CDAN1 – Congenital Dyserythropoietic Anemia

CDAN1 encodes Codanin-1, a ubiquitously expressed protein required for chromatin organization during erythroid maturation. Biallelic pathogenic variants in CDAN1 underlie congenital dyserythropoietic anemia type I (CDA-I), an autosomal recessive disorder characterized by ineffective erythropoiesis, macrocytic anemia, jaundice, and iron overload.

Initial genetic mapping in a cluster of 45 highly inbred Israeli Bedouin patients enabled localization of the CDAN1 gene to chromosome 15q15 and identification of 12 distinct variants in 9 families, including c.2605G>A (p.Val869Met)[PMID:12434312].

Subsequent case reports in diverse populations confirm autosomal recessive inheritance. A Japanese female with long-standing congenital hemolytic anemia was reclassified as CDA-I upon discovery of a novel CDAN1 mutation[PMID:23605369]. A severe fetal presentation with hydrops fetalis was traced to compound heterozygous c.1004G>A (p.Arg335Gln) and c.2174G>A (p.Arg725Gln)[PMID:29599085].

A European cohort study of 53 patients from 44 families identified CDAN1 variants in 21 individuals, with missense substitutions such as c.3128A>T (p.Asp1043Val)[PMID:29901818][PMID:32518175].

The variant spectrum is predominantly missense, clustering in conserved domains of Codanin-1; splice-site and deep-intronic changes have also been documented. Recurrent alleles such as c.3389C>T (p.Pro1130Leu) suggest potential founder effects in select populations.

Functional assays in HUDEP2 erythroid progenitors with patient-mimicking R1042 mutations demonstrate decreased viability, binucleation, chromatin bridging, and altered histone acetylation, recapitulating CDA-I cytopathology[PMID:33075436]. Structural and interaction studies reveal that CDAN1 forms obligate complexes with CDIN1 and ASF1A/B, sequestering histone chaperones and implicating disrupted histone delivery in pathogenesis[PMID:32518175].

Collectively, 69 probands across multiple cohorts (45 Bedouin[PMID:12434312], 21 European[PMID:29901818], and case reports[PMID:23605369, PMID:29599085]) and segregation in 9 families establish a definitive gene–disease relationship, corroborated by robust functional concordance. Key take-home: biallelic CDAN1 testing is essential for accurate diagnosis and management of CDA-I.

References

• American journal of human genetics • 2002 • Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1. PMID:12434312
• International journal of hematology • 2013 • Congenital dyserythropoietic anemia type 1 with a novel mutation in the CDAN1 gene previously diagnosed as congenital hemolytic anemia. PMID:23605369
• Blood cells, molecules & diseases • 2018 • Fetal presentation of congenital dyserythropoietic anemia type 1 with novel compound heterozygous CDAN1 mutations. PMID:29599085
• European journal of haematology • 2018 • Clinical and genetic features of congenital dyserythropoietic anemia (CDA). PMID:29901818
• Experimental hematology • 2020 • Codanin-1 mutations engineered in human erythroid cells demonstrate role of CDAN1 in terminal erythroid maturation. PMID:33075436
• Journal of medical genetics • 2021 • Genetic and functional insights into CDA-I prevalence and pathogenesis. PMID:32518175

Evidence Based Scoring (AI generated)