USH2014 Presentations - Dr. Heidi Rehm, Diagnostics, Epidemiology, and Population Genetics

Delivered by Dr. Heidi Rehm at the International Symposium on Usher Syndrome.

Download the presentation slides here.


The use of next generation sequencing (NGS) has enabled dramatic improvements in the ability to offer comprehensive diagnostic testing at affordable costs to patients. We developed the OtoGenome Test a comprehensive test for nonsyndromic hearing loss as well as many causes of syndromic hearing loss including all forms of Usher syndrome. A subpanel is offered for just Usher genes. The tests use barcoding and hybrid capture followed by NGS on the Illumina HiSeq. VisCap detects copy number variations (CNVs). Sanger sequencing fills in missing data from NGS and confirms variants. Validation showed 100% sensitivity for substitutions (335/335), 97% for indels (63/65), and 100% for CNVs (16/16). The most challenging aspect of the assay is data interpretation. Several hundred variants are identified in each sample. Although most are pre-classified as Benign or Likely Benign using population frequency data and other auto-classification rules, up to 26 novel variants per case are identified. A comprehensive evidence-based variant assessment strategy is used to support variant interpretation and our GeneInsight software auto-drafts patient reports to allow efficiency for the geneticist sign-out process and delivers them in structured form to the EHR enabling automated variant updates as classifications change over time. To date, 355 samples have been analyzed using the OtoGenome test with 42% (150) positive for at least one pathogenic or likely pathogenic variant, using our rigorous evidence-based classification system. Among patients with a possible or known diagnosis of Usher syndrome 65% were positive for one (n=11) or two (n=20) pathogenic or likely pathogenic variants. In addition, 3% of patients with apparent nonsyndromic hearing loss were positive for pathogenic or likely pathogenic variants in Usher syndrome genes. A major challenge of testing is that roughly 48% of cases are inconclusive due to variants of uncertain significance with limited available data in the literature and public databases to infer their potential impact. We recognized that community data sharing would be highly beneficial to enable better understanding of rare variants. To address this need for hearing loss and all diseases, the Clinical Genome Resource (ClinGen) program was launched in Sept 2013 and includes 3 funded NIH grants and the ClinVar database ( ClinVar currently contains over 65,000 variants with clinical interpretations, including our own hearing loss clinical data collected over the last 10 years with detailed evidence-based clinical classifications. This includes 3483 variants in 71 hearing loss genes from ~3000 probands. This presentation will include a review of the current state of the ClinVar database and ClinGen program including future plans to enhance community data-sharing of case and variant level data as well as expert curation of genes and variants.