Pathogenic missense variants altering codon 336 of
            <i>GARS1</i>
            lead to divergent dominant phenotypes

Meyer, Alayne P; Forrest, Megan E.; Nicolau, Stefan; Wiszniewski, Wojciech; Bland, Mary Pat; Tsao, Chang-Yong; Antonellis, Anthony; Abreu, Nicolas J.

doi:10.1002/humu.24372

Cited by 4 publications

(4 citation statements)

References 25 publications

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“…For example, the pathogenic missense variants which alter codon 336 in the GARS1 gene that results in different phenotypic expression in a range of genetic neuropathies [ 73 ]. Two pathogenic variants resulting in a missense modifying amino acid at codon 336 in the catalytic domain of GARS1 , were found in two unrelated patients - one a female with infantile spinal muscular atrophy; and the second, a male with Charcot–Marie–Tooth disease type 2D [ 73 ]. Exchanges in amino acids that change the pH of the residue have also been linked to cancers [ 75 ].…”

Section: Discussionmentioning

confidence: 99%

Section: [27])mentioning

confidence: 99%

“…It has been suggested that there can be notable variability found in phenotypes, pathogenicity and oncogenic effects, based on the specific substitution at a single location [73][74][75]. For example, the pathogenic missense variants which alter codon 336 in the GARS1 gene that results in different phenotypic expression in a range of genetic neuropathies [73]. Two pathogenic variants resulting in a missense modifying amino acid at codon 336 in the catalytic domain of GARS1, were found in two unrelated patients -one a female with infantile spinal muscular atrophy; and the second, a male with Charcot-Marie-Tooth disease type 2D [73].…”

Section: [27])mentioning

confidence: 99%

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Genetic characterization of intramuscular myxomas

Hatchett,

Brunetti,

Andersen

et al. 2024

Pathol. Oncol. Res.

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Introduction: Intramuscular myxomas are benign tumors that are challenging to diagnose, especially on core needle biopsies. Acquired chromosomal aberrations and pathogenic variants in codon 201 or codon 227 in GNAS complex locus gene (GNAS) have been reported in these tumors. Here we present our genetic findings in a series of 22 intramuscular myxomas.Materials and methods: The tumors were investigated for the presence of acquired chromosomal aberrations using G-banding and karyotyping. Pathogenic variants in codon 201 or codon 227 of GNAS were assessed using direct cycle Sanger sequencing and Ion AmpliSeq Cancer Hotspot Panel v2 methodologies.Results: Eleven tumors carried chromosomal abnormalities. Six tumors had numerical, four had structural, and one had both numerical and structural chromosomal aberrations. Gains of chromosomes 7 and 8 were the most common abnormalities being found in five and four tumors respectively. Pathogenic variants in GNAS were detected in 19 myxomas (86%) with both methodologies. The detected pathogenic variants were p.R201H in nine cases (seven with abnormal and two with normal karyotypes), p.R201C in five cases, all with normal karyotypes, p.R201S in three cases (two with abnormal and one with normal karyotype), p.R201G in one case with a normal karyotype, and p.Q227E in one case with a normal karyotype.Conclusion: Firstly, our data indicate a possible association between chromosomal abnormalities and GNAS pathogenic variants in intramuscular myxomas. Secondly, the presence of the rare pathogenic variants R201S, p.R201G and p.Q227E in 26% (5 out of 19) of myxomas with GNAS pathogenic variants shows that methodologies designed to detect only the common “hotspot” of p.R201C and p.R201H will give false negative results. Finally, a comparison between Ion AmpliSeq Cancer Hotspot Panel v2 and direct cycle Sanger sequencing showed that direct cycle Sanger sequencing provides a quick, reliable, and relatively cheap method to detect GNAS pathogenic variants, matching even the most cutting-edge sequencing methods.

