Characterization of autism spectrum disorder and neurodevelopmental profiles in youth with XYY syndrome

Lisa Joseph, Cristan Farmer, Colby Chlebowski, Laura Henry, Ari Fish, Catherine Mankiw, Anastasia Xenophontos, Liv Clasen, Bethany Sauls, Jakob Seidlitz, Jonathan Blumenthal, Erin Torres, Audrey Thurm, Armin Raznahan, Lisa Joseph, Cristan Farmer, Colby Chlebowski, Laura Henry, Ari Fish, Catherine Mankiw, Anastasia Xenophontos, Liv Clasen, Bethany Sauls, Jakob Seidlitz, Jonathan Blumenthal, Erin Torres, Audrey Thurm, Armin Raznahan

Abstract

Background: XYY syndrome is a sex chromosome aneuploidy that occurs in ~ 1/850 male births and is associated with increased risk for neurodevelopmental difficulties. However, the profile of neurodevelopmental impairments, including symptoms of autism spectrum disorder (ASD) in XYY remains poorly understood. This gap in knowledge has persisted in part due to lack of access to patient cohorts with dense and homogeneous phenotypic data.

Methods: We evaluated a single-center cohort of 64 individuals with XYY aged 5-25 years, using a standardized battery of cognitive and behavioral assessments spanning developmental milestones, IQ, adaptive behavior, academic achievement, behavioral problems, and gold-standard diagnostic instruments for ASD. Our goals were to (i) detail the neurodevelopmental profile of XYY with a focus on ASD diagnostic rates and symptom profiles, (ii) screen phenotypes for potential ascertainment bias effects by contrasting pre- vs. postnatally diagnosed XYY subgroups, and (iii) define major modules of phenotypic variation using graph-theoretical analysis.

Results: Although there was marked inter-individual variability, the average profile was characterized by some degree of developmental delay, and decreased IQ and adaptive behavior. Impairments were most pronounced for language and socio-communicative functioning. The rate of ASD was 14%, and these individuals exhibited autism symptom profiles resembling those observed in ASD without XYY. Most neurodevelopmental dimensions showed milder impairment among pre- vs. postnatally diagnosed individuals, with clinically meaningful differences in verbal IQ. Feature network analysis revealed three reliably separable modules comprising (i) cognition and academic achievement, (ii) broad domain psychopathology and adaptive behavior, and (iii) ASD-related features.

Conclusions: By adding granularity to our understanding of neurodevelopmental difficulties in XYY, these findings assist targeted clinical assessment of newly identified cases, motivate greater provision of specialized multidisciplinary support, and inform future efforts to integrate behavioral phenotypes in XYY with neurobiology.

Trial registrations: ClinicalTrials.gov NCT00001246 , "89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls."

Keywords: Adaptive behavior; Autism spectrum disorder symptoms; Cognitive functioning; Learning disabilities; Sex chromosome aneuploidies.

Conflict of interest statement

Ethics approval and consent to participate

Informed consent and assent was obtained from all participants and their parents; all study procedures were approved by a National Institutes of Health Institutional Review Board.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Phenotypic profiles. a All differences from the population mean of 100 are statistically significant, p < .0001. b Milestones. Two participants with extreme continence data (> 140 months) are not represented. c Neurodevelopmental phenotype
Fig. 2
Fig. 2
Phenotypic profiles of XYY participants younger than 18 years (n = 49). aZ normalized scores for each participant in the XYY sample (Y axis), using the means and standard deviations from the Simons Simplex Collection (SSC). b Boxplots of Z normalized scores by diagnostic status. cp values for pairwise comparisons
Fig. 3
Fig. 3
Network representation of phenotypic modules in XYY (N = 64). Nodes are phenotypic variables; color distinguishes reproducible clusters: cognitive ability/academic achievement (blue), adaptive functioning/psychopathology (yellow), and ASD-related features (green). Size indices the mean pairwise correlation between the variable and all others. Thicker edges show increased consistency of co-clustering based on bootstrapped analysis. The force-directed Fruchterman-Reingold Algorithm was used, such that further distance between nodes indicates weaker inter-relationships

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