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3q29 Awareness Day
Becky Powell Presents Latest Findings from 3q29 Registry Data
From L to R: Dr. Cheryl Klaiman, Becky Powell, Dr. Celine Saulnier
The articles listed in this section are available through the pre-print serviers bioRxiv (https://www.biorxiv.org; pronounced: bio archive) or medRxiv (https://www.medrxiv.org/; pronounced med archive).
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A distinct cognitive profile in individuals with 3q29 deletion syndrome
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Caregiver perspectives on a diagnosis of 3q29 deletion
Megan R. Glassford, Ryan H. Purcell, Sarah Pass, Melissa M. Murphy, Gary J. Bassell, Jennifer G. Mulle
medRxiv 2020.09.21.20198770; doi: https://doi.org/10.1101/2020.09.21.20198770
Symptoms of pediatric feeding disorders among individuals with 3q29 deletion syndrome
Addam J. Wawrzonek, T. Lindsey Burrell, William Sharp, Scott E. Gillespie, Rebecca Pollak, The Emory 3q29 Project, Melissa M Murphy, Jennifer Mulle
medRxiv 2020.09.18.20197301; doi: https://doi.org/10.1101/2020.09.18.20197301
Convergent and distributed effects of the schizophrenia-associated 3q29 deletion on the human neural transcriptome
Esra Sefik, Ryan H. Purcell, Megan Merritt-Garza, Sridhar Karne, Jessica Randall, The Emory 3q29 Project, Elaine F. Walker, Gary J. Bassell, Jennifer G. Mulle
bioRxiv 2020.05.25.111351; doi: https://doi.org/10.1101/2020.05.25.111351
Metabolic effects of the schizophrenia-associated 3q29 deletion are sex-specific and uncoupled from behavioral phenotypes
Rebecca M Pollak, Ryan H Purcell, Timothy P Rutkowski, Tamika Malone, Kimberly J Pachura, Gary J Bassell, Michael P Epstein, Paul A Dawson, Matthew R Smith, Dean P Jones, Michael E Zwick, the Emory 3q29 Project, Stephen T Warren, Tamara Caspary, David Weinshenker, Jennifer G Mulle
bioRxiv 2020.09.18.303412; doi: https://doi.org/10.1101/2020.09.18.303412
Sex-specific recombination predicts parent of origin for recurrent genomic disorders
Trenell Mosley, H. Richard Johnston, David J. Cutler, Michael E. Zwick, Jennifer G. Mulle
bioRxiv 2020.06.01.128553; doi: https://doi.org/10.1101/2020.06.01.128553
The articles listed in this section are published in scientific peer-reviewed journals. When an article is “peer-reviewed” it means that it has undergone objective evaluation and approval process by other experts prior to being published.
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Study protocol for The Emory 3q29 Project: evaluation of neurodevelopmental, psychiatric, and medical symptoms in 3q29 deletion syndrome
Murphy, M. M., Burrell, T. L., Cubells, J. F., España, R. A., Gambello, M. J., Goines, K. C., … & Russo, R. L. S. (2018). Study protocol for The Emory 3q29 Project: evaluation of neurodevelopmental, psychiatric, and medical symptoms in 3q29 deletion syndrome. BMC psychiatry, 18(1), 183.
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3q29 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.
We 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).
The 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.
3q29 Recurrent Deletion
Pagon, R. A., Adam, M. P., Ardinger, H. H., Wallace, S. E., Amemiya, A., Bean, L. J. H., … & Stephens, K. 3q29 Recurrent Deletion–GeneReviews (®).
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3q29 recurrent deletion is characterized by global developmental delay and/or intellectual disability, and commonly, speech delay, and increased risk for neuropsychiatric disorders (including autism spectrum disorder, anxiety disorder, psychosis, and/or schizophrenia). Other common findings are failure to thrive and feeding problems in infancy that persist into childhood, heart defects (especially patent ductus arteriosus), gastrointestinal disorders (including gastroesophageal reflux disease), and dental abnormalities. To date findings in fewer than 50 affected individuals have been reported.
