RFX3 – Autism Spectrum Disorder

Autosomal dominant de novo loss-of-function variants in RFX3 have been identified in individuals with ASD. In a cohort of 38 affected individuals from 33 unrelated families, three independent de novo predicted loss-of-function alleles (c.628C>T (p.Arg210Ter), c.584_586del (p.Glu195del), c.1486_1487del (p.Leu496fs)) in RFX3 were reported in unrelated probands (PMID:33658631).

Affected individuals commonly present with autistic behavior often accompanied by intellectual disability (HP:0001249) and attention-deficit/hyperactivity disorder (HP:0007018), as well as sensory hypersensitivity and sleep disturbances (PMID:33658631).

Functional studies in Rfx3-deficient mice demonstrate corpus callosum agenesis due to disrupted guidepost neuron distribution and aberrant Fgf8 expression downstream of altered Gli3 repressor–activator balance, recapitulating key ciliopathy features (PMID:22479201). In human iPSC-derived neurons, heterozygous RFX3 loss impairs activity-dependent gene expression by reducing CREB binding at synaptic target loci, linking RFX3 haploinsufficiency to synaptic development deficits (PMID:40060598).

Collectively, the genetic and experimental data support haploinsufficiency as the primary mechanism whereby de novo RFX3 variants confer ASD risk, with concordant phenotypes across species and model systems.

No reports of conflicting evidence or alternative phenotypes have been documented, underscoring a consistent association between RFX3 haploinsufficiency and ASD.

Key take-home: RFX3 should be considered in genetic testing for ASD, particularly in cases with co-occurring neurodevelopmental anomalies, to inform diagnosis and potential tailored interventions.

References

• PLoS genetics • 2012 • The ciliogenic transcription factor RFX3 regulates early midline distribution of guidepost neurons required for corpus callosum development PMID:22479201
• bioRxiv • 2025 • Multi-omic analysis of the ciliogenic transcription factor RFX3 reveals a role in promoting activity-dependent responses via enhancing CREB binding in human neurons PMID:40060598
• Unknown Journal • Unknown Year • Title Unavailable PMID:33658631

Evidence Based Scoring (AI generated)