Integrated Clinical-Genomic Reanalysis Identifies Diagnostic Gaps and Candidate Genes in a Pediatric Rare Disease Cohort
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Purpose 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. Methods 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. Results 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 ACHE variants with reduced enzymatic activity. Conclusion Integrated clinical-genomic reanalysis framework identified diagnostic gaps, recovered care-informing findings, and prioritized candidate genes for rare disease discovery.
Source: medRxiv
Authors: Hyunjung Gu, Aniko Sabo, Sharayu V. Jangam, Hirokazu Hashimoto, Christina Y. Miyake, Bo Yuan, Charul Gijavanekar, Eric Venner, Viktoriya Korchina, Sarah H. Elsea, Donna M. Muzny, Elizabeth Mizerik, Blake Vuocolo, Poyyapakkam Srivaths, Lisa F. Satter, Sebastian Ochoa, Stephanie Sisley, Polle B. Mihindou, Oguz Kanca, Shinya Yamamoto, Zhandong Liu, Michael F. Wangler, Richard A. Gibbs, Hugo J. Bellen, Katherine Y. King
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214886273