TY  - JOUR
A1  - Eisfeldt, Jesper
A1  - Ameur, Adam
A1  - Lenner, Felix
A1  - Ten Berk de Boer, Esmee
A1  - Ek, Marlene
A1  - Wincent, Josephine
A1  - Vaz, Raquel
A1  - Ottosson, Jesper
A1  - Jonson, Tord
A1  - Ivarsson, Sofie
A1  - Thunström, Sofia
A1  - Topa, Alexandra
A1  - Stenberg, Simon
A1  - Rohlin, Anna
A1  - Sandestig, Anna
A1  - Nordling, Margareta
A1  - Palmebäck, Pia
A1  - Burstedt, Magnus
A1  - Nordin, Frida
A1  - Stattin, Eva-Lena
A1  - Sobol, Maria
A1  - Baliakas, Panagiotis
A1  - Bondeson, Marie-Louise
A1  - Höijer, Ida
A1  - Saether, Kristine Bilgrav
A1  - Lovmar, Lovisa
A1  - Ehrencrona, Hans
A1  - Melin, Malin
A1  - Feuk, Lars
A1  - Lindstrand, Anna
T1  - A national long-read sequencing study on chromosomal rearrangements uncovers hidden complexities
Y1  - 2024/11/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 1774 
EP  - 1784 
DO  - 10.1101/gr.279510.124 
VL  - 34 
IS  - 11 
UR  - http://genome.cshlp.org/content/34/11/1774.abstract 
N2  - 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. 
ER  -