The diagnosis of the 3q29 recurrent deletion is established by detection of the 1.6-Mb heterozygous deletion by chromosomal microarray at the approximate position of chr3:195998129-197623129 in the reference genome (NCBI Build 38).
Treatment of manifestations: Early speech and language therapy to address speech delays; physical therapy as needed to address fine and gross motor delays; individualized education program (IEP) for school-age children; care by a child psychiatrist/psychologist as needed for neuropsychiatric disorders; feeding therapy and consideration of gastrostomy tube as needed; routine management of dental caries, congenital heart defects, recurrent ear infections. Surveillance: Continued assessment of feeding and nutrition, developmental milestones, cognitive development, and possible neuropsychiatric manifestations. Evaluation of relatives at risk: Parents and older and younger sibs of a proband should be tested for the 3q29 recurrent deletion to encourage close assessment/monitoring of developmental milestones (in children) and monitoring for neuropsychiatric manifestations (in children and adults).
The 3q29 recurrent deletion is inherited in an autosomal dominant manner. Although most deletions are de novo, inherited deletions have been reported. If the 3q29 recurrent deletion identified in the proband is not identified in one of the parents, the risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental germline mosaicism for the deletion. Once the 3q29 recurrent deletion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options.
Novel features of 3q29 deletion syndrome: Results from the 3q29 registry
Glassford, M. R., Rosenfeld, J. A., Freedman, A. A., Zwick, M. E., Unique Rare Chromosome Disorder Support Group, & Mulle, J. G. (2016). Novel features of 3q29 deletion syndrome: results from the 3q29 registry. American Journal of Medical Genetics Part A, 170(4), 999-1006.
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3q29 deletion syndrome is caused by a recurrent, typically de novo heterozygous 1.6 Mb deletion, but because incidence of the deletion is rare (1 in 30,000 births) the phenotype is not well described. To characterize the range of phenotypic manifestations associated with 3q29 deletion syndrome, we have developed an online registry (3q29deletion.org) for ascertainment of study subjects and phenotypic data collection via Internet-based survey instruments. We report here on data collected during the first 18 months of registry operation, from 44 patients. This is the largest cohort of 3q29 deletion carriers ever assembled and surveyed in a systematic way. Our data reveal that 28% of registry participants report neuropsychiatric phenotypes, including anxiety disorder, panic attacks, depression, bipolar disorder, and schizophrenia. Other novel findings include a high prevalence (64%) of feeding problems in infancy and reduced weight at birth for 3q29 deletion carriers (average reduction 13.9 oz (394 g), adjusted for gestational age and sex, P = 6.5e-07). We further report on the frequency of heart defects, autism, recurrent ear infections, gastrointestinal phenotypes, and dental phenotypes, among others. We also report on the expected timing of delayed developmental milestones. This is the most comprehensive description of the 3q29 deletion phenotype to date. These results are clinically actionable toward improving patient care for 3q29 deletion carriers, and can guide the expectations of physicians and parents. These data also demonstrate the value of patient-reported outcomes to reveal the full phenotypic spectrum of rare genomic disorders.
The 3q29 deletion confers greater than 40-fold increase in risk for schizophrenia
Mulle, J. G. (2015). The 3q29 deletion confers >40-fold increase in risk for schizophrenia. Molecular psychiatry, 20(9), 1028.
Microdeletions of 3q29 confer high risk for schizophrenia
Mulle, J. G., Dodd, A. F., McGrath, J. A., Wolyniec, P. S., Mitchell, A. A., Shetty, A. C., … & Cutler, D. J. (2010). Microdeletions of 3q29 confer high risk for schizophrenia. The American Journal of Human Genetics, 87(2), 229-236.
