Intellectual and Behavioral Phenotypes of Smith-Magenis Syndrome: Comparisons between Individuals with a 17p11.2 Deletion and Pathogenic RAI1 Variant

Abstract

Aim: Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder caused by a 17p11.2 deletion or pathogenic variant in the RAI1 gene. SMS is associated with developmental delay, intellectual disability (ID), and major sleep and behavioral disturbances. To explore how genetic variants may affect intellectual functioning and behavior, we compared intellectual and behavioral phenotypes between individuals with a 17p11.2 deletion and pathogenic RAI1 variant.

Method: We reviewed available clinical records from individuals (aged 0-45 years) with SMS, ascertained through a Dutch multidisciplinary SMS specialty clinic.

Results: We included a total of 66 individuals (n = 47, 71.2% with a 17p11.2 deletion and n = 19, 28.8% with a pathogenic RAI1 variant) for whom data were available on intellectual functioning, severity of ID (n = 53), and behavioral problems assessed with the Child Behavior Checklist (CBCL, n = 39). Median full-scale IQ scores were lower (56.0 vs. 73.5, p = 0.001) and the proportion of individuals with more severe ID was higher (p = 0.01) in the 17p11.2 deletion group. Median total CBCL 6-18 scores (73.5 vs. 66.0, p = 0.02) and scores on the sub-scales somatic complaints (68.0 vs. 57.0, p = 0.001), withdrawn/depressed behavior (69.5 vs. 55.0, p = 0.02), and internalizing behavior (66.0 vs. 55.0, p = 0.002) were higher in the RAI1 group.

Conclusion: The results of this study suggest that 17p11.2 deletions are associated with a lower level of intellectual functioning and less internalizing of problems compared to pathogenic RAI1 variants. The findings of this study may contribute to personalized-management strategies in individuals with SMS.

Keywords: 17p11.2 deletion; Smith–Magenis syndrome; behavioral problems; intellectual disability; pathogenic RAI1 variant; rare disorders.

Figure 1

Full-scale IQ scores of 41 individuals with Smith–Magenis syndrome. Median FSIQ scores were lower in the group of individuals with a 17p11.2 deletion (56.0, range 45–92) compared to individuals with a pathogenic RAI1 variant (73.5, range 50–95, p = 0.001). Horizontal lines indicate median FSIQ scores. FSIQ = full-scale intelligence quotient.

Figure 2

ID severity in 53 individuals with Smith–Magenis syndrome. The dotted line represents a line to divide the individuals with borderline/mild from those with moderate/severe ID. The proportion of individuals with moderate/severe ID was higher in the 17p11.2 deletion group (22 out of 34; 64.7%) than in the group with a pathogenic RAI1 variant (5 out of 19; 26.3%, p = 0.01). ID = intellectual disability.