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

Autor:	Lupski J; Baylor College of Medicine., Dardas Z, Marafi D, Duan R, Fatih J, El-Rashidy O, Grochowski C, Carvalho C; Pacific Northwest Research Institute., Jhangiani S, Bi W, Du H, Gibbs R, Posey J; Baylor College of Medicine., Calame D; Baylor College of Medicine, Houston., Zaki M; National Research Centre.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 Feb 19. Date of Electronic Publication: 2024 Feb 19.
DOI:	10.21203/rs.3.rs-3949622/v1
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 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. Competing Interests: Additional Declarations: J.R.L. has stock ownership in 23andMe, is a paid consultant for Genome International, and is a co-inventor on multiple U.S. and European patents related to molecular diagnostics for inherited neuropathies, genomic disorders, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical genomic sequencing (both ES and GS) offered in the Baylor Genetics Laboratory (http://bmgl.com). J.R.L. serves on the Scientific Advisory Board of BG.
Databáze:	MEDLINE
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