{"id":16618608,"url":"https://github.com/brentp/rare-disease-wf","last_synced_at":"2026-03-07T18:32:41.868Z","repository":{"id":66472224,"uuid":"357828935","full_name":"brentp/rare-disease-wf","owner":"brentp","description":"(WIP) best-practices workflow for rare disease","archived":false,"fork":false,"pushed_at":"2024-07-01T18:07:32.000Z","size":570,"stargazers_count":62,"open_issues_count":7,"forks_count":8,"subscribers_count":7,"default_branch":"main","last_synced_at":"2025-09-09T19:43:43.961Z","etag":null,"topics":["genomics","rare-disease","variants"],"latest_commit_sha":null,"homepage":"","language":"Nextflow","has_issues":true,"has_wiki":null,"has_pages":null,"mirror_url":null,"source_name":null,"license":"mit","status":null,"scm":"git","pull_requests_enabled":true,"icon_url":"https://github.com/brentp.png","metadata":{"files":{"readme":"README.md","changelog":null,"contributing":null,"funding":null,"license":"LICENSE","code_of_conduct":null,"threat_model":null,"audit":null,"citation":null,"codeowners":null,"security":null,"support":null,"governance":null,"roadmap":null,"authors":null,"dei":null,"publiccode":null,"codemeta":null}},"created_at":"2021-04-14T08:21:13.000Z","updated_at":"2025-09-05T12:33:23.000Z","dependencies_parsed_at":"2024-10-12T02:20:55.122Z","dependency_job_id":"d93e6837-28ab-4471-94c4-ee0516d6098d","html_url":"https://github.com/brentp/rare-disease-wf","commit_stats":null,"previous_names":[],"tags_count":2,"template":false,"template_full_name":null,"purl":"pkg:github/brentp/rare-disease-wf","repository_url":"https://repos.ecosyste.ms/api/v1/hosts/GitHub/repositories/brentp%2Frare-disease-wf","tags_url":"https://repos.ecosyste.ms/api/v1/hosts/GitHub/repositories/brentp%2Frare-disease-wf/tags","releases_url":"https://repos.ecosyste.ms/api/v1/hosts/GitHub/repositories/brentp%2Frare-disease-wf/releases","manifests_url":"https://repos.ecosyste.ms/api/v1/hosts/GitHub/repositories/brentp%2Frare-disease-wf/manifests","owner_url":"https://repos.ecosyste.ms/api/v1/hosts/GitHub/owners/brentp","download_url":"https://codeload.github.com/brentp/rare-disease-wf/tar.gz/refs/heads/main","sbom_url":"https://repos.ecosyste.ms/api/v1/hosts/GitHub/repositories/brentp%2Frare-disease-wf/sbom","scorecard":null,"host":{"name":"GitHub","url":"https://github.com","kind":"github","repositories_count":286080680,"owners_count":30226247,"icon_url":"https://github.com/github.png","version":null,"created_at":"2022-05-30T11:31:42.601Z","updated_at":"2026-03-07T18:12:09.766Z","status":"ssl_error","status_checked_at":"2026-03-07T18:11:58.786Z","response_time":53,"last_error":"SSL_read: unexpected eof while reading","robots_txt_status":"success","robots_txt_updated_at":"2025-07-24T06:49:26.215Z","robots_txt_url":"https://github.com/robots.txt","online":false,"can_crawl_api":true,"host_url":"https://repos.ecosyste.ms/api/v1/hosts/GitHub","repositories_url":"https://repos.ecosyste.ms/api/v1/hosts/GitHub/repositories","repository_names_url":"https://repos.ecosyste.ms/api/v1/hosts/GitHub/repository_names","owners_url":"https://repos.ecosyste.ms/api/v1/hosts/GitHub/owners"}},"keywords":["genomics","rare-disease","variants"],"created_at":"2024-10-12T02:20:50.096Z","updated_at":"2026-03-07T18:32:41.849Z","avatar_url":"https://github.com/brentp.png","language":"Nextflow","funding_links":[],"categories":[],"sub_categories":[],"readme":"For rare-disease, the [best practices and expected number of candidate variants for each inheritance mode are known](https://www.biorxiv.org/content/10.1101/2020.08.13.249532v3). The\nactual filtering is easily done with a tool like [slivar](https://github.com/brentp/slivar/wiki/rare-disease). \nThis is a necessary first step with the following limitations:\n\n 1. it leaves an analyst or clinician with choices on how to prioritize the 10-15 candidates variants or ~100 for autosomal (non *de novo*) dominant.