Genomic Balancing Act: deciphering DNA rearrangements in the complex chromosomal aberration involving 5p15.2, 2q31.1, and 18q21.32.

Autor: Dardas Z; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Marafi D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait., Duan R; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Fatih JM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., El-Rashidy OF; Department of Pediatrics, Faculty of Medicine Ain Shams University, Cairo, Egypt., Grochowski CM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Carvalho CMB; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Pacific Northwest Research Institute, Seattle, WA, USA., Jhangiani SN; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA., Bi W; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Baylor Genetics, Houston, TX, USA., Du H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Gibbs RA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA., Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Calame DG; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA.; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Zaki MS; Department of Clinical Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. jlupski@bcm.edu.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. jlupski@bcm.edu.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. jlupski@bcm.edu.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Sep 10. Date of Electronic Publication: 2024 Sep 10.
DOI: 10.1038/s41431-024-01680-1
Abstrakt: Despite extensive research into the genetic underpinnings of neurodevelopmental disorders (NDD), many clinical cases remain unresolved. We studied a female proband with a NDD, mildly dysmorphic facial features, and brain stem hypoplasia on neuroimaging. Comprehensive genomic analyses revealed a terminal 5p loss and a terminal 18q gain in the proband while a diploid copy number for chromosomes 5 and 18 in both parents. Genomic investigations in the proband identified an unbalanced translocation t(5;18) with additional genetic material from chromosome 2 (2q31.3) inserted at the breakpoint, pointing to a complex chromosomal rearrangement (CCR) involving 5p15.2, 2q31.3, and 18q21.32. Breakpoint junction analyses enabled by long-read genome sequencing unveiled the presence of four distinct junctions in the father, who is a carrier of a balanced CCR. The proband inherited from the father both the abnormal chromosome 5 resulting in segmental aneusomies of chr5 (loss) and chr18 (gain) and a der(2) homologue. Evidences suggest a chromoplexy mechanism for this CCR derivation, involving double-strand breaks (DSBs) repaired by non-homologous end joining (NHEJ) or alternative end joining (alt-EJ). The complexity of the CCR and the segregation of homologues elucidate the genetic model for this family. This study demonstrates the importance of combining multiple genomic technologies to uncover genetic causes of complex neurodevelopmental syndromes and to better understand genetic disease mechanisms.
(© 2024. The Author(s).)
Databáze: MEDLINE
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