ARFGEF2 was first reported in connection to autosomal recessive periventricular heterotopia with microcephaly in 2004 (Sheen et al., 2004 PMID:14647276). Common phenotypes for individuals with ARFGEF2 - periventricular heterotopia with microcephaly include progressive microcephaly, severe GDD/ID, hypotonia, spasticity, hyperkinetic movement disorder, epilepsy, failure to thrive, cardiomyopathy, corpus callosum thinning, and putamen T2 hyperintensity/atrophy.
Nine unique variants of different types (3 frameshift, 2 missense, 2 nonsense, 1 canonical splice site) reported in seven probands have been included in this curation (PMID:14647276, 19384555, 23755938, 23812912, 25160555, 26126837). The presumed mechanism is loss of function. The maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is further supported by functional alteration, protein interaction, and expression data (PMID:16320251, 14647276).
In summary, there is definitive evidence to support the relationship between ARFGEF2 and autosomal recessive periventricular heterotopia with microcephaly. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Brain Malformations expert panel on 09/12/2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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