Medhat Mahmoud from the Baylor College of Medicine’s Human Genome Sequencing Center presented at the Nanopore Community Meeting in Houston a session titled “Unraveling complex Mendelian diseases with nanopore sequencing.” They are in the Sedlacek lab and spoke about GREGoR: Genomics Research to Elucidate the Genetics of Rare Diseases project. GREGoR includes five research centers and one data coordinating center. Mahmoud explained why exome sequencing (1-2% of the entire genome) can be ineffective in complex polygenic conditions where multiple genes contribute to the phenotype. Mahmoud shared that whole genome sequencing is becoming more accessible now. GREGoR has enrolled over 1,600 and more than 400 families, capturing over 280 disorders. To obtain as much information as possible from these genomes, they conducted a pilot study to explore GREGoR samples with Oxford Nanopore Technologies (ONT) sequencing. Mahmoud focused on forty samples. Previously, Mahmoud developed the PRINCESS workflow for the detection of haplotype-resolved SNVs, SVs, and methylation. Mahmoud developed an annotation pipeline for the SNVs and SVs that were identified. However, SV annotation remains a challenge, with 93% of uniquely identified SVs in this pilot lacking annotation. Initiatives like All of Us and 1000 Genomes will help address this challenge. Mahmoud shared results from a 70-day-old male with a developmental disorder and birth defects. The whole exome sequencing results were inconclusive. Mahmoud’s work identified a deletion in the son affecting the first exon of the TUBASE gene region. The analysis workflow for variant prioritization that Mahmoud and the team developed integrates PRINCESS. The robust approach can be used for samples like the case study described. In the future, Mahmoud hopes to apply this approach to larger cohorts. The development of pipelines and programs will help overcome the challenges associated with discovering the implications of SVs in rare diseases.
