Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements

Abstract

Complex chromosomal rearrangements (CCRs) are rearrangements involving more than two chromosomes or more than two breakpoints. Whole genome sequencing (WGS) allows for outstanding high resolution characterization on the nucleotide level in unique sequences of such rearrangements, but problems remain for mapping breakpoints in repetitive regions of the genome, which are known to be prone to rearrangements. Hence, multiple complementary WGS experiments are sometimes needed to solve the structures of CCRs. We have studied three individuals with CCRs: Case 1 and Case 2 presented with de novo karyotypically balanced, complex interchromosomal rearrangements (46,XX,t(2;8;15)(q35;q24.1;q22) and 46,XY,t(1;10;5)(q32;p12;q31)), and Case 3 presented with a de novo, extremely complex intrachromosomal rearrangement on chromosome 1. Molecular cytogenetic investigation revealed cryptic deletions in the breakpoints of chromosome 2 and 8 in Case 1, and on chromosome 10 in Case 2, explaining their clinical symptoms. In Case 3, 26 breakpoints were identified using WGS, disrupting five known disease genes. All rearrangements were subsequently analyzed using optical maps, linked-read WGS, and short-read WGS. In conclusion, we present a case series of three unique de novo CCRs where we by combining the results from the different technologies fully solved the structure of each rearrangement. The power in combining short-read WGS with long-molecule sequencing or optical mapping in these unique de novo CCRs in a clinical setting is demonstrated.

Refined detection and phasing of structural aberrations in pediatric acute lymphoblastic leukemia by linked-read whole-genome sequencing

“…The present study is limited by the fact that we have not compared the linked-reads to other next generation approaches such as standard paired-end WGS, Hi-C, third-generation single-molecule sequencing, or optical mapping technologies, which when used in a multiplatform approach have been demonstrated to be a powerful method for resolving complex structural rearrangements [33][34][35] . Future studies will be required for more formal benchmarking of linked-read WGS and other next generation technologies for digital karyotyping specifically in ALL and for other cancer types.…”

Chromothripsis and DNA Repair Disorders

“…Chromothripsis was first described in a patient with chronic lymphocytic leukemia in 2011 [1], and it has subsequently been observed in a number of tumor types [18][19][20][21][22][23]. Germline chromothripsis with relatively milder complexity level has also been reported in patients with different congenital or developmental disorders [24][25][26][27][28][29][30][31]. Notably, chromothripsis may also be found in asymptomatic individuals and is associated with the truncation or deletion of many protein-coding genes [32,33].…”

Familial Infertility (Azoospermia and Cryptozoospermia) in Two Brothers—Carriers of t(1;7) Complex Chromosomal Rearrangement (CCR): Molecular Cytogenetic Analysis

“…aCGH analysis could not detect smaller intergenic CNV of few kb or smaller, such as indels of single exons or a few nucleotides. This suggests the need for whole exome or genome sequencing (WES/WGS) to investigate the presented familial case further, especially as genomic sequencing studies suggested that 85% of known genetic variants causing diseases are represented in the human coding sequence by point mutations causing the respective disorders [53][54][55]. In summary, chromosomal aberrations mostly do not affect the phenotype of the carrier, in contrast to the disruptive influence on spermatogenesis, which affects the gamete quantity (oligo-, azoospermia) and/or quality (generation of chromosomally abnormal sperm) of the carrier.…”