A de novo damaging missense variant and an inherited loss-of-function variant in the RFX3 gene were identified in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (De Rubeis et al., 2014; Krumm et al., 2015). A de novo loss-of-function variant and an inherited damaging missense variant in RFX3 were identified in Chinese ASD probands in Guo et al., 2017. Subsequent Transmission and De Novo Association (TADA) analysis in Guo et al., 2017 identified RFX3 as an ASD candidate gene, with a PTADA of 0.002128 in the Chinese ASD case-control cohort and a PTADA of 0.007677 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. A de novo deletion affecting exons 2-4 of the RFX3 gene has also been identified in a 13-year-old female patient presenting with a diagnosis of autism (Tabet et al., 2015). Deletion of Rfx3 in mice resulted in defects in right-left symmetry, malformation of the corpus callosum, and hydrocephalus (Magnani et al., 2015). Additional de novo loss-of-function and missense variants in this gene have since been identified in ASD probands from the SPARK cohort, the MSSNG cohort, and the Autism Sequencing Consortium (Feliciano et al., 2019; Satterstrom et al., 2020; Zhou et al., 2022); a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified RFX3 as a gene reaching study-wise significance based on 5,754 constraint genes (P < 8.69E-06).
Molecular Function
This gene is a member of the regulatory factor X gene family, which encodes transcription factors that contain a highly-conserved winged helix DNA binding domain. The protein encoded by this gene is structurally related to regulatory factors X1, X2, X4, and X5. It is a transcriptional activator that can bind DNA as a monomer or as a heterodimer with other RFX family members.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Synaptic, transcriptional and chromatin genes disrupted in autism.
Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior