GenOtoScope: Towards automating ACMG classification of variants associated with congenital hearing loss

Abstract

AbstractSince next-generation sequencing (NGS) has become widely available, large gene panels containing up to several hundred genes can be sequenced cost-efficiently. However, the interpretation of the often large numbers of sequence variants detected when using NGS is laborious, prone to errors and often not comparable across laboratories. To overcome this challenge, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) introduced standards and guidelines for the interpretation of sequencing variants. Further gene- and disease-specific refinements regarding hereditary hearing loss have been developed since then. With more than 200 genes associated with hearing disorders, the manual inspection of possible causative variants is especially difficult and time consuming. We developed an open-source bioinformatics tool GenOtoScope, which automates all ACMG/AMP criteria that can be assessed without further individual patient information or human curator investigation, including the refined loss of function criterion (“PVS1”). Two types of interfaces are provided: (i) a command line application to classify sequence variants in batches for a set of patients and (ii) a user-friendly website to classify single variants. We compared the performance of our tool with two other variant classification tools using two hearing loss data sets, which were manually annotated either by the ClinGen Hearing Loss Gene Curation Expert Panel or the diagnostics unit of our human genetics department. GenOtoScope achieved the best average accuracy and precision for both data sets. Compared to the second-best tool, GenOtoScope improved accuracy metric by 25.75% and 4.57% and precision metric by 52.11% and 12.13% on the two data sets respectively. The web interface is freely accessible. The command line application along with all source code, documentation and example outputs can be found via the project GitHub page.Author summaryNew high-throughput sequencing technologies can produce massive amounts of information and are utilized by laboratories to explain the often complex genetic aetiology of hereditary diseases. The most common sensory disease, hearing loss, is often hereditary and has a high impact on a patient’s every-day life. To use these sequencing technologies effectively, software tools were developed that can aid researchers interpreting genetic data by semi-automatically classifying the biologic (and thus potentially medical) impact of detected variants (the alterations of the patient’s genome compared to the human reference genome). The available genetic variant classification tools are either not designed specifically for the interpretation of variants detected in subjects with hearing loss or they do not allow researchers to use them for batch classification of all variants detected, e. g. in a study group. To address this drawback, we developed GenOtoScope, an open-source tool that automates the pathogenicity classification of variants potentially associated with congenital hearing loss. GenOtoScope can be applied for the automatic classification of all variants detected in a set of probands.