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A national long-read sequencing study on chromosomal rearrangements uncovers hidden complexities

Eisfeldt, Jesper ; Ameur, Adam ; Lenner, Felix ; Berk de Boer, Esmee Ten ; Ek, Marlene ; Wincent, Josephine ; Vaz, Raquel ; Ottosson, Jesper ; Jonson, Tord LU and Ivarsson, Sofie , et al. (2024) In Genome Research 34(11). p.1774-1784
Abstract

Clinical genetic laboratories often require a comprehensive analysis of chromosomal rearrangements/structural variants (SVs), from large events like translocations and inversions to supernumerary ring/marker chromosomes and small deletions or duplications. Understanding the complexity of these events and their clinical consequences requires pinpointing breakpoint junctions and resolving the derivative chromosome structure. This task often surpasses the capabilities of short-read sequencing technologies. In contrast, long-read sequencing techniques present a compelling alternative for clinical diagnostics. Here, Genomic Medicine Sweden—Rare Diseases has explored the utility of HiFi Revio long-read genome sequencing (lrGS) for digital... (More)

Clinical genetic laboratories often require a comprehensive analysis of chromosomal rearrangements/structural variants (SVs), from large events like translocations and inversions to supernumerary ring/marker chromosomes and small deletions or duplications. Understanding the complexity of these events and their clinical consequences requires pinpointing breakpoint junctions and resolving the derivative chromosome structure. This task often surpasses the capabilities of short-read sequencing technologies. In contrast, long-read sequencing techniques present a compelling alternative for clinical diagnostics. Here, Genomic Medicine Sweden—Rare Diseases has explored the utility of HiFi Revio long-read genome sequencing (lrGS) for digital karyotyping of SVs nationwide. The 16 samples from 13 families were collected from all Swedish healthcare regions. Prior investigations had identified 16 SVs, ranging from simple to complex rearrangements, including inversions, translocations, and copy number variants. We have established a national pipeline and a shared variant database for variant calling and filtering. Using lrGS, 14 of the 16 known SVs are detected. Of these, 13 are mapped at nucleotide resolution, and one complex rearrangement is only visible by read depth. Two Chromosome 21 rearrangements, one mosaic, remain undetected. Average read lengths are 8.3–18.8 kb with coverage exceeding 20× for all samples. De novo assembly results in a limited number of phased contigs per individual (N50 6–86 Mb), enabling direct characterization of the chromosomal rearrangements. In a national pilot study, we demonstrate the utility of HiFi Revio lrGS for analyzing chromosomal rearrangements. Based on our results, we propose a 5-year plan to expand lrGS use for rare disease diagnostics in Sweden.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Genome Research
volume
34
issue
11
pages
11 pages
publisher
Cold Spring Harbor Laboratory Press (CSHL)
external identifiers
  • scopus:85209737616
  • pmid:39472022
ISSN
1088-9051
DOI
10.1101/gr.279510.124
language
English
LU publication?
yes
id
e0a2fe62-144f-44cb-9cc0-b7f639e6562b
date added to LUP
2025-01-15 11:39:33
date last changed
2025-04-23 19:22:38
@article{e0a2fe62-144f-44cb-9cc0-b7f639e6562b,
  abstract     = {{<p>Clinical genetic laboratories often require a comprehensive analysis of chromosomal rearrangements/structural variants (SVs), from large events like translocations and inversions to supernumerary ring/marker chromosomes and small deletions or duplications. Understanding the complexity of these events and their clinical consequences requires pinpointing breakpoint junctions and resolving the derivative chromosome structure. This task often surpasses the capabilities of short-read sequencing technologies. In contrast, long-read sequencing techniques present a compelling alternative for clinical diagnostics. Here, Genomic Medicine Sweden—Rare Diseases has explored the utility of HiFi Revio long-read genome sequencing (lrGS) for digital karyotyping of SVs nationwide. The 16 samples from 13 families were collected from all Swedish healthcare regions. Prior investigations had identified 16 SVs, ranging from simple to complex rearrangements, including inversions, translocations, and copy number variants. We have established a national pipeline and a shared variant database for variant calling and filtering. Using lrGS, 14 of the 16 known SVs are detected. Of these, 13 are mapped at nucleotide resolution, and one complex rearrangement is only visible by read depth. Two Chromosome 21 rearrangements, one mosaic, remain undetected. Average read lengths are 8.3–18.8 kb with coverage exceeding 20× for all samples. De novo assembly results in a limited number of phased contigs per individual (N50 6–86 Mb), enabling direct characterization of the chromosomal rearrangements. In a national pilot study, we demonstrate the utility of HiFi Revio lrGS for analyzing chromosomal rearrangements. Based on our results, we propose a 5-year plan to expand lrGS use for rare disease diagnostics in Sweden.</p>}},
  author       = {{Eisfeldt, Jesper and Ameur, Adam and Lenner, Felix and Berk de Boer, Esmee Ten and Ek, Marlene and Wincent, Josephine and Vaz, Raquel and Ottosson, Jesper and Jonson, Tord and Ivarsson, Sofie and Thunström, Sofia and Topa, Alexandra and Stenberg, Simon and Rohlin, Anna and Sandestig, Anna and Nordling, Margareta and Palmebäck, Pia and Burstedt, Magnus and Nordin, Frida and Stattin, Eva Lena and Sobol, Maria and Baliakas, Panagiotis and Bondeson, Marie Louise and Höijer, Ida and Saether, Kristine Bilgrav and Lovmar, Lovisa and Ehrencrona, Hans and Melin, Malin and Feuk, Lars and Lindstrand, Anna}},
  issn         = {{1088-9051}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{1774--1784}},
  publisher    = {{Cold Spring Harbor Laboratory Press (CSHL)}},
  series       = {{Genome Research}},
  title        = {{A national long-read sequencing study on chromosomal rearrangements uncovers hidden complexities}},
  url          = {{http://dx.doi.org/10.1101/gr.279510.124}},
  doi          = {{10.1101/gr.279510.124}},
  volume       = {{34}},
  year         = {{2024}},
}