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ADA2 – Diamond-Blackfan Anemia

Biallelic loss-of-function variants in ADA2 (CECR1) have been identified in patients presenting with congenital hypoplastic anemia clinically consistent with Diamond-Blackfan anemia. Initially, a 6-year-old boy with transfusion-dependent anemia and absent bone marrow erythroid precursors was found to harbor compound heterozygous ADA2 variants after whole-genome sequencing (c.336C>G (p.His112Gln) and an intragenic deletion) and decreased ADA2 activity, following negative testing for classical DBA genes (PMID:30559313). Subsequently, in a series of 24 DADA2 patients, nine individuals exhibited a DBA-like pure red cell aplasia phenotype and were confirmed to carry biallelic ADA2 variants (PMID:31043544), yielding ten unrelated probands with autosomal recessive inheritance and confirmed parental carrier segregation.

Transcriptomic profiling of proerythroblasts from patients with RPS19 or CECR1 mutations showed a shared signature of impaired erythroid differentiation and upregulation of stress-response genes. Colony-forming unit-erythroid assays demonstrated failure of erythroid maturation in CECR1-mutated cells, mirroring classical DBA phenotypes (PMID:34177624). This concordant functional evidence supports a loss-of-function mechanism for ADA2 in erythropoiesis. No conflicting evidence has been reported. Although evidence is currently limited, ADA2 should be considered in genetically unsolved DBA cases.

Key Take-home: ADA2 deficiency constitutes a non-ribosomal, autosomal recessive cause of Diamond-Blackfan-like congenital hypoplastic anemia, meriting inclusion in diagnostic genomic panels.

References

  • Cold Spring Harbor molecular case studies • 2018 • Complexities of genetic diagnosis illustrated by an atypical case of congenital hypoplastic anemia. PMID:30559313
  • The Journal of rheumatology • 2020 • A Monogenic Disease with a Variety of Phenotypes: Deficiency of Adenosine Deaminase 2. PMID:31043544
  • Frontiers in physiology • 2021 • Proerythroblast Cells of Diamond-Blackfan Anemia Patients With RPS19 and CECR1 Mutations Have Similar Transcriptomic Signature. PMID:34177624

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Ten unrelated probands with biallelic ADA2 variants presenting with DBA-like congenital hypoplastic anemia; AR inheritance with parental carrier segregation.

Genetic Evidence

Limited

Autosomal recessive compound heterozygous or homozygous ADA2 variants in 10 probands; no extended familial segregation beyond parental carriers.

Functional Evidence

Limited

Shared proerythroblast transcriptomic signature with RPS19 DBA and erythroid differentiation failure in CFU-E assays in CECR1-mutated samples.