Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.

Autor: Ferreira T; Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge, Robinson Way, Cambridge, CB2 0PY, UK., Polavarapu K; Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada., Olimpio C; Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge, Robinson Way, Cambridge, CB2 0PY, UK.; East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Paramonov I; Centro Nacional de Análisis Genómico, Barcelona, Spain., Lochmüller H; Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.; Centro Nacional de Análisis Genómico, Barcelona, Spain.; Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada.; Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada.; Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany., Horvath R; Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge, Robinson Way, Cambridge, CB2 0PY, UK. rh732@medschl.cam.ac.uk.
Jazyk: angličtina
Zdroj: Journal of neurology [J Neurol] 2024 Jun; Vol. 271 (6), pp. 3546-3553. Date of Electronic Publication: 2024 Mar 28.
DOI: 10.1007/s00415-024-12319-y
Abstrakt: Background: Peripheral neuropathies in mitochondrial disease are caused by mutations in nuclear genes encoding mitochondrial proteins, or in the mitochondrial genome. Whole exome or genome sequencing enable parallel testing of nuclear and mtDNA genes, and it has significantly advanced the genetic diagnosis of inherited diseases. Despite this, approximately 40% of all Charcot-Marie-Tooth (CMT) cases remain undiagnosed.
Methods: The genome-phenome analysis platform (GPAP) in RD-Connect was utilised to create a cohort of 2087 patients with at least one Human Phenotype Ontology (HPO) term suggestive of a peripheral neuropathy, from a total of 10,935 patients. These patients' genetic data were then analysed and searched for variants in known mitochondrial disease genes.
Results: A total of 1,379 rare variants were identified, 44 of which were included in this study as either reported pathogenic or likely causative in 42 patients from 36 families. The most common genes found to be likely causative for an autosomal dominant neuropathy were GDAP1 and GARS1. We also detected heterozygous likely pathogenic variants in DNA2, MFN2, DNM2, PDHA1, SDHA, and UCHL1. Biallelic variants in SACS, SPG7, GDAP1, C12orf65, UCHL1, NDUFS6, ETFDH and DARS2 and variants in the mitochondrial DNA (mtDNA)-encoded MT-ATP6 and MT-TK were also causative for mitochondrial CMT. Only 50% of these variants were already reported as solved in GPAP.
Conclusion: Variants in mitochondrial disease genes are frequent in patients with inherited peripheral neuropathies. Due to the clinical overlap between mitochondrial disease and CMT, agnostic exome or genome sequencing have better diagnostic yields than targeted gene panels.
(© 2024. The Author(s).)
Databáze: MEDLINE
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