ARF1 – Periventricular Nodular Heterotopia

ARF1 has been implicated in periventricular nodular heterotopia through both single‐patient and multi‑patient studies. In a recent case report, a girl with intellectual disability and periventricular nodular heterotopia inherited an ARF1 variant from her father, who also showed a subtle nodular phenotype (PMID:34353862). This study provided initial evidence that haploinsufficiency of ARF1 can lead to abnormal neuronal migration. The clinical findings, including features of hypohidrotic ectodermal dysplasia in some cases, underscore a variable expressivity in affected individuals.

A subsequent international multi‑patient study further expanded the phenotypic spectrum associated with ARF1 variants. In this cohort of 17 unrelated individuals, de novo variants—including missense, frameshift, and splice‐altering events—were identified, with detailed phenotypic characterization noting intellectual disability, microcephaly, seizures, and microretrognathia (PMID:37185208). Familial segregation observed in the case report and consistent findings in this cohort lend strong support to an autosomal dominant inheritance pattern.

Genetic evidence is robust for ARF1 in this neurological disorder. Variants spanning several types have been reported, and one representative variant, converted to HGVS nomenclature, is included here: c.196T>C (p.Trp66Arg). The identification of such variants in 2 probands from the case report (PMID:34353862) together with 17 probands from a larger cohort (PMID:37185208) underscores the gene’s involvement in disease pathogenesis.

Functional studies corroborate the genetic data by demonstrating ARF1’s critical role in membrane trafficking and vesicle formation. Experimental evidence indicates that disruption of ARF1 function leads to vesiculation of the Golgi apparatus and impaired protein secretion, both of which are essential for proper neuronal migration (PMID:8294513; PMID:7961931). These studies, performed in vitro using mutant alleles, are concordant with the clinical phenotypes observed in affected individuals.

While variable clinical expressivity has been noted, particularly with overlapping ectodermal features, there remains no strong opposing evidence to weaken the association between ARF1 variants and periventricular nodular heterotopia. The convergence of data from both familial and cohort studies, together with supportive functional assays, builds a compelling case for ARF1’s role in the etiology of this neurodevelopmental disorder.

Both the genetic and experimental evidence support a strong association between ARF1 and periventricular nodular heterotopia. This integration of clinical and mechanistic data makes the association highly useful for diagnostic decision‑making, commercial applications, and future publication.

Key Take‑home sentence: The multi‑faceted evidence confirming ARF1 haploinsufficiency underlies a distinct neurodevelopmental disorder, positioning ARF1 as an essential diagnostic marker in periventricular nodular heterotopia.

References

• Journal of Medical Genetics • 2022 • ARF1 haploinsufficiency causes periventricular nodular heterotopia with variable clinical expressivity PMID:34353862
• Unspecified Journal • 2023 • Comprehensive clinical and molecular characterisation of ARF1-related neurodevelopmental disorder PMID:37185208
• The Journal of Cell Biology • 1994 • Expression of a dominant allele of human ARF1 inhibits membrane traffic in vivo PMID:8294513
• The Journal of Biological Chemistry • 1994 • The amino terminus of ADP-ribosylation factor (ARF) 1 is essential for interaction with Gs and ARF GTPase-activating protein PMID:7961931

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