{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:54:08Z","timestamp":1791194048301,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,30]]},"group-title":"Genetic and Genomic Medicine","reference-count":33,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["2025-361613"],"award-info":[{"award-number":["2025-361613"]}],"id":[{"id":"https:\/\/ror.org\/02qenvm24","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>Children with suspected rare genetic disorders often remain undiagnosed after exome, gene panel, or chromosomal microarray testing. We sought to define recurrent missed-diagnosis mechanisms and evaluate an integrated clinical-genomic reanalysis framework.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We studied 75 participants with rare or striking pediatric-onset phenotypes who remained undiagnosed after prior genetic testing. Trio genome sequencing evaluated SNVs, indels and copy-number variants. RNA sequencing was performed in 63 participants to assess aberrant expression and splicing, with targeted follow-up assays used selectively for prioritized variants. Clinician-genome scientist review integrated longitudinal phenotyping, physician input, and inheritance. Unresolved cases underwent research-level candidate prioritization.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Clinically reportable findings were returned in 9, including two with multilocus findings: 5 explained the primary phenotype and 4, while not fully explanatory, were clinically relevant and informing surveillance, management, or family follow-up. Previously missed findings reflected technical limitations, including deep intronic splice-altering variants supported by transcriptome analysis and a genomic deletion, and interpretive limitations related to incomplete phenotype integration or narrowly scoped prior testing. Research-level analysis prioritized six candidate genes, including biallelic\n                    <jats:italic>ACHE<\/jats:italic>\n                    variants with reduced enzymatic activity.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Integrated clinical-genomic reanalysis framework identified diagnostic gaps, recovered care-informing findings, and prioritized candidate genes for rare disease discovery.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.24.26363679","type":"posted-content","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:05:19Z","timestamp":1790795119000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrated Clinical-Genomic Reanalysis Identifies Diagnostic Gaps and Candidate Genes in a Pediatric Rare Disease Cohort"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8673-7326","authenticated-orcid":false,"given":"Hyunjung","family":"Gu","sequence":"first","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniko","family":"Sabo","sequence":"additional","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7389-0890","authenticated-orcid":false,"given":"Sharayu V.","family":"Jangam","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX"},{"name":"Jan and Dan Duncan Neurological Research Institute, Texas Children\u2019s Hospital, Houston, 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