Submission Details

RAI1 was first reported in relation to autosomal dominant Smith-Magenis syndrome in 2003 (Slager et al., PMID: 12652298). A microdeletion overlapping multiple genes in chromosome 17p11.2 was first identified in individuals with Smith-Magenis syndrome, and subsequent studies indicated that haploinsufficiency of RAI1 within the deleted region is responsible for most of the clinical manifestations. Affected individuals exhibit intellectual disability, delayed speech, dysmorphic facial features, sleep disturbances, and behavioral disorders, including autism.

Nine variants (missense, nonsense, and frameshift) that have been reported in nine probands in four publications (PMIDs: 15565467, 15788730, 17041942, 12652298) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. To date, 32 unique variants within RAI1 have been classified as pathogenic in ClinVar. The mechanism of pathogenicity is known to be loss of function.

This gene-disease relationship is also supported by mouse models and patient-derived cells. The experimental evidence collectively shows that RAI1 is critical for cognitive function (intellectual disability), craniofacial development (dysmorphic facial features), energy homeostasis (obesity), and circadian rhythm (sleep disturbances).

In summary, there is definitive evidence supporting the relationship between RAI1 and autosomal dominant Smith-Magenis syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 5, 2018 (SOP Version 5).

The RAI1 gene has been associated with Smith-Magenis syndrome using the ClinGen Validity Framework as of 9/3/2018. The affected individuals show intellectual disability, delayed speech, dysmorphic facial features, sleep disturbances, and behavioral problems. This disease association was made using case-level data and experimental data. At least 9 variants (missense, nonsense, and frameshift) were curated from four publications (PMID: 15565467, 17041942, 15788730, and 12652298). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. While a micro-deletion in short arm of chromosome 17 was first identified in individuals with Smith-Magenis syndrome, subsequent studies indicated that haploinsufficiency of RAI1 within the deletion region is responsible for most of the clinical manifestations. To date, 32 unique variants within RAI1 have been classified as Pathogenic in ClinVar. The gene-disease association is supported by mouse models and patient-derived cells. The experimental evidence collectively shows that RAI1 is critical for cognitive function (intellectual disability), craniofacial development (dysmorphic facial features), energy homeostasis (obesity), and circadian rhythm (sleep disturbances). In summary, RAI1 is definitively associated with Smith-Magenis syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.