Inheritance

Autosomal dominant

Prevalence

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

Source:

Open

Clinical Validity Points Total

Source:

Clinical Validity Classification

Definitive

Source: ClinGen GCEP (pre-publication)

Although de novo single gene deletions and protein truncating variants in RFX3 had been reported in individuals with developmental delay, intellectual disability (ID), and autism spectrum disorder (ASD) as early as 2011 (PMIDs: 21792059, 27525107, 31981491), the first report focusing on variants in RFX3 in relation to autosomal dominant complex neurodevelopmental disorder was published in 2021 (Harris et al., PMID: 33658631). RFX3 encodes a member of the regulatory factor X (RFX) family of genes that act as master regulators of central nervous system development and ciliogenesis.
Eight unique variants (2 nonsense, 3 frameshift, 1 canonical splice site, 1 multi-exon deletion, and 1 full gene deletion) reported in 8 probands in 4 publications (PMIDs: 25844147, 27525107, 31981491, 33658631) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Most reported variants are de novo, although one family was reported in which an affected parent transmitted a frameshift variant to three affected children (PMID: 33658631); there are also reports of inherited deletions (PMID: 21792059) and protein truncating variants (PMIDs: 25961944, 35982159) in individuals with ASD or ID. The mechanism of disease is suggested to be haploinsufficiency (PMID: 33658631). Three patients with missense or inframe indel variants have also been reported (PMID: 33658631), but were not scored in this curation due to lack of convincing functional data and unclear disease mechanism. RFX3 is highly constrained for both missense (Z = 3.17, gnomAD v4.0.0) and loss-of-function variants (pLI = 1).
There are a limited number of probands with detailed phenotypic features reported. Of those cases, affected individuals present with motor and speech delays, ID, ASD, and behavioral abnormalities; other variable features include attention deficit hyperactivity disorder, dysmorphic features, hypotonia, micro/macrocephaly, seizures, and sleep abnormalities (PMIDs: 25844147, 33658631).
This gene-disease relationship is also supported by experimental evidence demonstrating that individuals with variants in other RFX genes (RFX7 and RFX4) have been reported with global developmental delay, ID and ASD (PMID: 33658631).
In summary, there is definitive evidence supporting the relationship between RFX3 and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 3, 2024 (SOP Version 10).

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

Case ID, Curator name, Date, Jira ticket link