Neuropsychiatric phenotypes and a distinct constellation of ASD features in 3q29 deletion syndrome: results from the 3q29 registry

Abstract

Background: The 1.6 Mb 3q29 deletion is associated with neurodevelopmental and psychiatric phenotypes, including increased risk for autism spectrum disorder (ASD) and a 20 to 40-fold increased risk for schizophrenia. However, the phenotypic spectrum of the deletion, particularly with respect to ASD, remains poorly described.

Methods: We ascertained individuals with 3q29 deletion syndrome (3q29Del, "cases," n = 93, 58.1% male) and typically developing controls (n = 64, 51.6% male) through the 3q29 registry (https://3q29deletion.patientcrossroads.org). Self-report of neuropsychiatric illness was evaluated for 93 cases. Subsets of participants were evaluated with the Social Responsiveness Scale (SRS, n = 48 cases, 56 controls), Social Communication Questionnaire (n = 33 cases, 46 controls), Autism Spectrum Screening Questionnaire (n = 24 cases, 35 controls), and Achenbach Behavior Checklists (n = 48 cases, 57 controls).

Results: 3q29Del cases report a higher prevalence of autism diagnoses versus the general population (29.0% vs. 1.47%, p < 2.2E- 16). Notably, 3q29 deletion confers a greater influence on risk for ASD in females (OR = 41.8, p = 4.78E- 05) than in males (OR = 24.6, p = 6.06E- 09); this is aligned with the reduced male:female bias from 4:1 in the general population to 2:1 in our study sample. Although 71% of cases do not report a diagnosis of ASD, there is evidence of significant social disability (3q29Del SRS T-score = 71.8, control SRS T-score = 45.9, p = 2.16E- 13). Cases also report increased frequency of generalized anxiety disorder compared to controls (28.0% vs. 6.2%, p = 0.001), which is mirrored by elevated mean scores on the Achenbach diagnostic and statistical manual-oriented sub-scales (p < 0.001). Finally, cases show a distinct constellation of ASD features on the SRS as compared to idiopathic ASD, with substantially elevated Restricted Interests and Repetitive Behaviors, but only mild impairment in Social Motivation.

Conclusions: Our sample of 3q29Del is significantly enriched for ASD diagnosis, especially among females, and features of autism may be present even when an ASD diagnosis is not reported. Further, the constellation of ASD features in this population is distinct from idiopathic ASD, with substantially less impaired social motivation. Our study implies that ASD evaluation should be the standard of care for individuals with 3q29Del. From a research perspective, the distinct ASD subtype present in 3q29Del is an ideal entry point for expanding understanding of ASD.

Keywords: 3q29 deletion; Autism; Copy number variants; Developmental delay; Genomic disorder; Psychiatric genetics; SRS.

Fig. 1

Score distribution for 3q29Del and controls on the SRS, SCQ, ASSQ, and CBCL/ABCL. Total scores on the SRS (n = 48 3q29Del, 56 control), SCQ (n = 33 3q29Del, 46 control), ASSQ (n = 24 3q29Del, 35 control), and CBCL/ABCL (n = 48 3q29Del, 57 control) for registry participants. Self-reported diagnosis of ASD is denoted by shape (circle/ASD, triangle/no ASD), and sex of participant is denoted by color (red/female, blue/male). Controls are shown in black

Fig. 2

Comparison of ASD prevalence and SRS scores between 3q29Del and controls. a Proportion of participants with 3q29Del self-reporting a diagnosis of ASD (not all respondents completed symptom questionnaires); 27 cases report an ASD diagnosis (green), comprised of 20 males (blue) and 7 females (red). Compared to general population frequencies (black), cases report significantly higher incidence of ASD. b SRS scores split by control (n = 59), 3q29Del not reporting an ASD diagnosis (n = 31), and 3q29Del reporting an ASD diagnosis (n = 17), showing a significant association between self-reported diagnostic status and SRS score. c SRS scores split by sex, with control (n = 59), 3q29Del female (n = 22), and 3q29Del male (n = 26), showing a lack of sex bias in scores for 3q29Del participants. d SRS scores split by sex and self-reported diagnostic status, with control (n = 59), 3q29Del female reporting ASD (n = 5), 3q29Del female not reporting ASD (n = 17), 3q29Del male reporting ASD (n = 12), and 3q29Del male not reporting ASD (n = 14), showing inflated scores for 3q29Del participants irrespective of sex or diagnostic status. ***p < 0.001

Fig. 3

Comparison of SRS sub-scales and CBCL/ABCL DSM-oriented sub-scales between 3q29Del and controls. a Profile of individuals with 3q29Del (n = 48) and controls (n = 59) across SRS sub-scales, showing moderate to severe impairment of 3q29Del participants in all domains except Social Motivation (RRB, Restricted Interests and Repetitive Behaviors; SCI, Social Communication and Interaction). b Profile of 3q29Del males (n = 26) and females (n = 22) and controls (n = 59) across SRS sub-scales, showing that 3q29Del males and females both score significantly higher than controls and that there are no significant differences in score between males and females. c Profile of 3q29Del participants reporting an ASD diagnosis (n = 17) and participants not reporting an ASD diagnosis (n = 31) and controls (n = 59) across SRS sub-scales, showing that 3q29Del participants score significantly higher than controls irrespective of ASD status, with 3q29Del participants reporting an ASD diagnosis scoring significantly higher than those not reporting an ASD diagnosis. d Profile of 3q29Del participants (n = 48) and controls (n = 57) across 3 DSM-oriented sub-scales from the CBCL and ABCL, showing significantly increased pathology in 3q29Del participants in all 3 domains. ***p < 0.001