Dataset Information

Genomic Balancing Act: Deciphering DNA rearrangements in the Complex Chromosomal Aberration involving 5p15.2, 2q31.1 and 18q21.32.

ABSTRACT: 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 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 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 syndrome and to better understand genetic disease mechanisms.

SUBMITTER: Lupski J

PROVIDER: S-EPMC10925411 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genomic Balancing Act: Deciphering DNA rearrangements in the Complex Chromosomal Aberration involving 5p15.2, 2q31.1 and 18q21.32.

Lupski James J Dardas Zain Z Marafi Dana D Duan Ruizhi R Fatih Jawid J El-Rashidy Omnia O Grochowski Christopher C Carvalho Claudia C Jhangiani Shalini S Bi Weimin W Du Haowei H Gibbs Richard R Posey Jennifer J Calame Daniel D Zaki Maha M

Research square 20240219

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 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 ...[more]

PMID: 38464263

Similar Datasets

Project description:BackgroundComplex genomic rearrangements (CGRs) drive the restructuring of chromatin architecture, resulting in significant interactions among rearranged fragments, visible as anomalous interaction blocks in chromatin contact maps generated by chromosome conformation capture technologies such as Hi-C. These blocks not only offer the orientation and genome coordinates of rearranged fragments but also filter out false positive CGRs, thereby facilitating CGR assembly. Despite this, there is a lack of interactive graphical software tailored for this purpose.ResultsWe present DeCGR, a user-friendly Python toolbox specifically designed for deciphering CGRs in Hi-C data. DeCGR consists of four independent execution components. The Breakpoint Filtering module identifies and filters simple rearrangements, providing the coordinates of rearrangement breakpoints. The Fragment Assembly module automatically assembles CGRs and visualizes the assembly process, facilitating the direct association between anomalous interaction blocks and CGR events. The Validation CGRs module verifies the completeness and accuracy of CGRs by generating the Hi-C map with CGRs through a simulation process and examines the difference from the original Hi-C maps. This module displays both the original and the simulated Hi-C map with highlighted rearranged fragment boundaries for rapid review to assess the CGRs. Finally, the Reconstruct Hi-C Map module provides the reconstructed Hi-C map based on the determined CGRs, allowing users to directly observe the impact of rearrangements on chromatin structure.ConclusionsDeCGR is designed specifically for biologists who aim to explore CGRs from Hi-C data. It provides a validation module to ensure the completeness and correctness of CGRs. Additionally, it allows users to generate CGR assembly results and reconstruct the Hi-C map with just one click. DeCGR provides intuitive visualization results for each module, allowing users to easily associate CGRs with Hi-C maps. DeCGR is operable through a user-friendly graphical interface. Source codes are freely available at https://github.com/GaoLabXDU/DeCGR .

Dataset Information

Genomic Balancing Act: Deciphering DNA rearrangements in the Complex Chromosomal Aberration involving 5p15.2, 2q31.1 and 18q21.32.

Publications

Genomic Balancing Act: Deciphering DNA rearrangements in the Complex Chromosomal Aberration involving 5p15.2, 2q31.1 and 18q21.32.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets