Curating clinically relevant transcripts for the interpretation of sequence variants

摘要: Variant interpretation depends on accurate annotations using biologically relevant transcripts. We have developed a systematic strategy for designating primary transcripts, and applied it to 109 hearing loss-associated genes that were divided into 3 categories. Category 1 (n=38) had single transcript, 2 (n=32) multiple but transcript was sufficient represent all exons, transcripts with unique exons. Transcripts curated respect gene expression reported in the literature Genotype-Tissue Expression Project. In addition, high frequency loss of function variants Genome Aggregation Database, disease-causing ClinVar Human Gene Mutation Database across queried. These data used classify exons as clinically relevant, uncertain significance, or insignificant. Interestingly, 7% containing >124 significant variants, significance. Finally, we exon-level next generation sequencing quality metrics generated at two clinical labs, identified total 43 technically challenging 20 different inadequate coverage and/or homology issues which might lead false variant calls. demonstrated analysis plays critical role interpretation.