Genetic analysis of Charcot-Marie-Tooth disease in Denmark and the implementation of a next generation sequencing platform

Vaeth, Signe; Christensen, Rikke; Dunø, Morten; Lildballe, Dorte Launholt; Thorsen, Kasper; Vissing, John; Svenstrup, Kirsten; Hertz, Jens Michael; Andersen, Henning; Jensen, Uffe Birk

doi:10.1016/j.ejmg.2018.04.003

Cited by 22 publications

(19 citation statements)

References 31 publications

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“…Previous studies have shown that NGS panels are technically robust in terms of coverage and read depth and have reported rates of molecular diagnosis in inherited neuropathies ranging from 6% to 46%. [10][11][12][13][14][15][16][17][18][19] The differences in the diagnostic rate in these studies both between each other and compared to ours may be explained by the differences in the specific features of the cohorts being tested coming from general neurology, genetic or specialized inherited neuropathy clinics, the number of demyelinating CMT cases enrolled, and the variable exclusion of more common causative genes by previous MLPA and Sanger sequencing. As opposed to demyelinating cases, over 70% of axonal CMT cases remain genetically unconfirmed after NGS panel testing.…”

Section: Discussionmentioning

confidence: 85%

“…[10][11][12][13][14][15][16] Nevertheless, there are limited data on the effect of targeted NGS panels on the genetic diagnosis of CMT in everyday clinical practice. [17][18][19][20] This study describes the effect of targeted NGS panels on the molecular diagnosis of CMT and related disorders in routine clinical practice in 2 specialized clinics in different health systems in the United Kingdom (London) and United States (Iowa).…”

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confidence: 99%

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Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease

et al. 2020

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ObjectiveTo investigate the effectiveness of targeted next-generation sequencing (NGS) panels in achieving a molecular diagnosis in Charcot-Marie-Tooth disease (CMT) and related disorders in a clinical setting.MethodsWe prospectively enrolled 220 patients from 2 tertiary referral centers, one in London, United Kingdom (n = 120), and one in Iowa (n = 100), in whom a targeted CMT NGS panel had been requested as a diagnostic test. PMP22 duplication/deletion was previously excluded in demyelinating cases. We reviewed the genetic and clinical data upon completion of the diagnostic process.ResultsAfter targeted NGS sequencing, a definite molecular diagnosis, defined as a pathogenic or likely pathogenic variant, was reached in 30% of cases (n = 67). The diagnostic rate was similar in London (32%) and Iowa (29%). Variants of unknown significance were found in an additional 33% of cases. Mutations in GJB1, MFN2, and MPZ accounted for 39% of cases that received genetic confirmation, while the remainder of positive cases had mutations in diverse genes, including SH3TC2, GDAP1, IGHMBP2, LRSAM1, FDG4, and GARS, and another 12 less common genes. Copy number changes in PMP22, MPZ, MFN2, SH3TC2, and FDG4 were also accurately detected. A definite genetic diagnosis was more likely in cases with an early onset, a positive family history of neuropathy or consanguinity, and a demyelinating neuropathy.ConclusionsNGS panels are effective tools in the diagnosis of CMT, leading to genetic confirmation in one-third of cases negative for PMP22 duplication/deletion, thus highlighting how rarer and previously undiagnosed subtypes represent a relevant part of the genetic landscape of CMT.

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Section: Discussionmentioning

confidence: 85%

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confidence: 99%

Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease

et al. 2020

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“…The PMP22 duplication/deletion mutations, accounting for 23.3% of demyelinating CMT in Japan,8 were not involved in this study and were removed from the original data of previous studies to facilitate comparison. Consequently, we found that three genes, GJB1 , MFN2 , and MPZ , were the leading reasons in the present study, using data from Germany,9 USA,10 UK,11 Norway12 and Denmark13 studies; however, these results differ from previous reports from Japan,8 Spain,14Italy,15 Korea16 and a cross-country study 17. Particularly, in the other Japanese study,8 regarding other genes with mutation frequency higher than 1%, PMP22 (3.3%), NEFL (2.7%) and PRX (1.7%) have been reported, whereas we detected HSPB1 (1.4%) and PMP22 (1.3%) in the present study.…”

Section: Discussionmentioning

confidence: 55%

Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan

Yoshimura

Yuan

Hashiguchi

et al. 2018

J Neurol Neurosurg Psychiatry

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Objective To identify the genetic characteristics in a large-scale of patients with Charcot-Marie-Tooth disease (CMT).MethodsFrom May 2012 to August 2016, we collected 1005 cases with suspected CMT throughout Japan, whereas PMP22 duplication/deletion were excluded in advance for demyelinating CMT cases. We performed next-generation sequencing targeting CMT-related gene panels using Illumina MiSeq or Ion Proton, then analysed the gene-specific onset age of the identified cases and geographical differences in terms of their genetic spectrum.Results From 40 genes, we identified pathogenic or likely pathogenic variants in 301 cases (30.0%). The most common causative genes were GJB1 (n=66, 21.9%), MFN2 (n=66, 21.9%) and MPZ (n=51, 16.9%). In demyelinating CMT, variants were detected in 45.7% cases, and the most common reasons were GJB1 (40.3%), MPZ (27.1%), PMP22 point mutations (6.2%) and NEFL (4.7%). Axonal CMT yielded a relatively lower detection rate (22.9%), and the leading causes, occupying 72.4%, were MFN2 (37.2%), MPZ (9.0%), HSPB1 (8.3%), GJB1 (7.7%), GDAP1 (5.1%) and MME (5.1%). First decade of life was found as the most common disease onset period, and early-onset CMT cases were most likely to receive a molecular diagnosis. Geographical distribution analysis indicated distinctive genetic spectrums in different regions of Japan.Conclusions Our results updated the genetic profile within a large-scale of Japanese CMT cases. Subsequent analyses regarding onset age and geographical distribution advanced our understanding of CMT, which would be beneficial for clinicians.

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“…CMT shows considerable genetic heterogeneity. To date, variants in more than 80 genes have been shown to cause CMT [5]. CMT type 1 is characterized by decreased motor nerve conduction velocities (< 38 m/s), sensory loss, progressive muscle weakness, distal limb atrophy and myelin defects [6].…”

Section: Introductionmentioning

confidence: 99%

Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: Clinical gene panels versus genome-wide approaches to molecular diagnosis

Punetha

Mackay-Loder

Harel

et al. 2018

Molecular Genetics and Metabolism

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Charcot-Marie-Tooth (CMT) disease type 1 is an inherited peripheral neuropathy characterized by demyelination and reduced nerve conduction velocities. We present a multi-generational family with peripheral neuropathy in whom clinical CMT panel testing failed to conclude a molecular diagnosis. We found a PMP2 pathogenic variant c.155T > C, p.(Ile52Thr) that segregates with disease suggesting that PMP2 variants should be considered in patients with neuropathy and that it may be prudent to include in clinical CMT gene panels.

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Genetic analysis of Charcot-Marie-Tooth disease in Denmark and the implementation of a next generation sequencing platform

Cited by 22 publications

References 31 publications

Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease

Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease

Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan

Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: Clinical gene panels versus genome-wide approaches to molecular diagnosis

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