Targeted next-generation sequencing improves diagnosis of hereditary spastic paraplegia in Chinese patients

Cong, Lu; Li, Lixi; Dong, Hai‐Lin; Wei, Qiao; Liu, Zhijun; Wang, Ni; Gitler, Aaron D.; Wu, Zhi‐Ying

doi:10.1007/s00109-018-1655-4

Cited by 28 publications

(33 citation statements)

References 40 publications

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“…7,8 Owing to CMT's clinical and genetic heterogeneity, it is expensive and time-consuming to screen all the possible causative genes using conventional Sanger sequencing. However, highthroughput targeted next-generation sequencing (NGS) has been employed successfully in CMT 9,10 and other neurogenetic diseases such as amyotrophic lateral sclerosis (ALS), [11][12][13] hereditary spastic paraplegia (HSP), 14,15 and hereditary ataxia (HA). 16,17 Consequently, nearly 90 genes associated with CMT and other inherited peripheral neuropathies have been assembled in a gene panel, and parallel sequencing can be performed to interrogate these genes.…”

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confidence: 99%

Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot‐Marie‐Tooth disease

et al. 2019

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Charcot‐Marie‐Tooth (CMT) disease is a heterogeneous group of inherited sensorimotor neuropathies. To clarify the genetic spectrum and clinical profiles in Chinese CMT patients, we enrolled 150 unrelated CMT patients from southeast China. We performed multiplex ligation‐dependent probe amplification (MLPA) testing in all patients and next‐generation sequencing (NGS) among those patients without PMP22 rearrangements. We identified PMP22 duplications in 40 patients and deletions in 12 patients. In addition, we found 19 novel variants and 36 known mutations in 57 patients. Among these 55 variants, 45 pathogenic or likely pathogenic variants were identified in 48 cases, and 10 variants with uncertain significance were identified in 9 cases. Therefore, we obtained a genetic diagnosis in 63.8% (88/138) of CMT patients and 66.7% (100/150) of all included patients. PMP22, GJB1, and MFN2 are the most common causative genes in CMT1 (demyelinated form), intermediate CMT, and CMT2 (axonal form), respectively. In this study, we identified a higher proportion of intermediate CMT, a relatively high frequency of NDRG1 mutations and clinical features of later onset age in CMT1A patients. Our results broaden the genetic and clinical spectrum of CMT patients, which can help optimize the genetic and clinical diagnosis.

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confidence: 99%

Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot‐Marie‐Tooth disease

et al. 2019

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“…The MPS panel screening in a group of 30 Polish HSP families, that have previously shown negative results of several target DNA tests, revealed one familial SPG30 case [23]. MPS in 55 Chinese HSP patients that have previously underwent MLPA screening unraveled 34 cases with SPG mutations with one SPG30 familial case [24]. The referred data show that AD SPG30 contributes to HSP morbidity all over the world, but its proportions are different and some are difficult to be compared.…”

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confidence: 89%

KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families

et al. 2020

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Background: Spastic paraplegia type 30 (SPG30) caused by KIF1A mutations was first reported in 2011 and was initially considered a very rare autosomal recessive (AR) form. In the last years, thanks to the development of massive parallel sequencing, SPG30 proved to be a rather common autosomal dominant (AD) form of familial or sporadic spastic paraplegia (SPG),, with a wide range of phenotypes: pure and complicated. The aim of our study is to detect AD SPG30 cases and to examine their molecular and clinical characteristics for the first time in the Russian population. Methods: Clinical, genealogical and molecular methods were used. Molecular methods included massive parallel sequencing (MPS) of custom panel 'spastic paraplegias' with 62 target genes complemented by familial Sanger sequencing. One case was detected by the whole-exome sequencing. Results: AD SPG30 was detected in 10 unrelated families, making it the 3rd (8.4%) most common SPG form in the cohort of 118 families. No AR SPG30 cases were detected. In total, 9 heterozygous KIF1A mutations were detected, with 4 novel and 5 known mutations. All the mutations were located within KIF1A motor domain. Six cases had pure phenotypes, of which 5 were familial, where 2 familial cases demonstrated incomplete penetrance, early onset and slow relatively benign SPG course. All 4 complicated cases were caused by novel mutations without familial history. The phenotypes varied from severe in two patients (e.g. lack of walking, pronounced mental retardation) to relatively mild non-disabling symptoms in two others. Conclusion: AD SPG30 is one of the most common forms of SPG in Russia, the disorder has pronounced clinical variability while pure familial cases represent a significant part.

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“…Patients who exhibit agnogenic white matter abnormality, unexplained spastic paraparesis, or early‐onset dementia were suggestive of leukodystrophies . Firstly we screened causative genes for CADASIL, adrenoleukodystrophy, hereditary spastic paraplegia (HSP), and familial Alzheimer's disease (FAD) on these patients in our previous studies, and patients who carry pathogenic variants were excluded. Then, 28 unrelated patients (probands) were recruited consecutively between March 2015 and August 2018 from the Department of Neurology in Second Affiliated Hospital of Zhejiang University School of Medicine.…”

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confidence: 99%

New clinical characteristics and novel pathogenic variants of patients with hereditary leukodystrophies

et al. 2019

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Aim Leukodystrophies are a group of inherited white matter disorders with clinical, genetic, and imaging heterogeneity, which usually pose a diagnostic challenge for physicians. We aimed to identify new clinical characteristics and novel pathogenic variants of hereditary leukodystrophies in this study. Methods Whole exome sequencing (WES) was performed in 28 unrelated patients clinically suspected with leukodystrophies. Leukocytes enzyme activity test, electroencephalogram (EEG), electromyography (EMG), and brain MRI were conducted. Functional analysis was performed, and the pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Results We made definite diagnosis in 8 probands with 12 pathogenic variants and reported new clinical characteristics and imaging features of these patients. Three novel pathogenic variants were identified, including a microdeletion variant c.2654_2654+3del within CSF1R, a nonsense variant c.1321C>T, and a missense variant c.166G>C within GALC. Conclusion Our results have deepened the understanding of clinical, genetic, and imaging heterogeneity of hereditary leukodystrophies, and expanded the spectrum of pathogenic variants and clinical features.

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Targeted next-generation sequencing improves diagnosis of hereditary spastic paraplegia in Chinese patients

Abstract: We made a genetic diagnosis in 61.8% of families and identified 33 mutations. SPAST mutations are the most common in Chinese AD-HSP followed by ATL1. Our findings broaden the genetic spectrum and improve the diagnosis of HSP.

Cited by 28 publications

References 40 publications

Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot‐Marie‐Tooth disease

Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot‐Marie‐Tooth disease

KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families

New clinical characteristics and novel pathogenic variants of patients with hereditary leukodystrophies

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