Distinct Neuropsychiatric Profiles Associated With 17p11.2 Deletions and RAI1 Variants in Smith-Magenis Syndrome

Smith-Magenis syndrome (SMS) results from either a recurrent 17p11.2 deletion or pathogenic variants in the retinoic acid induced 1 gene (RAI1). While neurodevelopmental impairment and behavioral dysregulation are well recognized, systematic genotype-stratified analyses across psychiatric domains remain limited. We conducted a retrospective genotype-stratified study of 52 individuals with molecularly confirmed SMS (43 with 17p11.2 deletions; 9 with pathogenic RAI1 variants) evaluated at the French national coordinating Reference Center for Rare Diseases specializing in psychiatric manifestations (CRMR GénoPsy, Lyon, France). Standardized neurodevelopmental and psychiatric data were extracted and compared using Fisher's exact tests. Intellectual disability was observed in 37/43 deletion carriers (86.0%) and in none of the individuals with RAI1 variants (0/9; OR = 109.6, 95% CI [5.66-2122.3], p = 1.3 × 10^-6). Extended deletions were associated with maximal severity. Deletion carriers also exhibited prominent externalizing dysregulation, including self-injurious behavior (34/43 vs. 5/9) and hetero-aggressiveness (28/43 vs. 4/9). Dystonia was observed in 5/43 deletion carriers (11.6%), including 2/2 individuals with extended deletions, and in 0/9 individuals with RAI1 variants (p = 0.573; OR = 3.09; 95% CI [0.16-60.6]; Haldane correction). In contrast, RAI1 variants demonstrated relative cognitive preservation, with some individuals achieving normal-range IQ, but showed increased internalizing vulnerability, including anxiety (5/9 [55.6%] vs. 5/43 [11.6%]; OR = 0.11, 95% CI [0.02-0.53], p = 0.008) and social withdrawal (4/9 [44.4%] vs. 4/43 [9.3%]; OR = 0.13, 95% CI [0.02-0.68], p = 0.023). Across genotypes, ADHD and sleep-circadian disturbances were highly prevalent. This study refines genotype-phenotype correlations in SMS by delineating two partially divergent neuropsychiatric trajectories. 17p11.2 deletions are associated with pronounced developmental burden and externalizing dysregulation, whereas RAI1 variants are characterized by relatively preserved cognition and heightened internalizing vulnerability. Shared ADHD and sleep-circadian disturbances highlight cross-genotypic targets for genotype-informed clinical management.