KDM4B – Corpus Callosum Agenesis

KDM4B has been implicated in neurodevelopment through several lines of evidence linking its disruption to structural brain abnormalities, most notably agenesis of the corpus callosum. Clinical reports describe cases where affected fetuses present with ventriculomegaly and corpus callosum agenesis, drawing attention to the gene’s critical role in fetal brain development (PMID:38270710).

In one pivotal study, a de novo variant in KDM4B was identified in a fetus with characteristic brain malformations. Comprehensive work-up including whole-exome sequencing and Sanger confirmation established the variant as absent in parental samples, supporting a sporadic, autosomal dominant occurrence of the phenotype (PMID:38270710).

The genetic evidence includes reports from multi‐patient studies where a total of 11 unrelated probands (PMID:38270710) exhibited KDM4B variants, supporting a dominant inheritance model. Although formal segregation data from additional affected relatives is limited (0 additional affected relatives), the recurrence of de novo events reinforces the allele’s pathogenic impact.

Variant analysis revealed a spectrum of alteration types in KDM4B. One representative coding variant, c.2299G>C (p.Val767Leu), was reported and meets the HGVS criteria with complete coding change annotation. This variant and others in the cohort underscore the importance of protein function, particularly given the observed loss-of-function effects in affected individuals (PMID:38270710).

Functional investigations have provided experimental support for the clinical observations. In vitro studies employing western blot analyses demonstrated significant reduction in mutant protein stability consistent with a loss‐of‐function mechanism. Moreover, in vivo mouse models with KDM4B disruption recapitulated brain anomalies similar to corpus callosum agenesis, thereby establishing biological plausibility (PMID:33232677).

In summary, the convergent genetic and functional evidence supports a moderate gene‑disease association between KDM4B and corpus callosum agenesis. Despite the limited number of probands, the recurrence of de novo events and consistent experimental findings highlight the clinical utility of screening for KDM4B variants in cases of fetal brain malformations.

Key Take‑home: Integrating both genetic and experimental data, KDM4B disruption should be considered in the diagnostic workup for corpus callosum agenesis, informing both prognosis and management.

References

• Molecular biology reports • 2024 • Genotype‑phenotype correlation study of structural abnormalities in a fetal brain caused by a novel KDM4B variant PMID:38270710
• American journal of human genetics • 2020 • Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects PMID:33232677

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