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Schizophrenia (SZ) is a severe psychiatric illness that affects approximately 1% of the population and has a strong genetic underpinning. Recently, genome-wide analysis of copy-number variation (CNV) has implicated rare and de novo events as important in SZ. Here, we report a genome-wide analysis of 245 SZ cases and 490 controls, all of Ashkenazi Jewish descent. Because many studies have found an excess burden of large, rare deletions in cases, we limited our analysis to deletions over 500 kb in size. We observed seven large, rare deletions in cases, with 57% of these being de novo. We focused on one 836 kb de novo deletion at chromosome 3q29 that falls within a 1.3-1.6 Mb deletion previously identified in children with intellectual disability (ID) and autism, because increasing evidence suggests an overlap of specific rare copy-number variants (CNVs) between autism and SZ. By combining our data with prior CNV studies of SZ and analysis of the data of the Genetic Association Information Network (GAIN), we identified six 3q29 deletions among 7545 schizophrenic subjects and one among 39,748 controls, resulting in a statistically significant association with SZ (p = 0.02) and an odds ratio estimate of 17 (95% confidence interval: 1.36-1198.4). Moreover, this 3q29 deletion region contains two linkage peaks from prior SZ family studies, and the minimal deletion interval implicates 20 annotated genes, including PAK2 and DLG1, both paralogous to X-linked ID genes and now strong candidates for SZ susceptibility.
Neuropsychiatric phenotypes and a distinct constellation of ASD features in 3q29 deletion syndrome: results from the 3q29 registry
Pollak, R.M., Murphy, M.M., Epstein, M.P. et al. Neuropsychiatric phenotypes and a distinct constellation of ASD features in 3q29 deletion syndrome: results from the 3q29 registry. Molecular Autism 10, 30 (2019) doi:10.1186/s13229-019-0281-5.
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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.
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).
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.
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.
Comprehensive phenotyping of neuropsychiatric traits in a multiplex 3q29 deletion family: a case report
Murphy, M.M., Burrell, T.L., Cubells, J.F. et al. Comprehensive phenotyping of neuropsychiatric traits in a multiplex 3q29 deletion family: a case report. BMC Psychiatry20, 184 (2020).
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3q29 deletion syndrome is associated with a range of medical, neurodevelopmental, and psychiatric phenotypes. The deletion is usually de novo but cases have been reported where the deletion is inherited from apparently unaffected parents. The presence of these unaffected or mildly affected individuals suggests there may be an ascertainment bias for severely affected cases of 3q29 deletion syndrome, thus the more deleterious consequence of the 3q29 deletion may be overestimated. However, a substantial fraction of 3q29 deletion syndrome morbidity is due to psychiatric illness. In many case reports, probands and transmitting parents are not systematically evaluated for psychiatric traits. Here we report results from a systematic phenotyping protocol for neurodevelopmental and neuropsychiatric traits applied to all 3q29 deletion carriers in a multiplex family.
Through the 3q29 registry at Emory University, a multiplex family was identified where three offspring had a paternally inherited 3q29 deletion. We evaluated all 4 3q29 deletion family members using our previously described standardized, systematic phenotyping protocol. The transmitting parent reported no psychiatric history, however upon evaluation he was discovered to meet criteria for multiple psychiatric diagnoses including previously undiagnosed schizoaffective disorder. All four 3q29 deletion individuals in the pedigree had multiple psychiatric diagnoses that interfered with quality of life and prohibited successful academic and occupational functioning. Cognitive ability for all individuals was average or below average, but within the normal range.
This is the first case report of inherited 3q29 deletion syndrome where all affected individuals in the pedigree have been comprehensively and systematically evaluated for neurodevelopmental and psychiatric symptoms, using a standard battery of normed instruments administered by expert clinicians. Our investigation reveals that individuals with 3q29 deletion syndrome may have psychiatric morbidity that is debilitating, but only apparent through specialized evaluation by an expert. In the absence of appropriate evaluation, individuals with 3q29 deletion syndrome may suffer from psychiatric illness but lack avenues for access to care. The individuals evaluated here all have cognition in the normal range alongside multiple psychiatric diagnoses each, suggesting that cognitive ability alone is not a representative proxy for 3q29 deletion-associated disability. These results require replication in a larger cohort of individuals with 3q29 deletion syndrome.
