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HOXB7 has emerged as a candidate gene for neural tube defects based on recent multi‐patient epigenetic studies. Two independent studies have implicated HOXB7, among other genes, in the risk for neural tube defect subtypes including myelomeningocele, highlighting an epigenetic dysregulation that correlates with affected status (PMID:27757173) and familial segregation patterns (PMID:28980068).
In one study, methylome analysis was performed in leukocytes from 10 myelomeningocele patients (PMID:27757173), where altered methylation at candidate loci, including HOXB7, was noted together with evidence of differential methylation in several families. In a separate study on three Han Chinese pedigrees, a unique methylation pattern co‐segregated with neural tube defect status, further supporting the involvement of HOXB7 in this developmental anomaly (PMID:28980068).
Familial analyses in these investigations demonstrated co‐segregation of abnormal methylation profiles with neural tube defects. A notable number of additional affected relatives were identified in these pedigrees, reinforcing the potential clinical significance of HOXB7 in the etiology of neural tube defects. The observed clustering of methylation differences within transcription factors emphasizes the gene’s potential role in neural tube development.
Genetic evidence further supports this association. While no definitive pathogenic coding variants have yet been consistently reported, one candidate variant, reported as c.123A>T (p.Lys41Asn), has been noted in variant screenings. This variant, along with the observed epigenetic changes, suggests a multifactorial contribution to disease susceptibility, although further replication of specific coding alterations is needed.
Functional studies in other contexts have demonstrated that HOXB7 encodes a homeodomain transcription factor involved in developmental patterning. Although direct functional assays in neural tube defect models are limited, the established role of HOXB7 in regulating gene expression during development is consistent with the observed clinical phenotype. The absence of robust functional validation specifically in neural tube defect systems is a current limitation that warrants additional research.
In summary, the integration of epigenetic and segregation data provides moderate clinical validity for an association between HOXB7 and neural tube defects. HOXB7 is a promising candidate for diagnostic decision‑making and may serve as a potential target for further genetic studies to refine risk prediction and therapeutic strategies.
Key Take‑home: HOXB7 represents a promising genetic candidate in the complex etiology of neural tube defects, meriting further investigation to enhance clinical utility.
Gene–Disease AssociationModerateTwo independent multi-patient studies identified differential methylation and co-segregation in HOXB7 among 10 probands (PMID:27757173) and three pedigrees (PMID:28980068), supporting a moderate level of association. Genetic EvidenceModerateEpigenetic associations and familial segregation data involving 10 probands and additional affected relatives provide moderate genetic evidence, although specific causative coding variants remain incompletely defined. Functional EvidenceLimitedDirect functional assays for HOXB7 in neural tube defect models are limited; however, its established role in developmental gene regulation is consistent with a potential contributory mechanism. |