Genetic modifiers and phenotypic variability in neuromuscular disorders
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HUMAN GENETICS • REVIEW
Genetic modifiers and phenotypic variability in neuromuscular disorders Magdalena Mroczek 1
&
Maria Gabriela Sanchez 2
Received: 27 May 2020 / Revised: 31 August 2020 / Accepted: 6 September 2020 # Institute of Plant Genetics, Polish Academy of Sciences, Poznan 2020
Abstract Neuromuscular disorders are mostly rare diseases with autosomal dominant, recessive, or X-linked inheritance. Interestingly, among patients carrying the same mutations, a range of phenotypic severity is reported. This phenotypic variability in neuromuscular disorders is still not fully understood. This review will focus on genetic modifiers and will briefly describe metabolic pathways, in which they are involved. Genetic modifiers are variants in the same or other genes that modulate the phenotype. Proteins encoded by genetic modifiers in neuromuscular diseases are taking part in different metabolic processes, most commonly in inflammation, growth and regeneration, endoplasmic reticulum metabolism, and cytoskeletal activities. Recent advances in omics technologies, development of computational algorithms, and establishing large international consortia intensified discovery sped up investigation of genetic modifiers. As more individuals affected by neuromuscular disorders are tested, it is often suggested that classic models of genetic causation cannot explain phenotypic variability. There is a growing interest in their discovery and identifying shared metabolic pathways can contribute to design targeted therapies. We provide an update on variants acting as genetic modifiers in neuromuscular disorders and strategies used for their discovery. Keywords Genetic modifier . Neuromuscular disorders . Metabolic pathway
Introduction A human disease modifier gene is a gene that modulates another gene function or effects Modifier genes influence the disease expression and severity, but the presence of a modifier is not sufficient to cause a disease (Kousi and Katsanis 2015). A genetic modifier can interplay with a product of another gene in different ways. The effects can result from changes in penetrance and expressivity, direct interaction with the target gene product, mechanistic contribution to the same biological process, and/or from functional compensation through Communicated by: Michal Witt * Magdalena Mroczek [email protected] 1
John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
2
Molecular Biology Department, Simon Bolivar University, Sartenejas Valley, Caracas, Venezuela
alternative pathways (Riordan and Nadeau 2017). The genetic modifier can be located near the primary allele, mainly in the promotor sequence, or far from the causative gene. Genetic modifiers are usually rare variants, but some of them can be common. A modifier effect has an outcome in phenotypic variability: giving enhancing or suppressing effects. In humans, the phenotypic outcome
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