2020
DOI: 10.1016/j.brainres.2019.146459
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Genetic modifiers and non-Mendelian aspects of CMT

Abstract: Charcot-Marie-Tooth (CMT) neuropathies are amongst the most common inherited diseases in neurology. While great strides have been made to identify the genesis of these diseases, a diagnostic gap of 30-60% remains. Classic models of genetic causation may be limited to fully close this gap and, thus, we review the current state and future role of alternative, non-Mendelian forms of genetics in CMT. Promising synergies exist to further define the full genetic architecture of inherited neuropathies, including affo… Show more

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Cited by 31 publications
(37 citation statements)
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“…However, we cannot exclude that AARS1 duplication, just like MFN2 mutation, may modulate the phenotypic manifestation of this CMT axonal form, acting as “modifier allele”. The role of modifier alleles has been reported and analyzed in some cases of CMT disease [ 24 , 25 ].…”
Section: Discussionmentioning
confidence: 99%
“…However, we cannot exclude that AARS1 duplication, just like MFN2 mutation, may modulate the phenotypic manifestation of this CMT axonal form, acting as “modifier allele”. The role of modifier alleles has been reported and analyzed in some cases of CMT disease [ 24 , 25 ].…”
Section: Discussionmentioning
confidence: 99%
“…However, each of these terms can mean a specific phenomenon based on its context. For example, a mono/oligogenic disease can also be modified by other mutations causing incomplete penetrance and variable expressivity [26][27][28] (Figure 1). Genetic modifier can be involved in modifying pleotropic phenotype [29][30][31].…”
Section: Current State Of Rare Disease Genetic Modifier Researchmentioning
confidence: 99%
“…Oligogenicity refers to the multigenic inheritance (involving two or more genes), regardless of modifiers [27,[32][33][34]. More specifically, oligogenic diseases are caused by the co-occurrence of mutations in two or more genes.…”
Section: Oligogenicity and Genetic Modifiersmentioning
confidence: 99%
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“…Indeed, the advent of next-generation sequencing (NGS) techniques paved the way for a broader screening of the patients and for the discovery of rarer variants, thus providing a higher likelihood of identification. Notwithstanding this considerable progress, assuming a Mendelian inheritance, a genetic diagnosis remains elusive in 30–70% of CMT patients [ 1 , 2 , 3 , 4 ], depending on customized gene panels that generally cover only known disease-related coding sequences in order to provide a faster and affordable analysis with higher coverage, as well as fewer incidental findings. As an example, the most frequent culprit for CMT after peripheral myelin protein 22 ( PMP22) is the gap junction beta 1 protein gene ( GJB1 ), affecting about 6.5–17% of the patients with a presumptive inherited neuropathy [ 2 , 3 ].…”
Section: Introductionmentioning
confidence: 99%