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

Cathelijne C Linders; Agnies M van Eeghen; Janneke R Zinkstok; Marie-José van den Boogaard; Erik Boot

doi:10.3390/genes14081514

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

Genes (Basel). 2023 Jul 25;14(8):1514. doi: 10.3390/genes14081514.

Authors

Cathelijne C Linders^{1

2}, Agnies M van Eeghen^{1

3}, Janneke R Zinkstok^{4

5

6}, Marie-José van den Boogaard², Erik Boot^{1

7

8}

Affiliations

¹ Advisium, 's Heeren Loo, 3818 LA Amersfoort, The Netherlands.
² Department of Genetics, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.
³ Department of Pediatrics, Emma Children's Hospital, Amsterdam, University Medical Center, 1105 AZ Amsterdam, The Netherlands.
⁴ Department of Psychiatry, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands.
⁵ Karakter Child and Adolescent Psychiatry, 6501 BB Nijmegen, The Netherlands.
⁶ Department of Psychiatry and Brain Center, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
⁷ The Dalglish Family 22q Clinic, University Health Network, Toronto, ON M5G 2C4, Canada.
⁸ Department of Psychiatry & Neuropsychology, Maastricht University, 6200 AB Maastricht, The Netherlands.

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.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Chromosome Structures
Cognition
Humans
Intellectual Disability* / genetics
Phenotype
Problem Behavior*
Smith-Magenis Syndrome* / genetics

Grants and funding

The study was supported financially by the Dutch National Institutes of Health (ZonMw; #845006105). The funding body had no role in the study design, collection, analysis and interpretation of data, nor any role in writing or submitting this paper for publication.