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New phenotypes associated with 3q29 duplication syndrome: Results from the 3q29 registry.

ABSTRACT: 3q29 duplication syndrome (3q29dup) is a rare genomic disorder caused by a 1.6 Mb duplication (GRCh38 chr3:195,998,000-197,623,000). 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.

SUBMITTER: Pollak RM

PROVIDER: S-EPMC7785085 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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New phenotypes associated with 3q29 duplication syndrome: Results from the 3q29 registry.

Pollak Rebecca M RM Zinsmeister Michael C MC Murphy Melissa M MM Zwick Michael E ME Mulle Jennifer G JG

American journal of medical genetics. Part A 20200310 5

3q29 duplication syndrome (3q29dup) is a rare genomic disorder caused by a 1.6 Mb duplication (GRCh38 chr3:195,998,000-197,623,000). 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 devel ...[more]

PMID: 32154651

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Project description: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.

Project description:Background3q29 deletion syndrome is caused by a recurrent hemizygous 1.6 Mb deletion on the long arm of chromosome 3. The syndrome is rare (1 in 30,000 individuals) and is associated with mild to moderate intellectual disability, increased risk for autism and anxiety, and a 40-fold increased risk for schizophrenia, along with a host of physical manifestations. However, the disorder is poorly characterized, the range of manifestations is not well described, and the underlying molecular mechanism is not understood. We designed the Emory 3q29 Project to document the range of neurodevelopmental and psychiatric manifestations associated with 3q29 deletion syndrome. We will also create a biobank of samples from our 3q29 deletion carriers for mechanistic studies, which will be a publicly-available resource for qualified investigators. The ultimate goals of our study are three-fold: first, to improve management and treatment of 3q29 deletion syndrome. Second, to uncover the molecular mechanism of the disorder. Third, to enable cross-disorder comparison with other rare genetic syndromes associated with neuropsychiatric phenotypes.MethodsWe will ascertain study subjects, age 6 and older, from our existing registry ( 3q29deletion.org ). Participants and their families will travel to Atlanta, GA for phenotypic assessments, with particular emphasis on evaluation of anxiety, cognitive ability, autism symptomatology, and risk for psychosis via prodromal symptoms and syndromes. Evaluations will be performed using standardized instruments. Structural, diffusion, and resting-state functional MRI data will be collected from eligible study participants. We will also collect blood from the 3q29 deletion carrier and participating family members, to be banked at the NIMH Repository and Genomics Resource (NRGR).DiscussionThe study of 3q29 deletion has the potential to transform our understanding of complex disease. Study of individuals with the deletion may provide insights into long term care and management of the disorder. Our project describes the protocol for a prospective study of the behavioral and clinical phenotype associated with 3q29 deletion syndrome. The paradigm described here could easily be adapted to study additional CNV or single gene disorders with high risk for neuropsychiatric phenotypes, and/or transferred to other study sites, providing a means for data harmonization and cross-disorder analysis.

Dataset Information

New phenotypes associated with 3q29 duplication syndrome: Results from the 3q29 registry.

Publications

New phenotypes associated with 3q29 duplication syndrome: Results from the 3q29 registry.

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