Neuropsychiatric Phenotypes in 3q29 Deletion Syndrome and Novel Features of ASD: Results from the 3q29 Registry

Background: 3q29 deletion syndrome (3q29Del) is a rare (~1:30,000) genomic disorder characterized by a 1.6 Mb heterozygous deletion on chromosome 3. It is associated with a wide range of neurodevelopmental and neuropsychiatric disorders, as well as growth deficits, feeding problems, and congenital heart defects. Notably, the 3q29 deletion confers a 30-fold increased risk for Autism Spectrum Disorder (ASD), a 40-fold increased risk for schizophrenia, and a significantly increased risk for intellectual disability and generalized anxiety disorder.

Objectives: The aim of this study is to describe the spectrum of ASD-related features in the largest 3q29Del patient cohort ever assembled.

Methods: We used Emory University’s 3q29Del registry (3q29deletion.org) to obtain self-report data on 3q29Del patients and typically developing controls, including a custom medical and demographic questionnaire (n=94 3q29Del, 58.5% male, mean age=12.7 years; n=64 control, 51.6% male, mean age=10.6 years); Achenbach Behavior Checklists (CBCL/ABCL, n=48 3q29Del, 57 control); Social Responsiveness Scale (SRS, n=48 3q29Del, 59 control); and the Social Communication Questionnaire (SCQ, n=33 3q29Del, 46 control). Statistical testing and data visualization were performed in R.

Results: Self-reported ASD diagnosis in 3q29Del participants was significantly inflated versus the general population (30.7% vs. 1.47%, p<2.2e-16). The male:female ratio of self-reported ASD diagnosis in 3q29Del is 1.8:1, strikingly different from the 4:1 ratio. Additionally, some participants that do not report an ASD diagnosis scored in the clinical range on all self-report scales, and mean scores for all participants were elevated (mean SRS T-score=71.75; mean SCQ score=13.88; mean CBCL/ABCL T-score=62.5), indicating substantial behavioral impairment in the absence of a clinical diagnosis. Finally, 3q29Del individuals showed a novel constellation of ASD features on the SRS, with elevated mean scores on 5 of the 6 subscales (Social Awareness, Social Cognition, Social Communication, Social Communication and Interaction, and Restricted Interests and Repetitive Behaviors). The mean score for Social Motivation, however, was in the mild range (Figure 1), which is dramatically different from the profile observed in idiopathic ASD.

Conclusions: These results showed that the 3q29Del population is significantly enriched for ASD diagnosis and ASD features measured via standardized ASD surveys; however, several individuals scored in the clinical range on all scales, despite reporting no diagnosis of ASD. This implies that either ASD is underdiagnosed or not adequately assessed in 3q29Del patients, or additional psychopathology is present that may be independently elevating scores. Additionally, we find that potential confounders such as self-reported ID diagnosis are not driving the increase in scores for 3q29Del participants, indicating that the 3q29 deletion itself is the major risk factor for this impaired behavioral profile. Moreover, a unique pattern of ASD symptomatology was observed, with social motivation being relatively less impaired than other areas of social functioning; this profile is qualitatively different from what is observed in idiopathic ASD. These findings have implications for standard of care recommendations for individuals diagnosed with 3q29Del; they also suggest that 3q29Del could serve as an investigative inroad to a novel subtype of ASD.