4 kb deletion and a perfect inversion, both polymorphic in the general population. It correctly indicates the absence of the recurrent haemophilia inversions and allows conventional small-variant calling.

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

An appealing idea: obtaining near long-read information on an existing short-read platform. But this is a proof of concept on a single patient, with 8.6x vertical coverage: neither sensitivity nor specificity can be estimated. It needs evaluation in a cohort before any comparison with long-read or optical genome mapping.

Analysis by Dr Thibaut Benquey