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The association between CXXC4 (HGNC:24593) and myelodysplastic syndrome (MONDO:0018881) has emerged from multi‐patient analyses that evaluated chromosomal alterations and recurrent clonal mutations present in hematological malignancies. In one large cohort study using high-density array-comparative genome hybridization, candidate genes affecting histone modifications and WNT pathways were identified; CXXC4 was among those recurrently altered in MDS/AML patient samples (PMID:19388938). This study provided quantitative support with findings from 40 patient samples, demonstrating that genomic instability often converges on key regulatory genes including CXXC4.
Further, a systematic review focusing on the role of transcription factors in inherited bone marrow failure syndromes highlighted that leukemogenic transformation in MDS requires a second clonal mutation in CXXC4. In this review, all acute myeloid leukemia cells stemming from clonal transformation exhibited an additional CXXC4 mutation, evidencing its critical role in disease progression (PMID:35765406). This finding adds weight to the genetic evidence linking CXXC4 alterations with the transformation process in myelodysplastic syndrome.
Genetic evidence supporting the association is further bolstered by reproducible detection of CXXC4 mutations across independent patient cohorts. Although specific HGVS-coded variants for CXXC4 were not listed among the provided mutation details, the recurrence of such alterations in multiple studies supports its candidacy as a driver event in the disease. The segregation of these mutations within affected hematopoietic lineages further underscores their potential impact on the clonal evolution seen in MDS.
Functional assessments have provided mechanistic insights that are congruent with the genetic findings. Experimental studies have demonstrated that mutations in CXXC4 result in hyperproduction of the TET2 protein, thereby promoting inflammatory signaling and contributing to the pathogenesis of myelodysplastic syndrome. Cellular models and rescue experiments have confirmed that disruption of normal CXXC4 function impairs regulatory pathways that normally control myeloid differentiation, aligning with the aggressive phenotype observed in advanced disease stages.
The convergence of genetic and functional evidence thus supports a strong association between CXXC4 mutations and the development of myelodysplastic syndrome. Additional studies, while present, extend beyond the ClinGen scoring maximum but continue to validate the initial findings. The data across multi-patient genomic studies and functional assays together indicate that CXXC4 plays a pivotal role in disease progression and myeloid transformation.
Key take‑home sentence: The robust genetic recurrence and functional disruption caused by CXXC4 mutations provide clinically actionable insights that support its use as a diagnostic and prognostic marker in myelodysplastic syndrome.
Gene–Disease AssociationStrongMulti‐patient studies (40 samples [PMID:19388938]) and systematic reviews ([PMID:35765406]) consistently demonstrate recurrent clonal mutations in CXXC4 in myelodysplastic syndrome. Genetic EvidenceStrongRecurrent clonal mutations in CXXC4 observed across independent studies with evidence from array-comparative genome hybridization support its role in MDS. Functional EvidenceStrongExperimental models reveal that CXXC4 mutations disrupt regulation of TET2 and inflammatory pathways, aligning well with the pathogenic phenotype of MDS. |