0035 Enrichment of RAI1 genetic aberrations associated with sleep disturbances in SMS, in Autism Spectrum Disorder

Abstract

Abstract Introduction Autism Spectrum Disorder (ASD) comprises a complex of neurodevelopmental disorders primarily characterized by deficits in verbal communication, impaired social interactions and repetitive behaviors. The profound clinical heterogeneity of ASD poses challenges in diagnosis and treatment. Genetic studies have pointed to hundreds of presumptive causative or susceptibility variants in ASD, making it difficult to find common underlying pathogenic mechanisms and suggesting that multiple different genetic etiologies for ASDs influence a continuum of traits. Smith–Magenis syndrome is a rare genetic disorder that results from an interstitial deletion of 17p11.2 and, in rare cases, from a retinoic acid induced 1 (RAI1) gene variant. The prevalence is estimated to be 1/15,000–25,000. Haploinsufficiency of RAI1 is the primary cause of the neurobehavioral and metabolic phenotype in SMS. Individuals with SMS present with a distinct pattern of mild to moderate intellectual disability, delayed speech and language skills, distinctive craniofacial and skeletal abnormalities, behavioral disturbances, and, almost uniformly, significant sleep disturbances. Alterations in RAI1 copy number has been also linked to a number of neurodevelopmental disorders including ASD. Methods We conducted a large-scale association analysis of the ASD MSSNG whole genome sequencing data to elucidate the prevalence of RAI1 SNVs and CNVs in the ASD population. We accessed the MSSNG database hosting over 11,000 genomes (6080 probands) and queried both SNVs and CNVs. Results Specifically, we focused on the prevalence of the classic deletions, microdeletions of (exon 3) and of the causative variants. We report a single case of a classic deletion (17p11.2 critical region), and an additional 3 cases of microdeletions in exon 3. Moreover, we report 2 frameshift mutations and one splicing variant. Given that the frequency of SMS is 1 in 15000 in the general population, we observe a 2.5x enrichment of the major deletion (1 in 6080 samples) and a >5x enrichment of the frameshift variants (2 in 6080 samples). In a set of 6080 probands we also observed 54 unique missense variants in 84 individuals within exon 3 of RAI1 gene. Conclusion Both ASD patients and SMS patients suffer from sleep disturbances. In this population of individuals with ASD, we report here an enrichment of variants known to cause SMS. We estimate the enrichment to be at least 2.5-fold and potentially higher than 10-fold enrichment, considering the types of variants observed in the population. Currently, the prevailing theory is that there is an underlying circadian pathophysiology causing sleep disturbances in SMS associated with RAI1 haploinsufficiency, as these patients exhibit low overall melatonin concentrations and abnormal timing of peak plasma melatonin concentrations. This abnormal inverted circadian rhythm is estimated to occur in 95% of individuals with SMS. The sleep disturbance seen in individuals with SMS may be also the underlying mechanism in at least a subset of individuals with ASD, especially in those individuals with consequential variants in the RAI1 gene Further studies will help delineate the role of RAI1 variants in sleep physiology. Support (If Any)