Mutation Analysis of GARS and Genotype-Phenotype Correlation in CMT2D/HMN5A in Chinese Patients

Abstract BackgroundCMT2D is a rare subtype of axonal CMT, caused by a variant of the glycyl-tRNA synthetase (GARS) gene which is also a disease-causing gene of distal spinal muscular atrophy type V (dSMA-V) or hereditary motor neuropathy 5A (HMN5A). There were only several cases reported in China, all lacking an epidemiological study of CMT2D/ HMN5A.Methods206 patients of Chinese Han descent, clinically diagnosed with inherited peripheral neuropathy (IPN), were recruited in this study from December 20, 2012 to July 31, 2019. All patients underwent a detailed medical history screening, a neurological examination, a laboratory examination, several electrophysiological studies, and genetic testing.ResultsA total of 206 unrelated patients underwent genetic analysis. Four variants of GARS from four different families were found, including c.794C > T (p.S265F), c.374A > G (p.E125G), c.1000A > T (p.I334F), and c.781T > G (p.Y261D), with the first three being considered pathogenic. For the three pathogenic variant carriers, one was diagnosed with CMT2D, while the two others were diagnosed with HMN5A.ConclusionGARS mutation is a rare outcome of inherited peripheral neuropathy and the phenotype tends to be CMT2D or HMN5A.

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Screening for GARS Variants in A Cohort of Chinese Patients With Inherited Peripheral Neuropathy

10.21203/rs.3.rs-43866/v1 ◽

2020 ◽

Author(s):

Bo Sun ◽

Zheng-Qing He ◽

Yan-Ran Li ◽

Hong-Fen Wang ◽

Fang Cui ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Muscular Atrophy ◽

Case Reports ◽

Asian Population ◽

Trna Synthetase ◽

Chinese Patients ◽

Motor Neuropathy ◽

Chinese Han ◽

Spinal Muscular Atrophy Type ◽

Detailed Medical History

Abstract Background CMT2D is a rare subtype of axonal CMT, caused by the mutation of glycyl-tRNA synthetase (GARS) gene which is also a disease-causing gene of distal spinal muscular atrophy type V (dSMA-V) or hereditary motor neuropathy 5A (HMN5A). There were only several case reports in China, and no epidemiological study of CMT2D/ HMN5A yet.Methods We recruited the patients of Chinese Han descent clinically diagnosed with inherited peripheral neuropathy (IPN) from the Department of Neurology at Chinese PLA General Hospital (Beijing, China) from December 20, 2012 to July 31, 2019. All patients underwent a detailed medical history, neurological examination, laboratory examination, electrophysiological studies, and genetic testing.Results A total of 206 unrelated patients underwent genetic analysis, and we found four mutations of GARS from four different families, including c.794C>T (p.S265F), c.374A>G (p.E125G), c.1000A>T (p.I334F) and c.781T>G (p.Y261D), the first three of them were considered pathogenic. As for the three pathogenic mutation carriers, one patient was diagnosed as CMT2D, two patients were diagnosed as HMN5A.Conclusion GARS mutation is a rare cause of inherited peripheral neuropathy and the phenotype tends to be CMT2D or HMN5A. There might be a relatively higher mutation frequency in Asian population compared with Caucasians. Combination of clinical phenotype, auxiliary tests and genetic evidence to assess the pathogenicity of genetic variants in patients suspected as IPN is of vital importance.

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Glycyl tRNA Synthetase (GARS) Gene Variant Causes Distal Hereditary Motor Neuropathy V

Case Reports in Pediatrics ◽

10.1155/2018/8516285 ◽

2018 ◽

Vol 2018 ◽

pp. 1-4 ◽

Cited By ~ 3

Author(s):

Peter Chung ◽

Hope Northrup ◽

Misbah Azmath ◽

Ricardo A. Mosquera ◽

Shade Moody ◽

...

Keyword(s):

Muscular Atrophy ◽

Trna Synthetase ◽

Motor Neuropathy ◽

Inherited Disorders ◽

Causative Gene ◽

Hereditary Motor ◽

Pathogenic Variants ◽

Neurogenic Muscular Atrophy ◽

Hereditary Motor Neuropathy ◽

Type V

Distal hereditary motor neuropathies (dHMN) are a rare heterogeneous group of inherited disorders specifically affecting the motor axons, leading to distal limb neurogenic muscular atrophy. The GARS gene has been identified as a causative gene responsible for clinical features of dHMN type V in families from different ethnic origins and backgrounds. We present the first cohort of family members of Nigerian descent with a novel heterozygous p.L272R variant on the GARS gene. We postulate that this variant is the cause of dHMN-V in this family, leading to variable phenotypical expressions that are earlier than reported in previous cases. The exact cause for the observed clinical heterogeneity within the family is unknown. One explanation is that there are modifier genes that affect the phenotype. These cases highlight the possibility of considering pathogenic variants in the GARS gene as a potential cause of early onset axonal polyneuropathy with atypical presentation.

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Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V

The American Journal of Human Genetics ◽

10.1086/375039 ◽

2003 ◽

Vol 72 (5) ◽

pp. 1293-1299 ◽

Cited By ~ 357

Author(s):

Anthony Antonellis ◽

Rachel E. Ellsworth ◽

Nyamkhishig Sambuughin ◽

Imke Puls ◽

Annette Abel ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Muscular Atrophy ◽

Trna Synthetase ◽

Disease Type ◽

Charcot Marie Tooth ◽

Spinal Muscular Atrophy Type ◽

Charcot Marie Tooth Disease ◽

Type V ◽

Tooth Disease

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The G526R glycyl-tRNA synthetase gene mutation in distal hereditary motor neuropathy type V

Neurology ◽

10.1212/01.wnl.0000218304.02715.04 ◽

2006 ◽

Vol 66 (11) ◽

pp. 1721-1726 ◽

Cited By ~ 38

Author(s):

O. Dubourg ◽

H. Azzedine ◽

R. B. Yaou ◽

J. Pouget ◽

A. Barois ◽

...

Keyword(s):

Gene Mutation ◽

Trna Synthetase ◽

Motor Neuropathy ◽

Hereditary Motor ◽

Hereditary Motor Neuropathy ◽

Type V

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Biallelic SORD pathogenic variants cause Chinese patients with distal hereditary motor neuropathy

npj Genomic Medicine ◽

10.1038/s41525-020-00165-6 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Hai-Lin Dong ◽

Jia-Qi Li ◽

Gong-Lu Liu ◽

Hao Yu ◽

Zhi-Ying Wu

Keyword(s):

Ex Vivo ◽

Protein Solubility ◽

Chinese Patients ◽

Hereditary Neuropathy ◽

Motor Neuropathy ◽

Causative Gene ◽

Hereditary Motor ◽

Functional Studies ◽

Hereditary Motor Neuropathy

AbstractSorbitol dehydrogenase gene (SORD) has been identified as a novel causative gene of recessive forms of hereditary neuropathy, including Charcot–Marie–Tooth disease type 2 and distal hereditary motor neuropathy (dHMN). Our findings reveal two novel variants (c.404 A > G and c.908 + 1 G > C) and one known variant (c.757delG) within SORD in four Chinese dHMN families. Ex vivo cDNA polymerase chain reaction confirmed that c.908 + 1 G > C variant was associated with impaired splicing of the SORD transcript. In vitro cell functional studies showed that c.404 A > G variant resulted in aggregate formation of SORD and low protein solubility, confirming the pathogenicity of SORD variants. We have provided more evidence to establish SORD as a causative gene for dHMN.

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