Characterization of an unbalanced translocation causing 3q28qter duplication and 10q26.2qter deletion in a patient with global developmental delay and self-injury

• DOI: 10.1101/mcs.a005884
• Publication Date: 2020-12-22T23:20:00Z
• Authors: Ikeoluwa A. Osei-...; Alexis L. Norris; Anya T. Joynt; Jeremy Thorpe; Soonweng Cho; Elaine Tierney; Jonathan Schmidt; Louis Hagopian; Jacqueline Harris; Jonathan Pevsner
• Keywords: Research Report; 0301 basic medicine; Adolescent; Whole Genome Sequencing; Autism Spectrum Disorder; Nervous System Malformations; Translocation, Genetic; rac GTP-Binding Proteins; 3. Good health; Discs Large Homolog 1 Protein; Specific Language Disorder; 03 medical and health sciences; Phenotype; Attention Deficit Disorder with Hyperactivity; Intellectual Disability; Humans; Female; Autistic Disorder; Chromosome Deletion; Self-Injurious Behavior; Transcription Factors

Chromosomal structural variation can cause severe neurodevelopmental and neuropsychiatric phenotypes. Here we present a nonverbal female adolescent with severe stereotypic movement disorder with severe problem behavior (e.g., self-injurious behavior, aggression, and disruptive and destructive behaviors), autism spectrum disorder, severe intellectual disability, attention deficit hyperactivity disorder, and global developmental delay. Previous cytogenetic analysis revealed balanced translocations present in the patient's apparently normal mother. We hypothesized the presence of unbalanced translocations in the patient due to maternal history of spontaneous abortions. Whole-genome sequencing and whole-genome optical mapping, complementary next-generation genomic technologies capable of the accurate and robust detection of structural variants, identified t(3;10), t(10;14), and t(3;14) three-way balanced translocations in the mother and der(10)t(3;14;10) and der(14)t(3;14;10) translocations in the patient. Instead of a t(3;10), she inherited a normal maternal copy of Chromosome 3, resulting in an unbalanced state of a 3q28qter duplication and 10q26.2qter deletion. Copy-imbalanced genes in one or both of these regions, such as DLG1, DOCK1, and EBF3, may contribute to the patient's phenotype that spans neurodevelopmental, musculoskeletal, and psychiatric domains, with the possible contribution of a maternally inherited 15q13.2q13.3 deletion.