Autism Symptoms in Children and Young Adults With Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex, and Neurofibromatosis Type 1: A Cross-Syndrome Comparison

Kyra Lubbers, Eefje M. Stijl, Bram Dierckx, Doesjka A. Hagenaar, Leontine W. ten Hoopen, Jeroen S. Legerstee, Pieter F.A. de Nijs, André B. Rietman, Kirstin Greaves-Lord, Manon H.J. Hillegers, Gwendolyn C. Dieleman, Sabine E. Mous*, ENCORE Expertise Center for AS

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Objective: The etiology of autism spectrum disorder (ASD) remains unclear, due to genetic heterogeneity and heterogeneity in symptoms across individuals. This study compares ASD symptomatology between monogenetic syndromes with a high ASD prevalence, in order to reveal syndrome specific vulnerabilities and to clarify how genetic variations affect ASD symptom presentation. Methods: We assessed ASD symptom severity in children and young adults (aged 0-28 years) with Fragile X Syndrome (FXS, n = 60), Angelman Syndrome (AS, n = 91), Neurofibromatosis Type 1 (NF1, n = 279) and Tuberous Sclerosis Complex (TSC, n = 110), using the Autism Diagnostic Observation Schedule and Social Responsiveness Scale. Assessments were part of routine clinical care at the ENCORE expertise center in Rotterdam, the Netherlands. First, we compared the syndrome groups on the ASD classification prevalence and ASD severity scores. Then, we compared individuals in our syndrome groups with an ASD classification to a non-syndromic ASD group (nsASD, n = 335), on both ASD severity scores and ASD symptom profiles. Severity scores were compared using MANCOVAs with IQ and gender as covariates. Results: Overall, ASD severity scores were highest for the FXS group and lowest for the NF1 group. Compared to nsASD, individuals with an ASD classification in our syndrome groups showed less problems on the instruments' social domains. We found a relative strength in the AS group on the social cognition, communication and motivation domains and a relative challenge in creativity; a relative strength of the NF1 group on the restricted interests and repetitive behavior scale; and a relative challenge in the FXS and TSC groups on the restricted interests and repetitive behavior domain. Conclusion: The syndrome-specific strengths and challenges we found provide a frame of reference to evaluate an individual's symptoms relative to the larger syndromic population and to guide treatment decisions. Our findings support the need for personalized care and a dimensional, symptom-based diagnostic approach, in contrast to a dichotomous ASD diagnosis used as a prerequisite for access to healthcare services. Similarities in ASD symptom profiles between AS and FXS, and between NF1 and TSC may reflect similarities in their neurobiology. Deep phenotyping studies are required to link neurobiological markers to ASD symptomatology.

Original languageEnglish
Article number852208
JournalFrontiers in Psychiatry
Publication statusPublished - 16 May 2022

Bibliographical note

Funding Information: This research was financially supported by the Sophia Children's Hospital Fund (Rotterdam, Netherlands) under grant numbers S16-14 and B14-02. This research was supported (not financially) by the European Reference Network on Genetic Tumor Risk Syndromes (ERN GENTURIS) – Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme ERN-2016-Framework Partnership Agreement 2017–2021.

Publisher Copyright: Copyright © 2022 Lubbers, Stijl, Dierckx, Hagenaar, ten Hoopen, Legerstee, de Nijs, Rietman, Greaves-Lord, Hillegers, Dieleman, Mous and ENCORE Expertise Center.


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