Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
ARF3 encodes a small GTPase of the ADP-ribosylation factor family, regulating Golgi dynamics and vesicular trafficking. Disruption of Golgi function during neurodevelopment can lead to a spectrum of brain malformations known as Golgipathies. Rare de novo missense variants in ARF3 have been implicated in an autosomal dominant neurodevelopmental disorder characterized by global developmental delay, microcephaly, epilepsy and characteristic brainstem malformations.
To date, three unrelated individuals have been reported: two children with de novo variants c.200A>T (p.Asp67Val) and c.296C>T (p.Arg99Leu) in a multi-patient study (PMID:34346499), and a third patient with c.200A>T (p.Asp67Val) in a recent case report (PMID:38712921). All patients presented with global developmental delay (HP:0001263), acquired microcephaly, drug-resistant epilepsy, white matter reduction, corpus callosum thinning and a Z-shaped brainstem morphology.
The variant spectrum is currently limited to missense substitutions affecting conserved switch regions of the GTP-binding pocket. The recurrent c.200A>T (p.Asp67Val) allele has been observed in two unrelated patients (PMID:34346499; PMID:38712921). All cases are confirmed de novo, consistent with an autosomal dominant mechanism; no familial segregation has been reported.
Functional studies provide concordant evidence for a dominant-negative and gain-of-function effect. In vitro assays demonstrate that p.Asp67Val disrupts Golgi localization and abolishes GTP-dependent effector binding, mimicking the dominant-negative p.Thr31Asn (PMID:34346499). In vivo modeling in zebrafish shows that ARF3 variants perturb neural precursor proliferation and planar cell polarity, recapitulating microcephaly and brain malformations (PMID:36369169). Fly transgenesis further confirms allele-specific effects: p.Asp67Val causes lethality, whereas p.Arg99Leu yields a rough eye phenotype.
Integration of genetic and experimental data establishes ARF3 as a key regulator of Golgi homeostasis in neural development. The tight correlation between variant-induced Golgi disruption and human phenotype supports a mechanism involving impaired vesicle biogenesis and trafficking. ARF3-associated neurodevelopmental disorder extends the spectrum of Golgipathies and underscores the utility of cellular and animal models in validating pathogenicity.
Collectively, current evidence supports a Moderate clinical validity classification for the ARF3–neurodevelopmental disorder association. ARF3 variant testing should be considered in patients with unexplained global developmental delay, acquired microcephaly and characteristic brainstem anomalies.
Key Take-home: De novo missense variants in ARF3 disrupt Golgi integrity, causing an autosomal dominant neurodevelopmental disorder amenable to molecular diagnosis.
Gene–Disease AssociationModerateThree unrelated probands with de novo ARF3 variants and concordant functional data in zebrafish and cellular models Genetic EvidenceModerateThree de novo missense variants in unrelated probands (two in [PMID:34346499]; one in [PMID:38712921]) Functional EvidenceModerateAllele-specific in vitro assays demonstrating Golgi disruption and in vivo modeling in zebrafish and Drosophila |