Systematic Description of 3q29 Duplication Syndrome Reveals New Syndromic Phenotypes: Results from the 3q29 Registry

Abstract

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.