Ending diagnostic odyssey by reanalysis of whole exome sequencing data : reclassification of suspected Fanconi anemia cases to dyskeratosis congenita and Diamond-Blackfan anemia
Tejero Laguna, Eudald (Institut de Recerca Sant Pau)
Pujol Calvet, Maria Roser (Institut de Recerca Sant Pau)
Bogliolo, Massimo (Institut de Recerca Sant Pau)
Rodriguez Santiago, Benjamin (Institut de Recerca Sant Pau)
Surralles, Jordi (Institut de Recerca Sant Pau)
Ramírez de Haro, Ma. José (Institut de Recerca Sant Pau)

Date:	2025
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.
Grants:	Agencia Estatal de Investigación PID2021-122411OB-I00 Agencia Estatal de Investigación PDC2022-133233-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00835
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	WES Reanalysis ; Rare Genetic Diseases ; Fanconi Anemia ; Diamond-Blackfan Anemia ; Dyskeratosis Congenita ; RPL5 ; TERT
Published in:	Orphanet journal of rare diseases, Vol. 20 (October 2025) , art. 511, ISSN 1750-1172

DOI: 10.1186/s13023-025-03928-5
PMID: 41088272

10 p, 1.3 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles