CDAN1 – Congenital Dyserythropoietic Anemia Type I

Congenital dyserythropoietic anemia type I (CDA I) is an autosomal recessive disorder characterized by ineffective erythropoiesis, macrocytic anemia, and progressive iron overload. The CDAN1 gene encodes codanin-1, a ubiquitously expressed 1,226-amino-acid protein implicated in nuclear envelope integrity and histone dynamics. CDA I was first linked to CDAN1 through mapping in a cluster of Israeli Bedouin families, identifying 12 distinct mutations in 9 unrelated pedigrees (PMID:12434312).

Subsequent clinical series have described >100 genetically confirmed CDA I cases from 19 families with biallelic CDAN1 variants, including missense, frameshift, splice-site, and in-frame deletions (PMID:16141353). The phenotype spans neonatal to adult presentations, from hydrops fetalis to diabetes and hypogonadism secondary to systemic iron overload. A Japanese adult with lifelong hemolytic anemia was diagnosed at age 48 with homozygous c.3389C>T (p.Pro1130Leu) (PMID:22504250); an Italian man exhibited compound heterozygosity for a frameshift 3367del4 and c.1811G>T (p.Gly565Val) (PMID:27408412).

Variant spectrum in CDAN1 includes >40 missense substitutions (e.g., c.1004G>A (p.Arg335Gln)), multiple frameshift and nonsense alleles (e.g., c.3062dup (p.Pro1022fs)), and splice-site disruptions. A founder missense variant, c.3124C>T (p.Arg1042Trp), was detected homozygously in 34 patients from a Bedouin isolate, contributing to early-onset macrocytic anemia (PMID:28755517).

Segregation analysis in familial studies has confirmed cosegregation of biallelic CDAN1 variants with CDA I in affected sib pairs, including one Italian kindred with two brothers sharing the 3367del4 and Gly565Val alleles (PMID:27408412).

Functional assays in HUDEP-2 erythroid cells with engineered R1042 mutations recapitulate CDA I defects: binucleation, chromatin bridges, altered histone acetylation, and premature erythroid gene expression (PMID:33075436). A Cdan1 knockout mouse model exhibits primitive erythropoiesis failure and embryonic lethality, underscoring a loss-of-function mechanism (PMID:35441598).

No conflicting reports refute the CDAN1–CDA I association. Collectively, genetic and experimental data satisfy ClinGen criteria for a definitive gene-disease relationship. CDAN1 sequencing is clinically indicated in patients with unexplained macrocytic anemia, characteristic marrow morphology, or iron overload. Early molecular diagnosis enables tailored management, including iron chelation and interferon-α therapy.

Key Take-home: CDAN1 biallelic variants definitively cause CDA I; genetic testing informs diagnosis, prognosis, and therapeutic decisions.

References

• American journal of human genetics • 2002 • Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1. PMID:12434312
• Blood • 2006 • Congenital dyserythropoietic anemia type I (CDA I): molecular genetics, clinical appearance, and prognosis based on long-term observation. PMID:16141353
• Internal medicine (Tokyo, Japan) • 2012 • A case of congenital dyserythropoietic anemia type 1 in a Japanese adult with a CDAN1 gene mutation and an inappropriately low serum hepcidin-25 level. PMID:22504250
• Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion • 2016 • New Codanin-1 Gene Mutations in a Italian Patient with Congenital Dyserythropoietic Anemia Type I and Heterozygous Beta-Thalassemia. PMID:27408412
• European journal of haematology • 2017 • Morphological features of congenital dyserythropoietic anemia type I: The role of electron microscopy in diagnosis. PMID:28755517
• Experimental hematology • 2020 • Codanin-1 mutations engineered in human erythroid cells demonstrate role of CDAN1 in terminal erythroid maturation. PMID:33075436
• Current opinion in hematology • 2022 • The congenital dyserythropoieitic anemias: genetics and pathophysiology. PMID:35441598

Evidence Based Scoring (AI generated)