\n    - This is quite a small number, but the prioritization after this is highly variable across tools and analysts.\n 2. it is limited text/spreadsheet output\n 3. it assumes a high-quality, jointly-called VCF is already available\n 4. it leaves the analyst with the chore of getting IGV set up, and browsing each candidate for each family.\n\n\n## Quickstart \n\nNote, it is early days for the project. It will produce high-quality SNP/indel candidates\nbut you may need experience with [nextflow](https://nextflow.io) to run it easily.\n\nThis project **currently** has workflow that can be run as:\n\n```\n# NOTE that you need to remove everything after \\ on each line for the command to work\n# the comments here are just for documentation purposes.\nnextflow run -resume -profile slurm rare-disease.nf \\\n    -config nextflow.config \\    # a starting config is included in this repo. adjust from there.\n    --xams \"/path/to/*/*.cram\" \\ # NOTE that this is a string glob\n    --ped $pedigree_file \\       # see: https://gatk.broadinstitute.org/hc/en-us/articles/360035531972-PED-Pedigree-format\n    --fasta $reference_fasta \\\n    --gff $gff \\                   # e.g. from: ftp://ftp.ensembl.org/pub/current_gff3/homo_sapiens/\n    --slivarzip gnomad.hg38.zip  \\  # from: https://github.com/brentp/slivar#gnotation-files\n    --cohort_name my_rare_disease\n```\n\n## Output\n\nSee [this wiki page](https://github.com/brentp/rare-disease-wf/wiki/Workflow-Output) for more information about how to use the output.\n\nThis does:\n\n 1. Run [DeepVariant](https://github.com/google/deepvariant) and [GLNexus](https://github.com/dnanexus-rnd/GLnexus) (we have shown these tools to give higher quality results for trios) in an efficient nextflow workflow that can be easily run in the cloud or on a cluster.\n 1. Decompose and normalize variants.\n 1. Annotate with [bcftools csq](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870570/) and [snpEff](https://pcingola.github.io/SnpEff/adds/SnpEff_paper.pdf) \n 1. Annotate with allele frequency and inheritance modes using [slivar](https://github.com/brentp/slivar)\n 1. Annotate with gene-based annotations:\n    - clinvar-gene-phenotype\n    - loss-of-function intolerance\n 1. Output high-quality calls from [slivar](https://github.com/brentp/slivar) for recessive, dominant, x-linked, compound-het and other\n    inheritance modes.\n 1. Generates and links pre-made, standalone [igv.js](https://github.com/igvteam/igv.js)/[jigv](https://github.com/brentp/jigv) outputs for each candidate.\n\nAnd the key output will be in: `results-rare-disease/${cohort_name}.slivar.candidates.tsv` which is something one can easily view in excel or other spreadsheet software.\nIn addition, it will create: `results-rare-disease/${cohort_name}.jigv.html` and `results-rare-disease/jigv_plots/*` which together provide an HTML table and interactive [igv.js](https://github.com/brentp/igvteam/igv.js) views of each variant and associated alignments that do not rely on the original alignment files.