Integrated Clinical-Genomic Reanalysis Identifies Diagnostic Gaps and Candidate Genes in a Pediatric Rare Disease Cohort
- 1Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, TX; Texas Children's Hospital, Houston, TX
Abstract
PurposeChildren 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.
MethodsWe 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.
ResultsClinically 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.
ConclusionIntegrated clinical-genomic reanalysis framework identified diagnostic gaps, recovered care-informing findings, and prioritized candidate genes for rare disease discovery.
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BibTeX
@misc{gu2026integrated,
title = {{Integrated Clinical-Genomic Reanalysis Identifies Diagnostic Gaps and Candidate Genes in a Pediatric Rare Disease Cohort}},
author = {H. Gu and A. Sabo and S. V. Jangam and H. Hashimoto and C. Y. Miyake and B. Yuan and C. Gijavanekar and E. Venner and V. Korchina and S. H. Elsea and D. M. Muzny and E. Mizerik and B. Vuocolo and P. Srivaths and L. F. Satter and S. Ochoa and S. Sisley and P. B. Mihindou and O. Kanca and S. Yamamoto and Z. Liu and M. F. Wangler and R. A. Gibbs and H. J. Bellen and K. Y. King},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.26363679},
url = {https://www.medrxiv.org/content/10.64898/2026.09.24.26363679v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Integrated Clinical-Genomic Reanalysis Identifies Diagnostic Gaps and Candidate Genes in a Pediatric Rare Disease Cohort
AU - H. Gu
AU - A. Sabo
AU - S. V. Jangam
AU - H. Hashimoto
AU - C. Y. Miyake
AU - B. Yuan
AU - C. Gijavanekar
AU - E. Venner
AU - V. Korchina
AU - S. H. Elsea
AU - D. M. Muzny
AU - E. Mizerik
AU - B. Vuocolo
AU - P. Srivaths
AU - L. F. Satter
AU - S. Ochoa
AU - S. Sisley
AU - P. B. Mihindou
AU - O. Kanca
AU - S. Yamamoto
AU - Z. Liu
AU - M. F. Wangler
AU - R. A. Gibbs
AU - H. J. Bellen
AU - K. Y. King
PY - 2026
DA - 2026/09/24
PB - medRxiv
DO - 10.64898/2026.09.24.26363679
UR - https://www.medrxiv.org/content/10.64898/2026.09.24.26363679v1
AB - PurposeChildren 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. MethodsWe 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. ResultsClinically 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. ConclusionIntegrated clinical-genomic reanalysis framework identified diagnostic gaps, recovered care-informing findings, and prioritized candidate genes for rare disease discovery.
ER -