Although a de novo protein truncating variant in RFX7 was reported in an individual with autism spectrum disorder (ASD) as early as 2014 (PMID: 25363760), the first report focusing on variants in RFX7 in relation to autosomal dominant complex neurodevelopmental disorder was published in 2021 (Harris et al., PMID: 33658631). RFX7 encodes a member of the regulatory factor X (RFX) family of genes that act as master regulators of central nervous system development and ciliogenesis.
Seven unique de novo variants (3 nonsense, 4 frameshift) reported in 7 probands in 2 publications (PMIDs: 25363760, 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. All reported variants are de novo, and the mechanism of disease is suggested to be haploinsufficiency (PMID: 33658631). RFX7 is highly constrained for loss-of-function variants (pLI = 1), but not missense variants (Z = 2.02, gnomAD v4.1.0).
There are a limited number of probands with detailed phenotypic features reported. Of those cases, affected individuals present with motor and speech delays, and intellectual disability; other variable features include ASD, attention deficit hyperactivity disorder, behavioral abnormalities, dysmorphic features, micro/macrocephaly, and sensory hypersensitivity (PMID: 33658631).
This gene-disease relationship is also supported by experimental evidence demonstrating that individuals with variants in other RFX genes (RFX3 and RFX4) have been reported with global developmental delay, intellectual disability and ASD (PMID: 33658631).
In summary, there is definitive evidence supporting the relationship between RFX7 and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 15, 2024 (SOP Version 11).
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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