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 chr3:195,998,623,000). 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

Convergent and distributed effects of the 3q29 deletion on the human neural transcriptome

“…As a result, some of the network partners identified in this study are expected to function upstream of their co-expressed 3q29 gene partner and would likely not be affected by 3q29Del. Simultaneously, this direction-agnostic property also suggests that network-based predictions formulated in this study are likely relevant to biological pathways and processes implicated in 3q29 duplication syndrome [ 121 ], which was recently shown to manifest phenotypic concordance with 3q29Del syndrome in multiple clinical areas, similar to relationships identified in other reciprocal CNV disorders [ 122 ].…”

Multi-modal investigation of the schizophrenia-associated 3q29 genomic interval reveals global genetic diversity with unique haplotypes and segments that increase the risk for non-allelic homologous recombination

“…In 2008, reciprocal 3q29 duplications were identified in 19 individuals when analyzing the genomes of 14,698 individuals with idiopathic mental retardation using array comparative genomic hybridization (aCGH) 11 . The 3q29 deletion syndrome is associated with a >40-fold increased risk for schizophrenia, and patients are also predisposed to developmental delay, intellectual disability, autism spectrum disorder (ASD), anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), congenital heart defects, and additional somatic, neurodevelopmental, and psychiatric phenotypes [12][13][14] . Similarly, phenotypes observed in individuals with the reciprocal 3q29 duplication syndrome include developmental delay, speech delay, intellectual disability, ocular and cardiac anomalies, microcephaly, dental anomalies, obesity, seizures, and behavioral similarities to ASD 11,[14][15][16][17][18][19][20][21][22][23] .…”

“…The 3q29 deletion syndrome is associated with a >40-fold increased risk for schizophrenia, and patients are also predisposed to developmental delay, intellectual disability, autism spectrum disorder (ASD), anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), congenital heart defects, and additional somatic, neurodevelopmental, and psychiatric phenotypes [12][13][14] . Similarly, phenotypes observed in individuals with the reciprocal 3q29 duplication syndrome include developmental delay, speech delay, intellectual disability, ocular and cardiac anomalies, microcephaly, dental anomalies, obesity, seizures, and behavioral similarities to ASD 11,[14][15][16][17][18][19][20][21][22][23] . The 3q29 deletion syndrome has an estimated population prevalence of 1:30,000 24 , and 3q29 duplication syndrome has a population prevalence of 1:8,000-75,000 14 .…”

“…Similarly, phenotypes observed in individuals with the reciprocal 3q29 duplication syndrome include developmental delay, speech delay, intellectual disability, ocular and cardiac anomalies, microcephaly, dental anomalies, obesity, seizures, and behavioral similarities to ASD 11,[14][15][16][17][18][19][20][21][22][23] . The 3q29 deletion syndrome has an estimated population prevalence of 1:30,000 24 , and 3q29 duplication syndrome has a population prevalence of 1:8,000-75,000 14 . Although most deletions are de novo, a small number of inherited deletions (7%) have been reported 25 .…”

3q29 microduplication syndrome: New evidence for the refinement of the critical region

“…The 3q29 microduplication syndrome is a rare genomic disorder (MIM 611936), characterized by an extremely variable neurodevelopmental phenotype. Heterogenous clinical features, including autism, intellectual disability, global development delay, speech delay, learning disabilities, and seizures have been reported (Coyan & Dyer, 2020 ; Pollak et al, 2020 ; Streata et al, 2020 ; Tassano et al, 2018 ). Mild facial dysmorphism, microcephaly, obesity, ocular and cardiac defects, hypotonia, and musculoskeletal anomalies may also be present.…”