Thomas et al., 2021 identified 13 individuals with both de novo and inherited likely pathogenic heterozygous variants in the ARFGEF1 gene; affected individuals typically presented with developmental delay, intellectual disability, and behavioral problems (including autism spectrum disorder in three individuals), with approximately half of this cohort also presenting with neurological features, abnormal brain MRI findings, and epilepsy. Private likely gene-disruptive (LGD) variants that were exclusively transmitted to ASD probands in two independent families were observed in this highly constrained (pLI 0.99) gene in Wilfert et al., 2021; one of these families consisted of a multiplex family from the iHART cohort originally described in Ruzzo et al., 2019 in which a maternally-inherited frameshift variant in ARFGEF1 was transmitted to both ASD-affected siblings.
Molecular Function
ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP. It contains a Sec7 domain, which may be responsible for guanine-nucleotide exchange activity and also brefeldin A inhibition.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity
