{"doi":"10.1016/j.gimo.2023.100708","title":"P643: Transcriptome sequencing increases yield of Mendelian disease diagnosis","abstract":"Introduction: Rare and undiagnosed disorders affect approximately 400 million people worldwide and genetic causes mainly involve pathogenic variants in single genes.Despite advancements in diagnostic DNA tests, a substantial portion of patients with rare diseases remains unsolved.At the Miami Clinical Site of the Undiagnosed Diseases Network (UDN), we seek to provide diagnoses for patients with undiagnosed diseases using a multi-omics approach in a highly diverse population.Methods: We evaluated 42 probands who previously remained etiologically undiagnosed after genetic investigations including chromosomal microarrays, disease-specific gene panels, and exome sequencing.We applied a multi-omics approach, including genomics, transcriptomics, and metabolomics combined with deep phenotyping.Genome and transcriptome sequencing was performed on blood and/or fibroblast samples.Targeted and untargeted metabolomics studies were performed on serum, plasma, and urine samples.Data were analyzed utilizing an in-house genomic and transcriptomic evaluation pipeline to search for expression outliers and splice-altering variants along with expert reviews of metabolomics and phenotypic findings.Results: We have identified a genetic cause in 10 probands (24%).Genome and transcriptome sequencing combined approach identified a deep intronic variant in the PLA2G6 gene in one participant.Genome sequencing revealed causative variants in eight participants who previously received negative or inconclusive exome results during clinical evaluations.These included a large deletion in the non-coding region of LMNB1, and coding variants in POLR3B, RNUATAC, RTN2, TBCD, ATP1A1, THOC2, and H4C5.First reports of variants in H4C5 causing intellectual disabilities were published during our evaluation of a participant.In one participant, a new phenotype attributable to a variant in KIF21A, associated with syndromic congenital fibrosis of the extraocular muscles, was described.Conclusion: In this study, we identified causative variants in undiagnosed cases by using a multi-omics approach.Genome sequencing was the most helpful modality to identify causative variants in all solved participants.RNAseq assisted in confirming a splice-disrupting effect of a non-coding variant in 10% of diagnosed participants.","journal":"Genetics in Medicine Open","year":2023,"id":403678,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9383,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1181038,"name":"Rachel Ungar","orcid":"0000-0001-6680-5459","position":1,"is_corresponding":false},{"id":534668,"name":"Pagé C. Goddard","orcid":"0000-0001-8187-5316","position":2,"is_corresponding":false},{"id":464477,"name":"Jennefer N. Kohler","orcid":null,"position":3,"is_corresponding":false},{"id":129025,"name":"Chloe Reuter","orcid":"0000-0002-0429-9922","position":4,"is_corresponding":false},{"id":690754,"name":"Shruti Marwaha","orcid":"0000-0002-1877-2629","position":5,"is_corresponding":false},{"id":55845,"name":"Jonathan A. Bernstein","orcid":"0000-0001-5369-346X","position":6,"is_corresponding":false},{"id":52,"name":"Stephen B. Montgomery","orcid":"0000-0002-5200-3903","position":7,"is_corresponding":false},{"id":11028,"name":"Matthew T. Wheeler","orcid":"0000-0001-8721-3022","position":8,"is_corresponding":false},{"id":308556,"name":"Devon Bonner","orcid":"0000-0002-8771-0886","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T01:20:36.280647Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}