A study published in GenomeMedicine has identified 35 new likely diagnoses in probands with an unsolved rare disease by examining splicing variants in whole-genome sequencing data from the 100,000 Genomes Project.
]. For this reason, the systematic classification of near-splice variants remains challenging, and clinical interpretation of these variants is still dependent on expert phenotype matching and functional validation of candidate variants.
Surprisingly, several strong diagnostic candidates were apparently overlooked in the standard variant interpretation pipeline, including at least nine CSS variants and four D + 5 variants, all in known rare disease genes. Of ten de novo D + 5 variants, none were previously labelled as pathogenic, despite their high prior probability of being diagnostic in this context [Clearly, many new diagnoses remain to be found.
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