Integrated Clinical-Genomic Reanalysis Identifies Diagnostic Gaps and Candidate Genes in a Pediatric Rare Disease Cohort.

Diagnoses missed through technical limitations (splice-altering deep intronic variants, genomic deletion) or interpretive limitations (incomplete phenotype, narrowly scoped testing)

This study evaluates an integrated clinical-genomic reanalysis framework in 75 children with rare phenotypes who remained undiagnosed after exome, panel or chromosomal microarray testing: trio genome sequencing (SNVs, indels, CNVs), RNA-seq in 63 participants, selective targeted assays and joint clinician–genome scientist review integrating longitudinal phenotyping. Reportable findings were returned for 9 participants, 2 with multilocus findings: 5 explained the primary phenotype and 4, while not fully explanatory, informed surveillance, management or family follow-up. Missed diagnoses reflected technical limitations (splice-altering deep intronic variants supported by transcriptome analysis, and a genomic deletion) and interpretive limitations (incomplete phenotype integration, narrowly scoped prior testing). Research-level analysis prioritised six candidate genes, including ACHE with biallelic variants reducing enzyme activity.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A preprint not yet peer reviewed. The raw yield (9 of 75, i.e. 12%) is modest but realistic for an already heavily investigated cohort, and the typology of failures is the main contribution: part of it stems from interpretation rather than technology. A message for laboratories: reanalysis benefits from an updated phenotype and clinician–laboratory dialogue, with RNA reserved for selected cases.

Analysis by Dr Thibaut Benquey