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

Authors

Zain Dardas
Dana Marafi
Ruizhi Duan
Jawid M Fatih
Omnia F El-Rashidy
Christopher M Grochowski
Claudia M B Carvalho
Shalini N Jhangiani
Weimin Bi
Haowei Du
Richard A Gibbs
Jennifer E Posey
Daniel G Calame
Maha S Zaki
James R Lupski

Language

English

Publication Date

3-1-2025

Journal

European Journal of Human Genetics

DOI

10.1038/s41431-024-01680-1

PMID

39256534

PMCID

PMC11840051

PubMedCentral® Posted Date

9-10-2024

PubMedCentral® Full Text Version

Post-print

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 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.

Keywords

Humans, Female, Chromosomes, Human, Pair 18, Chromosomes, Human, Pair 2, Translocation, Genetic, Neurodevelopmental Disorders, Chromosome Aberrations, Male, Cytogenetics, Neurodevelopmental disorders, Genetics research

Published Open-Access

yes

Recommended Citation

Dardas, Zain; Marafi, Dana; Duan, Ruizhi; et al., "Genomic Balancing Act: Deciphering DNA Rearrangements in the Complex Chromosomal Aberration Involving 5p15.2, 2q31.1, and 18q21.32" (2025). Faculty and Staff Publications. 5067.
https://digitalcommons.library.tmc.edu/baylor_docs/5067