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Peer-reviewedCC BYHematology, Transfusion and Cell Therapy

DECIPHERING DIAMOND-BLACKFAN ANEMIA GERMLINE VARIANTS: CHARACTERIZING A BRAZILIAN COHORT AGAINST INTERNATIONAL COHORTS

  • Marília Bazzo CATTO1
  • Luiz Fernando Bazzo CATTO2
  • Willian Walter De França DA COSTA1
  • Fernanda GUTIERREZ-RODRIGUES3
  • Matthew GIANFERANTE4
  • Luiz Guilherme DARRIGO JúNIOR5
  • Xing FAN4
  • Flavia Sacilotto DONAIRES1
  • Sharon Ann SAVAGE4
  • Neelam GIRI4
  • Cynthia Elizabeth DUNBAR6
  • David James YOUNG2
1 more authors
  • Rodrigo Tocantins CALADO1
6 affiliations
  1. 1Department of Medical Imaging, Hematology, and Clinical Oncology, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP, Brazil
  2. 2Translational Stem Cell Biology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA; Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA, United States
  3. 3Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA, United States
  4. 4Clinical Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, United States
  5. 5Department of Pediatrics, Departamento de Imagens Médicas, Hematologia e Oncologia Clínica, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP, Brazil
  6. 6Translational Stem Cell Biology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA, United States
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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.

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Cite

BibTeXRIS
BibTeX
@article{catto2026deciphering,
  title = {{DECIPHERING DIAMOND-BLACKFAN ANEMIA GERMLINE VARIANTS: CHARACTERIZING A BRAZILIAN COHORT AGAINST INTERNATIONAL COHORTS}},
  author = {Marília Bazzo CATTO and Luiz Fernando Bazzo CATTO and Willian Walter De França DA COSTA and Fernanda GUTIERREZ-RODRIGUES and Matthew GIANFERANTE and Luiz Guilherme DARRIGO JúNIOR and Xing FAN and Flavia Sacilotto DONAIRES and Sharon Ann SAVAGE and Neelam GIRI and Cynthia Elizabeth DUNBAR and David James YOUNG and Rodrigo Tocantins CALADO},
  journal = {Hematology, Transfusion and Cell Therapy},
  year = {2026},
  month = oct,
  doi = {10.1016/j.htct.2026.106563},
  url = {https://doi.org/10.1016/j.htct.2026.106563},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - DECIPHERING DIAMOND-BLACKFAN ANEMIA GERMLINE VARIANTS: CHARACTERIZING A BRAZILIAN COHORT AGAINST INTERNATIONAL COHORTS
AU  - Marília Bazzo CATTO
AU  - Luiz Fernando Bazzo CATTO
AU  - Willian Walter De França DA COSTA
AU  - Fernanda GUTIERREZ-RODRIGUES
AU  - Matthew GIANFERANTE
AU  - Luiz Guilherme DARRIGO JúNIOR
AU  - Xing FAN
AU  - Flavia Sacilotto DONAIRES
AU  - Sharon Ann SAVAGE
AU  - Neelam GIRI
AU  - Cynthia Elizabeth DUNBAR
AU  - David James YOUNG
AU  - Rodrigo Tocantins CALADO
PY  - 2026
DA  - 2026/10/23
JO  - Hematology, Transfusion and Cell Therapy
DO  - 10.1016/j.htct.2026.106563
UR  - https://doi.org/10.1016/j.htct.2026.106563
AB  - 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.
SN  - 2531-1379
SN  - 2531-1387
ER  -