\n\nIn coming releases, this will:\n\n 1. Output QC with [somalier](https://github.com/brentp/somalier) and other tools to be shown in [multiQC](https://multiQC.info)\n 1. Output high-quality SVs (using manta-\u003e graphtyper)\n\n## Octopus\n\ncurrently, [octopus](https://doi.org/10.1038/s41587-021-00861-3) is included as\na separate workflow. This octopus.nf pipeline will detect trios and families\nand run them together and then iteratively merge across families using the\n`n+1` schema [described in the octopus\ndocs](https://luntergroup.github.io/octopus/docs/guides/models/population)\nFinally, the workflow will do the forest filtering as recommended by the\noctopus documentation.\nWe plan to integrate the octopus and deepvariant calls in the future.\n\n\n## Future Development\n\nDevelopment and research is underway so that it will:\n\n 1. Add a high-quality set of SV/CNVs\n    - [Manta](https://github.com/Illumina/manta) + SVchannels and [duphold](https://github.com/brentp/duphold) filtering\n 1. Add some **prioritization** of variants\n    - For example, lower priority to variants filtered in gnomAD\n 1. Integrate SV/CNV calls with the snp/indels to find, for example compound heterozygotes with a snp:SV pair.\n 1. Evaluate use of [octopus](https://github.com/luntergroup/octopus) to find large indels (and/or SNPs and indels).\n 1. Use GTex + phenotypes to further prioritize variants in a family and phenotype-specific way, such that, for example\n    variants in genes that are not expressed in relevant tissues are down-weighted.\n 1. Provide a graphical-user-interface so that sorting, filtering, note-taking, sharing is simplified\n\n\n## Software Used\n\n+ [DeepVariant](https://github.com/google/deepvariant) Variant Calling with Deep Learning. https://doi.org/10.1038/nbt.4235\n+ [GLNexus](https://github.com/dnanexus-rnd/GLnexus) Joint variant calling. http://dx.doi.org/10.1101/343970\n+ [octopus](https://github.com/luntergroup/octopus) haplotype-based mutation caller. https://doi.org/10.1038/s41587-021-00861-3\n+ [bcftools](https://github.com/samtools/bcftools) BCF/VCF manipulation. https://doi.org/10.1093/gigascience/giab008\n+ [bcftools csq](https://github.com/samtools/bcftools) variant consequence annotation. https://doi.org/10.1093/bioinformatics/btx100\n+ [htslib](https://github.com/samtools/htslib) C libary for genomics data. https://doi.org/10.1093/gigascience/giab007\n+ [slivar](https://github.com/brentp/slivar) variant filtering and annotation. https://doi.org/10.1101/2020.08.13.249532\n+ [igv.js](https://github.com/igvteam/igv.js/). javascript genomics viewer. https://doi.org/10.1101/2020.05.03.075499\n+ [nextflow](https://nextflow.io/) scientific workflows. https://doi.org/10.1038/nbt.3820\n+ [manta](https://github.com/Illumina/manta) structural variant caller. https://doi.org/10.1093/bioinformatics/btv710\n+ [dysgu](https://github.com/kcleal/dysgu) structural variant caller. https://doi.org/10.1101/2021.05.28.446147 \n+ [paragraph](https://github.com/Illumina/paragraph) structural variant genotyper. https://doi.org/10.1186/s13059-019-1909-7\n+ [jasmine](https://github.com/mkirsche/Jasmine) structural variant merging. https://doi.org/10.1101/2021.05.27.445886\n+ [duphold](https://github.com/brentp/duphold) structural variant depth annotation. https://doi.org/10.1093/gigascience/giz040\n+ [snpEff](http://pcingola.github.io/SnpEff/) variant consequence annotation. https://doi.org/10.4161/fly.19695\n+ [svpack](https://github.com/amwenger/svpack/) structural variant annotation.\n","project_url":"https://awesome.ecosyste.ms/api/v1/projects/github.com%2Fbrentp%2Frare-disease-wf","html_url":"https://awesome.ecosyste.ms/projects/github.com%2Fbrentp%2Frare-disease-wf","lists_url":"https://awesome.ecosyste.ms/api/v1/projects/github.com%2Fbrentp%2Frare-disease-wf/lists"}