C15orf41 – Congenital Dyserythropoietic Anemia Type I

Congenital dyserythropoietic anemia type I (CDA I) is an autosomal recessive disorder characterized by ineffective erythropoiesis, macrocytic anemia, relative reticulocytopenia, and congenital anomalies (HP:0001903, HP:0001974). Biallelic mutations in C15orf41 (HGNC:26929) or CDAN1 (HGNC:1713) underlie disease pathogenesis.

C15orf41 encodes a predicted divalent metal ion–dependent restriction endonuclease with unknown physiological substrates. Gene expression of C15orf41 tightly correlates with CDAN1, suggesting a shared regulatory mechanism in erythroid cells and an obligate protein complex enriched in the nucleolus (PMID:32518175).

Two unrelated probands were reported with novel biallelic C15orf41 variants: c.281A>C (p.Tyr94Ser) and c.689A>C (p.His230Pro), both disrupting conserved domains and segregating with disease in families (PMID:31191338). A third novel C15orf41 variant was identified in a larger cohort, further supporting CDIN1 genetic heterogeneity in CDA I (PMID:32518175).

Population genetics analyses indicate that CDA I prevalence may be higher than currently estimated, with underdiagnosis due to clinical heterogeneity and overlapping features with other anemias (PMID:32518175). Transcriptomic profiling of CDIN1 variants reveals impaired erythroid differentiation and disruptions in cell proliferation and histone regulation.

Functional studies demonstrate that the H230P variant leads to markedly reduced mRNA stability, protein expression, and impaired erythroid maturation, while Y94S causes a modest decrease in expression and similar differentiation block. Both mutants produce an increased S‐phase fraction in K562 cells, implicating defective cell cycle dynamics as a pathogenic mechanism (PMID:31191338).

Collectively, the genetic and experimental data establish a loss‐of‐function mechanism for C15orf41 in CDA I. Biallelic C15orf41 testing should be incorporated into diagnostic panels for autosomal recessive macrocytic anemias. Key take‐home: C15orf41 is a validated CDA I gene with clinical utility for diagnosis and management.

References

• Frontiers in Physiology • 2019 • Characterization of Two Cases of Congenital Dyserythropoietic Anemia Type I Shed Light on the Uncharacterized C15orf41 Protein. PMID:31191338
• Journal of Medical Genetics • 2021 • Genetic and functional insights into CDA-I prevalence and pathogenesis. PMID:32518175

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