Optical Genome Mapping Identifies a Second Xq27.1 Rearrangement Associated With Charcot-Marie-Tooth Neuropathy CMTX3.

Autor: Rahikkala E; Department of Genomics, Turku University Hospital, Turku, Finland.; Research Unit of Clinical Medicine and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland., Komulainen-Ebrahim J; Research Unit of Clinical Medicine and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.; Division of Pediatric Neurology, Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland., Tolonen JP; Research Unit of Clinical Medicine and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.; Division of Pediatric Neurology, Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland., Vorimo S; Laboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Medical Research Center Oulu and Biocenter Oulu, University of Oulu, Oulu, Finland., Suo-Palosaari M; Department of Diagnostic Radiology, Physics and Technology, Research Unit of Health Sciences and Technology, University of Oulu, Oulu, Finland.; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland., Vieira P; Research Unit of Clinical Medicine and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.; Division of Pediatric Neurology, Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland., Piispala J; Department of Clinical Neurophysiology, Oulu University Hospital, Oulu, Finland., Uusimaa J; Research Unit of Clinical Medicine and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.; Division of Pediatric Neurology, Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland., Pylkäs K; Laboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Medical Research Center Oulu and Biocenter Oulu, University of Oulu, Oulu, Finland.; Northern Finland Laboratory Centre Nordlab, Oulu, Finland., Mantere T; Laboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Medical Research Center Oulu and Biocenter Oulu, University of Oulu, Oulu, Finland.
Jazyk: angličtina
Zdroj: Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2024 Sep; Vol. 12 (9), pp. e70014.
DOI: 10.1002/mgg3.70014
Abstrakt: Background: X-linked recessive type 3 Charcot-Marie-Tooth (CMTX3) is a rare subtype of childhood-onset CMT. To date, all reported CMTX3 patients share a common founder 78 kb insertion from chromosome 8 into the Xq27.1 palindrome region.
Methods: We conducted patient-parent trio optical genome mapping (OGM) on a male patient presenting with clinically diagnosed Dejerine-Sottas disease for whom initial standard diagnostic genetic tests, including whole-genome sequencing (WGS), yielded negative results.
Results: OGM analysis revealed a maternally inherited interchromosomal insertion from chromosome region 7q31.1 into Xq27.1. Coupled with manual reassessment of WGS data, this confirmed the molecular diagnosis of atypical CMTX3 and showed that the 122.4 kb inserted fragment contained DLD and partially LAMB1. Subsequent analyses confirmed that the rearrangement had arisen de novo in the proband's mother.
Conclusion: We report the second Xq27.1 rearrangement associated with CMTX3, providing novel clinical insights into its phenotypic and genotypic spectrum. Our findings highlight the importance of including genomic rearrangement analysis of Xq27.1 in standard diagnostic pipelines for childhood-onset CMT. Given the overlap in polyneuropathy phenotypes resulting from insertions from chromosomes 7 and 8 into the same Xq27.1 palindrome region, the pathogenic mechanism underlying peripheral neuropathy in CMTX3 likely involves dysregulation of genes within this region.
(© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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