Haplotype information of large neuromuscular disease genes provided by linked-read sequencing has a potential to increase diagnostic yield.

Autor: Lehtonen J; Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway.; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.; Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland.; Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Sulonen AM; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Almusa H; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Lehtokari VL; Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland.; Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Johari M; Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland.; Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia., Palva A; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Hakonen AH; Clinical Genetics, Helsinki University Hospital, Helsinki, Finland., Wartiovaara K; Clinical Genetics, Helsinki University Hospital, Helsinki, Finland., Lehesjoki AE; Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland.; Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Udd B; Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland.; Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Wallgren-Pettersson C; Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland.; Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Pelin K; Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland.; Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland., Savarese M; Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland.; Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Saarela J; Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway. j.s.saarela@ncmm.uio.no.; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. j.s.saarela@ncmm.uio.no.; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. j.s.saarela@ncmm.uio.no.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Feb 21; Vol. 14 (1), pp. 4306. Date of Electronic Publication: 2024 Feb 21.
DOI: 10.1038/s41598-024-54866-4
Abstrakt: Rare or novel missense variants in large genes such as TTN and NEB are frequent in the general population, which hampers the interpretation of putative disease-causing biallelic variants in patients with sporadic neuromuscular disorders. Often, when the first initial genetic analysis is performed, the reconstructed haplotype, i.e. phasing information of the variants is missing. Segregation analysis increases the diagnostic turnaround time and is not always possible if samples from family members are lacking. To overcome this difficulty, we investigated how well the linked-read technology succeeded to phase variants in these large genes, and whether it improved the identification of structural variants. Linked-read sequencing data of nemaline myopathy, distal myopathy, and proximal myopathy patients were analyzed for phasing, single nucleotide variants, and structural variants. Variant phasing was successful in the large muscle genes studied. The longest continuous phase blocks were gained using high-quality DNA samples with long DNA fragments. Homozygosity increased the number of phase blocks, especially in exome sequencing samples lacking intronic variation. In our cohort, linked-read sequencing added more information about the structural variation but did not lead to a molecular genetic diagnosis. The linked-read technology can support the clinical diagnosis of neuromuscular and other genetic disorders.
(© 2024. The Author(s).)
Databáze: MEDLINE
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