Elevated Lyso-Gb3 Suggests the R118C GLA Mutation Is a Pathological Fabry Variant

Talbot, Andrew; Nicholls, Kathy

doi:10.1007/8904_2018_146

Cited by 13 publications

(14 citation statements)

References 18 publications

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“…Initially, this variant was considered pathogenic, leading to its inclusion in calculations of FD prevalence in young stroke patients screening [30]. Later, the variant was reclassified at VUS [29], although recently emerging information is in favour of the original classification [31].…”

Section: Discussionmentioning

confidence: 99%

Detailed Phenotype of GLA Variants Identified by the Nationwide Neurological Screening of Stroke Patients in the Czech Republic

Reková

Dostálová

Kemlink

et al. 2021

JCM

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Fabry disease (FD) is a rare X-linked disorder of glycosphingolipid metabolism caused by pathogenic variants within the alpha-galactosidase A (GLA) gene, often leading to neurological manifestations including stroke. Multiple screening programs seeking GLA variants among stroke survivors lacked detailed phenotype description, making the interpretation of the detected variant’s pathogenicity difficult. Here, we describe detailed clinical characteristics of GLA variant carriers identified by a nationwide stroke screening program in the Czech Republic. A total of 23 individuals with 8 different GLA variants were included in the study. A comprehensive diagnostic workup was performed by a team of FD specialists. The investigation led to the suggestion of phenotype reclassification for the G325S mutation from late-onset to classical. A novel variant R30K was found and was classified as a variant of unknown significance (VUS). The typical manifestation in our FD patients was a stroke occurring in the posterior circulation with an accompanying pathological finding in the cerebrospinal fluid. Moreover, we confirmed that cornea verticillata is typically associated with classical variants. Our findings underline the importance of detailed phenotype description and data sharing in the correct identification of pathogenicity of gene variants detected by high-risk-population screening programs.

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Section: Discussionmentioning

confidence: 99%

Detailed Phenotype of GLA Variants Identified by the Nationwide Neurological Screening of Stroke Patients in the Czech Republic

Reková

Dostálová

Kemlink

et al. 2021

JCM

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“…This assessment can be troublesome and may even be conflicting. For instance, variant c.352C>T (R118C) was categorized 'apathogenic' [24] and 'possibly disease triggering' [25,26]. The same applies to variant c.937G>T (D313Y) [27][28][29].…”

Section: Discussionmentioning

confidence: 99%

Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure

et al. 2020

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Background. Fabry disease (FD) is an X-linked lysosomal storage and multi-system disorder due to mutations in the a-galactosidase A (a-GalA) gene. We investigated the impact of individual amino acid exchanges in the a-GalA 3D-structure on the clinical phenotype of FD patients. Patients and methods. We enrolled 80 adult FD patients with a-GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the a-GalA 3Dstructure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD-specific treatment. Results. Patients with active site or buried mutations showed a severe phenotype with multi-organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. a-GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso-Gb3 levels were higher (P < 0.01 in men; <0.05 in women). Conclusions. The type of amino acid exchange location in the a-GalA 3D-structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.

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“…All but two variants in Table 2 were classi ed as pathogenic by a combination of variant effect prediction tools (CADD, REVEL, SIFT, MutationTaser, Polyphen2) and 4 of them were already classi ed by ClinVar as pathogenic. One patient carried the variant R118C that has con icting pathogenicity interpretation 29,30 . Indeed, he did not present any of the signs and symptoms that are shown in Table 1.…”

Section: Downsampling For Designing Higher Multiplexed Sequencingmentioning

confidence: 99%

Detection of Single Nucleotide and Copy Number Variants in the Fabry Disease-associated GLA Gene Using Nanopore Sequencing

Nowak

Murik

Mann

et al. 2021

Preprint

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Introduction: More than one thousand variants have been described in the GLA gene. Some intronic variants and copy number variants in GLA can cause Fabry disease but will not be detected by classical Sanger sequence.Aims: We aimed to design and validate a method for sequencing the GLA gene using long read Oxford Nanopore sequencing technology.Methods: Twelve Fabry patients were blindly analyzed, both by conventional Sanger sequence and by long read sequencing of a 13kb PCR amplicon. We used minimap2 to align the long read data and Nanopolish and Sniffles to call variants.Results: All the variants detected by Sanger (including a deep intronic variant) were also detected by long read sequencing. One patient had a deletion that was not detected by Sanger sequencing but was detected by the new technology.Conclusions: Our long read sequencing-based method was able to detect missense variants and an exonic deletion, with the added advantage of intronic analysis. It can be used as an efficient and cost-effective tool for screening and diagnosing Fabry disease.

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Elevated Lyso-Gb3 Suggests the R118C GLA Mutation Is a Pathological Fabry Variant

Cited by 13 publications

References 18 publications

Detailed Phenotype of GLA Variants Identified by the Nationwide Neurological Screening of Stroke Patients in the Czech Republic

Detailed Phenotype of GLA Variants Identified by the Nationwide Neurological Screening of Stroke Patients in the Czech Republic

Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure

Detection of Single Nucleotide and Copy Number Variants in the Fabry Disease-associated GLA Gene Using Nanopore Sequencing

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