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Section: Discussionmentioning

confidence: 99%

Section: [27])mentioning

confidence: 99%

Section: [27])mentioning

confidence: 99%

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Genetic characterization of intramuscular myxomas

Hatchett,

Brunetti,

Andersen

et al. 2024

Pathol. Oncol. Res.

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“…Moreover, de novo variants in GARS1 have been associated with infantile-onset SMA (iSMA) similar to childhood SMA caused by mutations in SMN1 [17]. Recently, variants that alter the same amino-acid residue (p. Pro336His and p.Pro336Arg) were seen to lead to distinct neuropathic phenotypes, which range from iSMA to CMT2D [18].…”

Section: Distal Hereditary Motor Neuropathies With Upper Limb Predomi...mentioning

confidence: 99%

Hereditary motor neuropathies

Frasquet

Sevilla

2022

Current Opinion in Neurology

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Purpose of reviewDistal hereditary motor neuropathies (dHMN) are a clinically and genetically diverse group of disorders that are characterized by length-dependent axonal degeneration of lower motor neurons. In this review, we will provide an overview of dHMN, and we will correlate the distinct clinical subtypes with their causative genes, focusing on the most recent advances in the field. Recent findingsDespite the massive use of new-generation sequencing (NGS) and the discovery of new genes, only a third of dHMN patients receive a molecular diagnosis. Thanks to international cooperation between researchers, new genes have been implicated in dHMN, such as SORD and VWA1. Mutations in SORD are the most frequent cause of autosomal recessive forms of dHMN. As a result of these findings, the potential benefits of some pharmacological compounds are being studied in cell and animal models, mainly targeting axonal transport and metabolic pathways. SummaryDespite the wide use of NGS, the diagnosis of dHMN remains a challenge. The low prevalence of dHMN makes international cooperation necessary in order to discover new genes and causal mechanisms. Genetic diagnosis of patients and identification of new pathomechanism are essential for the development of therapeutical clinical trials.

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Insights into phenotypic variability caused by GARS1 pathogenic variants

Jiménez‐Jiménez,

Navarrete,

Azorín

et al. 2024

Euro J of Neurology

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Background and PurposePathogenic variants of the glycyl‐tRNA synthetase 1 (GARS1) gene have been described as a cause of Charcot–Marie–Tooth disease type 2D, motor axonal neuropathy with upper limb predominance (distal hereditary motor neuropathy [dHMN] type V), and infantile spinal muscular atrophy.MethodsThis cross‐sectional, retrospective, observational study was carried out on 12 patients harboring the c.794C>T (p.Ser265Phe) missense pathogenic variant in GARS1. The patients' clinical data, nerve conduction studies, magnetic resonance imaging (MRI), and intraepidermal nerve fiber density in skin biopsies were reviewed.ResultsThe mean age at onset was 9.5 years; the intrinsic hand muscles were affected before or at the same time as the distal leg musculature. The clinical examination revealed greater weakness of the distal muscles, with a more pronounced involvement of the thenar complex and the first dorsal interosseous in upper limbs. Electrophysiological studies were concordant with an exclusively motor axonal neuropathy. A pathologic split hand index was found in six patients. Muscle MRI showed predominant fatty infiltration and atrophy of the anterolateral and superficial posterior compartment of the legs. Most patients reported distal pinprick sensory loss. A reduced intraepidermal nerve fiber density was evident in skin biopsies from proximal and distal sites in nine patients.ConclusionsGARS1 variants may produce a dHMN phenotype with “split hand” and sensory disturbances, even when sensory nerve conduction studies are normal. This could be explained by a dysfunction of sensory neurons in the dorsal ganglion that is reflected as a reduction of dermal nerve endings in skin biopsies without a distal gradient.

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Pathogenic missense variants altering codon 336 of GARS1 lead to divergent dominant phenotypes

Cited by 4 publications

References 25 publications

Genetic characterization of intramuscular myxomas

Genetic characterization of intramuscular myxomas

Hereditary motor neuropathies

Insights into phenotypic variability caused by GARS1 pathogenic variants

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