Overcoming a diagnostic blindspot: Identifying balanced translocations in Mendelian rare disease cohorts

Structural variant callers represent balanced translocations as breakend pairs, most of which are false positives, which has kept their detection out of routine workflows. The authors developed a highly specific pipeline, applied to short-read genomes from 16,131 individuals across five cohorts (including 1000 Genomes, structural birth defects, GREGoR, UDN and neonates undergoing rapid genome sequencing). Balanced translocations were identified in 0.196% of birth-defect probands (2/1,017), 0.25% of GREGoR probands (9/3,574), 0.39% of UDN probands (8/2,027) and 0.24% of neonates (1/409), and all six translocations in the birth-defect cohort were confirmed by Sanger sequencing. About 31% of translocations across the three patient cohorts disrupted a known disease gene, establishing or refining a diagnosis in five previously unresolved cases.

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

Specificity is shown by Sanger confirmation of all six translocations in the birth-defect cohort, but the abstract reports no sensitivity, which limits the reach of the yield gain: five diagnoses across thousands of genomes. This is a preprint not yet peer-reviewed. Its interest is to show that a category of structural variants can be recovered from genomes already produced, without long-read sequencing.

Analysis by Dr Thibaut Benquey