Genetic modifiers and non-Mendelian aspects of CMT

Bis-Brewer, Dana M.; Fazal, Sarah; Züchner, Stephan

doi:10.1016/j.brainres.2019.146459

Cited by 31 publications

(37 citation statements)

References 62 publications

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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%

One Multilocus Genomic Variation Is Responsible for a Severe Charcot–Marie–Tooth Axonal Form

et al. 2020

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Charcot–Marie–Tooth (CMT) disease is a heterogeneous group of inherited disorders affecting the peripheral nervous system, with a prevalence of 1/2500. So far, mutations in more than 80 genes have been identified causing either demyelinating forms (CMT1) or axonal forms (CMT2). Consequentially, the genotype–phenotype correlation is not always easy to assess. Diagnosis could require multiple analysis before the correct causative mutation is detected. Moreover, it seems that approximately 5% of overall diagnoses for genetic diseases involves multiple genomic loci, although they are often underestimated or underreported. In particular, the combination of multiple variants is rarely described in CMT pathology and often neglected during the diagnostic process. Here, we present the complex genetic analysis of a family including two CMT cases with various severities. Interestingly, next generation sequencing (NGS) associated with Cov’Cop analysis, allowing structural variants (SV) detection, highlighted variations in MORC2 (microrchidia family CW-type zinc-finger 2) and AARS1 (alanyl-tRNA-synthetase) genes for one patient and an additional mutation in MFN2 (Mitofusin 2) in the more affected patient.

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Section: Discussionmentioning

confidence: 99%

One Multilocus Genomic Variation Is Responsible for a Severe Charcot–Marie–Tooth Axonal Form

et al. 2020

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“…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%

“…A review on Hereditary spastic paraplegias (HSPs) [143] and another very recently on Charcot-Marie-Tooth (CMT) [27] discuss how genetic modifier studies are uncovering the 'missing heritability' for these rare Mendelian disorders. The authors argued that despite being a monogenic disorder, non-Mendelian factors are essential to consider to overcome the diagnostic gap and to provide better therapeutics.…”

Section: Prospects and Challenges Of Computational Model In Modifier mentioning

confidence: 99%

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Genetic Modifiers and Rare Mendelian Disease

Rahit

Tarailo‐Graovac

2020

Genes

114

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Despite advances in high-throughput sequencing that have revolutionized the discovery of gene defects in rare Mendelian diseases, there are still gaps in translating individual genome variation to observed phenotypic outcomes. While we continue to improve genomics approaches to identify primary disease-causing variants, it is evident that no genetic variant acts alone. In other words, some other variants in the genome (genetic modifiers) may alleviate (suppress) or exacerbate (enhance) the severity of the disease, resulting in the variability of phenotypic outcomes. Thus, to truly understand the disease, we need to consider how the disease-causing variants interact with the rest of the genome in an individual. Here, we review the current state-of-the-field in the identification of genetic modifiers in rare Mendelian diseases and discuss the potential for future approaches that could bridge the existing gap.

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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%

Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis

et al. 2020

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The second most common form of Charcot-Marie-Tooth disease (CMT) follows an X-linked dominant inheritance pattern (CMTX1), referring to mutations in the gap junction protein beta 1 gene (GJB1) that affect connexin 32 protein (Cx32) and its ability to form gap junctions in the myelin sheath of peripheral nerves. Despite the advances of next-generation sequencing (NGS), attention has only recently also focused on noncoding regions. We describe two unrelated families with a c.-17+1G>T transversion in the 5′ untranslated region (UTR) of GJB1 that cosegregates with typical features of CMTX1. As suggested by in silico analysis, the mutation affects the regulatory sequence that controls the proper splicing of the intron in the corresponding mRNA. The retention of the intron is also associated with reduced levels of the transcript and the loss of immunofluorescent staining for Cx32 in the nerve biopsy, thus supporting the hypothesis of mRNA instability as a pathogenic mechanism in these families. Therefore, our report corroborates the role of 5′ UTR of GJB1 in the pathogenesis of CMTX1 and emphasizes the need to include this region in routine GJB1 screening, as well as in NGS panels.

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Genetic modifiers and non-Mendelian aspects of CMT

Cited by 31 publications

References 62 publications

One Multilocus Genomic Variation Is Responsible for a Severe Charcot–Marie–Tooth Axonal Form

One Multilocus Genomic Variation Is Responsible for a Severe Charcot–Marie–Tooth Axonal Form

Genetic Modifiers and Rare Mendelian Disease

Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis

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