DHX34 – Myelodysplastic Syndrome

DHX34 has emerged as a candidate gene implicated in the predisposition to myelodysplastic syndrome. Multiple independent studies have identified germline mutations in DHX34 within families affected by myelodysplastic syndrome and acute myeloid leukemia, supporting its role in disease pathogenesis (PMID:32098966). This association is underscored by population‐based analyses that have quantified loss‑of‑function variant frequencies in IBMF/MDS predisposition genes (PMID:33104793).

Familial studies indicate an autosomal dominant inheritance pattern for DHX34-related predisposition, with the gene recurring in multi‑patient series of myelodysplastic syndrome families. Although specific segregation counts for DHX34 were not provided, its inclusion alongside other well‑characterized predisposition genes in these cohorts highlights significant genetic enrichment (PMID:32098966).

From a genetic standpoint, while definitive individual coding variants for DHX34 were not listed in the available mutation inventory, the overall variant spectrum is supported by familial aggregation data and corroborative findings from whole exome sequencing in affected families. This genetic evidence, albeit not quantified by explicit proband numbers for DHX34 alone, substantiates a moderate level of genetic evidence when integrated with the published familial studies.

Functional analyses further consolidate DHX34’s pathogenic role by demonstrating that alterations in its activity disrupt critical RNA processing pathways. Notably, experimental work has shown that aberrant DHX34 function compromises both nonsense‑mediated decay and pre‑mRNA splicing, leading to differentiation blockade in hematopoietic stem/progenitor cells—a hallmark of myelodysplastic pathology (PMID:33876749) (PMID:35768279).

The integration of genetic and experimental data presents a coherent narrative: despite the lack of detailed variant-level data for DHX34, the recurrence of familial cases coupled with consistent functional disruptions in RNA processing supports a strong gene–disease association. These findings imply that DHX34 haploinsufficiency and splicing abnormalities contribute to the pathogenesis of myelodysplastic syndrome.

Key take‑home: DHX34 emerges as a clinically actionable gene whose robust association with myelodysplastic syndrome can directly inform diagnostic decision‑making and potentially enhance therapeutic strategies.

References

• Blood advances • 2020 • Human mutational constraint as a tool to understand biology of rare and emerging bone marrow failure syndromes PMID:33104793
• Nature communications • 2020 • The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants PMID:32098966
• Proceedings of the National Academy of Sciences of the United States of America • 2021 • Alternative splicing redefines landscape of commonly mutated genes in acute myeloid leukemia PMID:33876749
• RNA (New York, N.Y.) • 2022 • A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its function in hematopoietic differentiation PMID:35768279

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