Identification of Genetic Causes of Inherited Peripheral Neuropathies by Targeted Gene Panel Sequencing

Nam, Soo Hyun; Hong, Young Bin; Hyun, Young Se; Nam, Da Eun; Kwak, Geon; Hwang, Sun Hee; Choi, Byung‐Ok; Chung, Ki Wha

doi:10.14348/molcells.2016.2288

Cited by 66 publications

(27 citation statements)

References 25 publications

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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: Discussioncontrasting

confidence: 99%

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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Section: Discussioncontrasting

confidence: 99%

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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“…Because of the large number of genes implicated in this heterogeneous group of disease, this and other studies [22,23,24,25] together highlight the practical advantage of high-throughput sequencing in rapidly reaching the specific genetic diagnosis over previously proposed stepwise diagnostic algorithms [26,27,28]. As illustrated in Case 1, the patient had undergone screening for PMP22 duplication, mutation of GJB1 and MFN2 and active investigation for more than two years before the gene-panel method was attempted.…”

Section: Discussionmentioning

confidence: 94%

Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing

Tai

Lee

et al. 2017

IJMS

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Charcot-Marie-Tooth disease (CMT) is a common inherited peripheral neuropathy affecting up to 1 in 1214 of the general population with more than 60 nuclear genes implicated in its pathogenesis. Traditional molecular diagnostic pathways based on relative prevalence and clinical phenotyping are limited by long turnaround time, population-specific prevalence of causative variants and inability to assess multiple co-existing variants. In this study, a CMT gene panel comprising 27 genes was used to uncover the pathogenic mutations in two index patients. The first patient is a 15-year-old boy, born of consanguineous parents, who has had frequent trips and falls since infancy, and was later found to have inverted champagne bottle appearance of bilateral legs and foot drop. His elder sister is similarly affected. The second patient is a 37-year-old woman referred for pre-pregnancy genetic diagnosis. During early adulthood, she developed progressive lower limb weakness, difficulties in tip-toe walking and thinning of calf muscles. Both patients are clinically compatible with CMT, have undergone multiple genetic testings and have not previously received a definitive genetic diagnosis. Patients 1 and 2 were found to have pathogenic homozygous HSPB1:NM_001540:c.250G>A (p.G84R) variant and heterozygous GDAP1:NM_018972:c.358C>T (p.R120W) variant, respectively. Advantages and limitations of the current approach are discussed.

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“… 32 Therefore, it remains unclear whether the p.T54I variant is really pathogenic. Moreover, DCTN1 variants have been reported in primary lateral sclerosis, 34 neuropathy 35 and complex neurological disease with a slowly progressive, chronic axonal-distal motor neuropathy and extrapyramidal syndrome. 36 The case of extrapyramidal syndrome presented with ataxia, and also had NEFH and KIF5A variants.…”

Section: Resultsmentioning

confidence: 99%

Establishing diagnostic criteria for Perry syndrome

Mishima

Fujioka

Tomiyama

et al. 2017

J Neurol Neurosurg Psychiatry

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ObjectiveTo establish international diagnostic criteria for Perry syndrome, a disorder characterised by clinical signs of parkinsonism, depression/apathy, weight loss, respiratory symptoms, mutations in the DCTN1 gene and TAR DNA-binding protein 43 (TDP-43) pathology.MethodsData from the published literature and newly identified patients were gathered and analysed during and after the International Symposium on Perry syndrome in Tokyo to identify diagnostic criteria for Perry syndrome.ResultsEighty-seven patients with Perry syndrome carrying DCTN1 mutations from 20 families were included in this study, and common signs of the disorder were identified, including parkinsonism (95.2% of patients), depression/apathy (71.4%), respiratory symptoms (66.7%) and weight loss (49.2%).ConclusionsBased on our findings, we propose the following definitive diagnostic criteria for Perry syndrome: the presence of four cardinal signs of Perry syndrome, accompanied by a mutation in DCTN1; or a family history of the disease, parkinsonism and a mutation in DCTN1; or the presence of four cardinal signs and pathological findings that include nigral neuronal loss and TDP-43 pathology. As patients with Perry syndrome present with uniform clinical, genetic and pathological features, we further propose the disorder be termed ‘Perry disease.’

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Identification of Genetic Causes of Inherited Peripheral Neuropathies by Targeted Gene Panel Sequencing

Cited by 66 publications

References 25 publications

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

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

Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing

Establishing diagnostic criteria for Perry syndrome

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