Ending diagnostic odyssey by reanalysis of whole exome sequencing data: reclassification of suspected Fanconi anemia cases to dyskeratosis congenita and Diamond-Blackfan anemia.

BACKGROUND

Initial Whole Exome Sequencing frequently fails to resolve rare disease cases. Bioinformatic reanalysis of existing genomic data utilizes advancing knowledge to enhance diagnosis without additional testing. This study investigated six patients with clinical features consistent with Fanconi Anemia but negative chromosomal breakage tests, whose initial genetic analyses were inconclusive.

RESULTS

Whole Exome Sequencing data from these patients (collected 2005-2009) underwent comprehensive reanalysis, including single nucleotide variants, insertions/deletions, and copy number variants across genes beyond those typically associated with Fanconi Anemia. Telomere length was assessed via monochrome multiplex quantitative PCR. Reanalysis identified clinically significant variants in two patients (33.3% yield): one harboured a heterozygous pathogenic loss-of-function variant in the Diamond-Blackfan anemia gene RPL5, while the second exhibited compound heterozygous variants in the TERT gene, indicative of dyskeratosis congenita.

CONCLUSIONS

This study underscores the clinical value of reanalyzing existing genomic data in unresolved suspected genetic disorders, even when phenotype-specific assays are negative. The 33.3% diagnostic yield aligns with gains from larger reanalysis studies (10-25%). Systematic reassessment after sufficient time (24 + months) for genomic advancements offers a cost-effective diagnostic approach for long-undiagnosed cases, highlighting the dynamic nature of genomic interpretation as gene-disease understanding evolves.