A chromoanagenesis-driven ultra-complex t(5;7;21)dn truncates neurodevelopmental genes in a disabled boy as revealed by whole-genome sequencing |
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| Affiliation: | 1. Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico;2. Doctorado en Genética Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico;3. División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico;4. Departamento de Ciencias Básicas, Vicerrectoría de Ciencias de la Salud, Universidad de Monterrey, San Pedro Garza García, Mexico;5. Laboratorio Internacional de Investigación Sobre el Genoma Humano, Universidad Nacional Autónoma de México, Campus Juriquilla, Santiago de Querétaro, Mexico;6. Wellcome Sanger Institute, Hinxton, UK;7. Hospital de Pediatría, UMAE-CMNO, Instituto Mexicano del Seguro Social, Guadalajara, Mexico;1. First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, 450000, China;2. Medical College of Pediatrics, Henan University of Traditional Chinese Medicine, Zhengzhou, 450000, China;1. Department of Neurology, Ghent University Hospital, Corneel Heymanslaan 10, 9000, Ghent, Belgium;2. Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, 9000, Ghent, Belgium;3. Center for Medical Genetics, Ghent University Hospital, Corneel Heymanslaan 10, 9000, Ghent, Belgium;1. Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, 500039, India;2. Graduate Studies, Regional Centre for Biotechnology, Faridabad, Haryana, India;3. Godavari Institute of Diabetes & Endocrinology (GIDE), Andhra Pradesh, India;4. Goa Medical College and Hospital, Bambolim, Goa, India;1. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan;2. Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan;3. Department of Maxillofacial Orthognathics, Tokyo Medical and Dental University, Tokyo, Japan;4. Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan;5. Department of Medical Genetics, Tokyo Medical and Dental University, Tokyo, Japan |
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| Abstract: | ![]()
Germline or constitutional chromoanagenesis-related complex chromosomal rearrangements (CCRs) are rare, apparently “all-at-once”, catastrophic events that occur in a single cell cycle, exhibit an unexpected complexity, and sometimes correlate with a severe abnormal phenotype. The term chromoanagenesis encompasses three distinct phenomena, namely chromothripsis, chromoanasynthesis, and chromoplexy. Herein, we found hallmarks of chromothripsis and chromoplexy in an ultra-complex t(5;7;21)dn involving several disordered breakpoint junctions (BPJs) accompanied by some microdeletions and the disruption of neurodevelopmental genes in a patient with a phenotype resembling autosomal dominant MRD44 (OMIM 617061). G-banded chromosomes and FISH showed that the CCR implied the translocation of the 5p15.2→pter segment onto 7q11.23; in turn, the fragment 7q11.23→qter of der(7) separated into two pieces: the segment q11.23→q32 translocated onto 5p15.2 and fused to 21q22.1→ter in the der(5) while the distal 7q32→qter segment translocated onto der(21) at q22.1. Subsequent whole-genome sequencing unveiled that CCT5, CMBL, RETREG1, MYO10, and TRIO from der(5), IMMP2L, TES, VPS37D, DUS4L, TYW1B, and FEZF1-AS1 from der(7), and TIAM1 and SOD1 from der(21), were disrupted by BPJs, whereas some other genes (predicted to be haplosufficient or inconsequential) were completely deleted. Although remarkably CCT5, TRIO, TES, MYO10, and TIAM1 (and even VPS37D) cooperate in key biological processes for normal neuronal development such as cell adhesion, migration, growth, and/or cytoskeleton formation, the disruption of TRIO most likely caused the patient's MRD44-like phenotype, including intellectual disability, microcephaly, finger anomalies, and facial dysmorphia. Our observation represents the first truncation of TRIO related to a chromoanagenesis event and therefore expands the mutational spectrum of this crucial gene. Moreover, our findings indicate that more than one mechanism is involved in modeling the architecture of ultra-complex rearrangements. |
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| Keywords: | Whole-genome sequencing Chromoanagenesis-related complex translocation MRD44 Neurodevelopmental disorders |
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