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. Electronic supplementary material The o...
The 3q29 deletion confers increased risk for neuropsychiatric phenotypes including intellectual disability, autism spectrum disorder, generalized anxiety disorder, and a >40-fold increased risk for schizophrenia. To investigate consequences of the 3q29 deletion in an experimental system, we used CRISPR/Cas9 technology to introduce a heterozygous deletion into the syntenic interval on C57BL/6 mouse chromosome 16. mRNA abundance for 20 of the 21 genes in the interval was reduced by ~50%, while protein levels were reduced for only a subset of these, suggesting a compensatory mechanism. Mice harboring the deletion manifested behavioral impairments in multiple domains including social interaction, cognitive function, acoustic startle, and amphetamine sensitivity, with some sex-dependent manifestations. Additionally, 3q29 deletion mice showed reduced body weight throughout development consistent with the phenotype of 3q29 deletion syndrome patients. Of the genes within the interval, DLG1 has been hypothesized as a contributor to the neuropsychiatric phenotypes. However, we show that Dlg1+/− mice did not exhibit the behavioral deficits seen in mice harboring the full 3q29 deletion. These data demonstrate the following: the 3q29 deletion mice are a valuable experimental system that can be used to interrogate the biology of 3q29 deletion syndrome; behavioral manifestations of the 3q29 deletion may have sex-dependent effects; and mouse-specific behavior phenotypes associated with the 3q29 deletion are not solely due to haploinsufficiency of Dlg1.
BackgroundThe 1.6 Mb 3q29 deletion is associated with a 40-fold increased risk for schizophrenia.However, additional behavioral phenotypes, including autism spectrum disorder (ASD), are not well characterized. MethodsWe ascertained individuals with 3q29 deletion syndrome (3q29DS, "cases", n=94) and typically developing controls (n=64) through the 3q29 registry (https://3q29deletion.patientcrossroads.org). Self-report of neuropsychiatric illness was evaluated for 94 cases. Subsets of case and control records were evaluated with the SRS, SCQ, ASSQ, and Achenbach Behavior Checklists. ResultsCases report increased prevalence of autism diagnosis versus the general population (29.8% vs.1.47%, p<2.22e-16). 3q29DS also report increased frequency of generalized anxiety disorder and attention deficit/hyperactivity disorder, which is mirrored by elevated scores on the Achenbach DSM-oriented subscales (p<0.001). The SRS reveals that individuals with 3q29DS demonstrate less compromised social motivation than other ASD sub-domains, which is strikingly different from idiopathic ASD. ConclusionsOur sample of 3q29DS is significantly enriched for ASD diagnosis, especially among females, and features of autism may be present even when individuals with 3q29DS do not report an ASD diagnosis. Further, the presentation of ASD in this population is novel, with substantially less impaired social motivation compared to idiopathic ASD. Our study implies that ASD evaluation should be the standard of care for individuals with 3q29DS. From a research perspective, the . CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/386243 doi: bioRxiv preprint first posted online Rebecca M Pollak 3 novel ASD subtype present in 3q29DS is an ideal entry point for expanding our understanding of ASD.. CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/386243 doi: bioRxiv preprint first posted online Rebecca M Pollak 4 INTRODUCTION 3q29 deletion syndrome (3q29DS) is a rare (~1 in 30,000) (Stefansson), poorly understood genomic disorder characterized by a 1.6 Mb typically de novo deletion on chromosome 3 (1-3) .The interval contains 21 distinct protein-coding genes, 3 antisense transcripts, 1 long noncoding RNA, and 1 microRNA. Initial reports of the syndrome found developmental delay/intellectual disability universal among 3q29 deletion carriers, though some case reports have since identified individual without cognitive impairment (4). The 3q29 deletion is associated with schizophrenia (SZ) (5-7), and studies with large sample sizes indicate that the 3q29 deletion is enriched in ASD samples (8). However, no systematic evaluation of the ASD phen...
The 3q29 deletion confers increased risk for neuropsychiatric phenotypes including intellectual disability, autism spectrum disorder, generalized anxiety disorder, and a >40-fold increased risk for schizophrenia. To investigate consequences of the 3q29 deletion in an experimental system, we used CRISPR/Cas9 technology to introduce a heterozygous deletion into the syntenic interval on C57BL/6 mouse chromosome 16.mRNA abundance for 20 of the 21 genes in the interval was reduced by ~50%, while protein levels were reduced for only a subset of these, suggesting a compensatory mechanism. Mice harboring the deletion manifested behavioral impairments in multiple domains including social interaction, cognitive function, acoustic startle, and amphetamine sensitivity, with some sex-dependent manifestations. Additionally, 3q29 deletion mice showed reduced body weight throughout development consistent with the phenotype of 3q29 deletion syndrome patients. Of the genes within the interval, DLG1 has been hypothesized as a contributor to the neuropsychiatric phenotypes. However, we show that Dlg1 +/mice did not exhibit the behavioral deficits seen in mice harboring the full 3q29 deletion. These data demonstrate the following: the 3q29 deletion mice are a valuable experimental system that can be used to interrogate the biology of 3q29 deletion syndrome; behavioral manifestations of the 3q29 deletion may have sexdependent effects; and mouse-specific behavior phenotypes associated with the 3q29 deletion are not solely due to haploinsufficiency of Dlg1.
3q29 duplication syndrome (3q29dup) is a rare genomic disorder caused by a 1.6 Mb duplication (GRCh38 chr3:195,998,623,000). Case reports indicate the 3q29dup is likely to be pathogenic, but the full range of manifestations is not well understood. We used the 3q29 registry (https://3q29.com) to ascertain 31 individuals with 3q29dup, the largest cohort ever surveyed in a systematic way. For comparison, we ascertained 117 individuals with the reciprocal 3q29 deletion and 64 typically developing controls. We used a custom medical and demographic questionnaire to assess physical and developmental phenotypes, and two standardized instruments, the Social Responsiveness Scale and Child Behavior Checklist/Adult Behavior Checklist, to assess social disability. Participants with 3q29dup report a high rate of problems in the first year of life (80.6%), including feeding problems (55%), failure to gain weight (42%), hypotonia (39%), and respiratory distress (29%). In early childhood, learning problems (71.0%) and seizures (25.8%) are common. Additionally, the rate of self-reported autism spectrum disorder diagnoses (39%) is substantially elevated compared to the general population, suggesting that the 3q29 duplication may be an autism susceptibility locus. This is the most comprehensive description of 3q29dup to date. Our findings can be used to develop evidence-based strategies for early intervention and management of 3q29dup. K E Y W O R D S3q29 duplication, autism, epilepsy, genomic disorder, intellectual disability
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