Refining Mendelian disease analysis via detection of clinically relevant repeat variants

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Project Summary Next-generation sequencing (NGS) has the potential to profile all clinically relevant genetic variants simultane- ously in a single genetic test. However, clinical variant discovery pipelines have mostly focused on coding single nucleotide variants (SNVs), regulatory SNVs and small indels. This proposal aims to make repeat analysis a standard component of existing pipelines, focusing in particular on short tandem repeats (STRs), variable number tandem repeats (VNTRs), and low-copy repeats or segmental duplications. Together, these repeats account for 8% of the human genome, but are implicated in a disproportionately large number of Mendelian diseases. The proposed methods are primarily aimed at Illumina sequencing, which forms the vast majority of current Mendelian sequencing pipelines, but also includes alternative technologies such as Pacific Biosciences and 10X Genomics. The first aim develops algorithms for discovery of repeat variants currently inaccessible from NGS. In the second aim, the PIs propose to generate gold-standard validation data for Mendelian repeats using multiple technologies. In the third aim, the PIs will integrate the proposed methods into existing NGS pipelines for clinical variant discov- ery, and also apply them to large existing data-sets to obtain genotype frequencies of large control populations. The project serves an unmet need by augmenting Mendelian variant pipelines to include highly relevant disease variants.