Deciphering Diamond-blackfan Anemia Germline Variants: Characterizing a Brazilian Cohort Against International Cohorts
Year: 2026
Type: article
Study design: Observational Study
Abstract: Introduction Diamond-Blackfan Anemia (DBA) is a rare inherited bone marrow failure syndrome primarily driven by ribosomal protein gene haploinsufficiency. International registries have defined the global genetic landscape of DBA, but Latin American populations remain underrepresented. Characterizing the germline genetic spectrum of DBA in Brazil is essential to uncover regional variation in diagnostic yield, gene frequency, copy number variants (CNVs), and population-specific alleles, and to refine local diagnostic pipelines. Methods We developed an error-corrected sequencing panel covering 181 genes implicated in DBA, myeloid neoplasms, erythropoiesis, iron metabolism, and ribosome biology, with integrated copy number detection. DNA was retrospectively sequenced from 146 DBA patients across 3 centers: one in Brazil (USP, n=42) and two in the USA (NHLBI, NCI, n=104). Clinical data were extracted from medical records and genomic and clinical profiles of the Brazilian cohort were compared against North American cohorts. Results Median age was 10 years (range 0–57), differing significantly by cohort (median [range]; NCI: 12 [0–56]; NHLBI: 27 [2–57]; USP: 3 [0–43]; p<0.001); 44% (n=64) were female. Pathogenic germline variants (PGVs) were identified before panel sequencing in 108 (73.5%) patients across 16 genes, most often RPS19 (35.2%), RPS26 (12.0%), RPS29 (10.2%), RPL5 (8.3%), RPL11 (7.4%), and RPL35A (7.4%). Coding variants accounted for 75.0% of these cases, splice-site variants 13.9%, and CNVs 11.9%. Error-corrected panel sequencing identified PGVs in an additional 18/38 (47.4%) previously unsolved cases, most commonly in RPS19, RPS7, and RPS26, including 6 large deletions, 5 splicing variants, and 7 coding regions. Two patients had somatic-range variant allele fraction (VAF): one in RPL26 (29%), confirmed as germline mosaicism by parallel fibroblast and bone marrow sequencing, and one in RPS19 (30%) with copy-neutral loss of heterozygosity confirmed by SNP array. One patient with clinical diagnosis of DBA was found to have a homozygous ADA2 mutation and was reclassified as DADA2 syndrome. The PGV spectrum differed significantly between cohorts (p<0.01): RPS19 predominated in the US (33.3%), while RPS26 was most common in Brazil (23.8% vs. 6.7% in the USA); RPS29 and RPL35A were absent in Brazil. Mutational spectrum also differed (p<0.001): coding variants predominated in North America (78.3%), while splice-region variants were markedly enriched in Brazil (38.2% vs. 6.5%). CNV rates were similar (Brazil 14.7%, USA 13.0%). Conclusion These findings reveal a genetically distinct DBA landscape in Brazil, marked by enrichment of RPS26 and splice-region variants relative to North American cohorts, and absence of RPS29 and RPL35A alterations common in the USA. Error-corrected sequencing improved diagnostic yield in unsolved cases, underscoring the value of CNV-integrated, mosaicism-sensitive approaches. These results highlight the importance of population-specific genomic characterization for equitable diagnosis and precision care in bone marrow failure.
Authors: Marília Bazzo CATTO, Luiz Fernando Bazzo CATTO, Willian Walter De França DA COSTA, Fernanda GUTIERREZ-RODRIGUES, Matthew GIANFERANTE, Luiz Guilherme DARRIGO JúNIOR, Xing FAN, Flavia Sacilotto DONAIRES, Sharon Ann SAVAGE, Neelam GIRI, Cynthia Elizabeth DUNBAR, David James YOUNG, Rodrigo Tocantins CALADO
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223118325