Systematic Description of 3q29 Duplication Syndrome Reveals New Syndromic Phenotypes: Results from the 3q29 Registry
3q29 duplication syndrome (3q29Dup) is a rare genomic disorder caused by the reciprocal duplication of the 1.6 Mb 3q29 deletion syndrome region. Case reports indicate the 3q29Dup is likely to be pathogenic, but because no systematic study of the syndrome exists, the full range of manifestations is not well-understood. To develop a better understanding of 3q29 duplication syndrome, we used the 3q29 registry (https://3q29deletion.patientcrossroads.org/) 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 syndrome (3q29Del) 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 (SRS) and Achenbach Behavior Checklists (CBCL/ABCL), to assess social disability. We find that our 3q29Dup participants report a high rate of problems in the first year of life (80.6%), including feeding problems (58%), failure to gain weight (42%), hypotonia (39%), and respiratory distress (29%). In early childhood, learning problems (87.1%) and seizures (25.8%) are common. Additionally, we find a rate of self-reported ASD diagnoses (39%) similar to that previously identified in 3q29Del (29%), and the granular characteristics of social disability measured using the SRS and CBCL/ABCL are comparable between 3q29Dup and 3q29Del. 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 3q29 duplication syndrome.
Deep phenotyping in 3q29 deletion syndrome: recommendations for clinical care
Rossana Sanchez Russo, Michael J Gambello, Melissa M Murphy, Katrina Aberizk, Emily Black, T. Lindsey Burrell, Grace Carlock, Joseph F Cubells, Michael T Epstein, Roberto Espana, Katrina Goines, Ryan Guest, Cheryl Klaiman, Sookyong Koh, Elizabeth Leslie, Stormi White, Longchuan Li, Derek Novacek, Celine A Saulnier, Esra Sefik, Sarah Schultz, Elaine F Walker, The Emory 3q29 Project, Jennifer Gladys Mulle
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To understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, brain structural, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care.
Thirty-two individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments.
Medical manifestations were varied and reported across nearly every organ system. The most severe manifestations were congenital heart defects (25%) and the most common were gastrointestinal symptoms (81%). Physical examination revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), and attention deficit–hyperactivity disorder (ADHD) (63%). Neuroimaging revealed structural anomalies of the posterior fossa, but on neurological exam study subjects displayed only mild or moderate motor vulnerabilities.
By direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.
Craniofacial features of 3q29 deletion syndrome: application of next generation phenotyping technology.
Bryan C Mak, Rossana Sanchez Russo, Michael J Gambello, Emily Black, Elizabeth Leslie, Melissa M Murphy, The Emory 3q29 Project, Jennifer Mulle
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3q29 deletion syndrome (3q29del) is a recurrent deletion syndrome associated with neuropsychiatric disorders and congenital anomalies. Dysmorphic facial features have been described but not systematically characterized. This study aims to detail the 3q29del craniofacial phenotype and use a machine learning approach to categorize individuals with 3q29del through analysis of 2D photos. Detailed dysmorphology exam and 2D facial photos were ascertained from 31 individuals with 3q29del. Photos were used to train the next-generation phenotyping algorithm DeepGestalt (Face2Gene by FDNA, Inc, Boston, MA) to distinguish 3q29del cases from controls and all other recognized syndromes. Area under the curve of receiver operating characteristic curves (AUC-ROC) was used to determine the capacity of Face2Gene to identify 3q29del cases against controls. In this cohort, the most common observed craniofacial features were prominent forehead (48.4%), prominent nose tip (35.5%), and thin upper lip vermillion (25.8%). The FDNA technology showed an ability to distinguish cases from controls with an AUC-ROC value of 0.873 (p = 0.006) and led to the inclusion of 3q29del as one of the supported syndromes. This study found a recognizable facial pattern in 3q29del, as observed by trained clinical geneticists and next-generation phenotyping technology. These results expand the potential application of automated technology such as FDNA in identifying rare genetic syndromes, even when facial dysmorphology is subtle.
The Emory 3q29 Project ♦ Department of Human Genetics ♦ Emory University School of Medicine
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