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

TL;DR

Reanalyzing old genetic data helped diagnose two patients with rare conditions after initial tests failed, showing the value of updating genomic analysis over time.

Contribution

Demonstrates the effectiveness of reanalyzing outdated exome data to achieve new diagnoses in unresolved genetic cases.

Findings

Reanalysis identified pathogenic variants in two patients with previously inconclusive results.

One patient had a variant in RPL5 (linked to Diamond-Blackfan anemia), and another had TERT variants (linked to dyskeratosis congenita).

A 33.3% diagnostic yield was achieved, comparable to larger reanalysis studies.

Abstract

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.

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.

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.

The online version contains supplementary material available at 10.1186/s13023-025-03928-5.

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