Retinoic Acid-Induced 1 gene variants associated with Smith-Magenis syndrome circadian phenotypes enriched in autism spectrum disorder: whole-genome sequencing study

Background This study aimed to characterize the frequency of RAI1 genetic aberrations associated with Smith-Magenis syndrome (SMS), in a large cohort of autism spectrum disorder (ASD) whole-genome sequencing samples. We aimed to determine the frequencies of RAI1 single-nucleotide variants (SNVs) and copy number variants (CNVs). Results We report a 2.5 x enrichment of the major deletion and a > 5 x enrichment of the frameshift variants as compared to the known prevalence of SMS 1/15,000. Additionally, we report a significant enrichment of RAI1 rare missense variants in ASD subjects with respect to controls (54 variants/6080 ASD subjects and 6 variants/2541 controls, p-value < 0.002, OR 3.78, CI 1.62-8-81). Conclusions The SMS phenotype including circadian dysregulation and associated sleep disturbances is mainly caused by RAI1 haploinsufficiency. Sleep disturbances as seen in SMS may overlap in ASD, especially in patients with consequential variants in RAI1 gene.