Clinical glycomics in the diagnostic laboratory

Post, Merel A.; Lefeber, Dirk

doi:10.21037/atm.2019.08.74

Cited by 7 publications

(9 citation statements)

References 16 publications

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“…Transferrin glycosylation analysis is established for CDG diagnosis, either via isoelectric focusing or by intact mass analysis [ 9 , 10 , 26 ]. In this study, we performed various MS glycomics analyses, including novel linkage-specific sialylation analysis of total plasma proteins and IgG glycosylation, to a wide range of CDGs.…”

Section: Discussionmentioning

confidence: 99%

“…Conventional clinical diagnostic techniques include screening for glycosylation defects by transferrin isoelectric focussing (TIEF) [ 6 , 7 ]. Recent advances in the field include the implementation of mass spectrometric analysis of the abnormal glycan structures attached to transferrin (Tf) to support diagnosis [ 8 , 9 , 10 ]. Specific Tf glycosylation patterns driven by (abnormal) glycan structure abundances often correlate with very specific defects of e.g., nucleotide sugars or enzymes in the biosynthetic pathway.…”

Section: Introductionmentioning

confidence: 99%

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Dissecting Total Plasma and Protein-Specific Glycosylation Profiles in Congenital Disorders of Glycosylation

Ederveen

Haan

Baerenfaenger

et al. 2020

IJMS

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Protein N-glycosylation is a multifactorial process involved in many biological processes. A broad range of congenital disorders of glycosylation (CDGs) have been described that feature defects in protein N-glycan biosynthesis. Here, we present insights into the disrupted N-glycosylation of various CDG patients exhibiting defects in the transport of nucleotide sugars, Golgi glycosylation or Golgi trafficking. We studied enzymatically released N-glycans of total plasma proteins and affinity purified immunoglobulin G (IgG) from patients and healthy controls using mass spectrometry (MS). The applied method allowed the differentiation of sialic acid linkage isomers via their derivatization. Furthermore, protein-specific glycan profiles were quantified for transferrin and IgG Fc using electrospray ionization MS of intact proteins and glycopeptides, respectively. Next to the previously described glycomic effects, we report unprecedented sialic linkage-specific effects. Defects in proteins involved in Golgi trafficking (COG5-CDG) and CMP-sialic acid transport (SLC35A1-CDG) resulted in lower levels of sialylated structures on plasma proteins as compared to healthy controls. Findings for these specific CDGs include a more pronounced effect for α2,3-sialylation than for α2,6-sialylation. The diverse abnormalities in glycomic features described in this study reflect the broad range of biological mechanisms that influence protein glycosylation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dissecting Total Plasma and Protein-Specific Glycosylation Profiles in Congenital Disorders of Glycosylation

Ederveen

Haan

Baerenfaenger

et al. 2020

IJMS

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“…The biomarker potential of glycans was identified in numerous studies ( Kavur et al. 2021 ) and the clinical analysis of glycosylation is routinely used for the diagnostics of congenital disorders of glycosylation ( Post and Lefeber 2019 ). Another example of a clinically validated assay that is based on glycosylation profiling is the Glyco Liver Profile test from Helena Biosciences ( Vanderschaeghe et al.…”

Section: Perspectives For the Wider Application Of Ht Glycomicsmentioning

confidence: 99%

Developments and perspectives in high-throughput protein glycomics: enabling the analysis of thousands of samples

et al. 2022

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Glycans expand the structural complexity of proteins by several orders of magnitude, resulting in a tremendous analytical challenge when including them in biomedical research. Recent glycobiological research is painting a picture in which glycans represent a crucial structural and functional component of the majority of proteins with alternative glycosylation of proteins and lipids being an important regulatory mechanism in many biological and pathological processes. Since inter-individual differences in glycosylation are extensive, large studies are needed to map the structures and understand the role of glycosylation in human (patho)physiology. Driven by these challenges, methods have emerged which can tackle the complexity of glycosylation in thousands of samples, also known as high-throughput glycomics. For facile dissemination and implementation of high-throughput glycomics technology, the sample preparation, analysis as well as data mining, needs to be stable over a long period of time (months/years), amenable to automation, and available to non-specialized laboratories. Current high-throughput glycomics methods mainly focus on protein N-glycosylation and allow to extensively characterize this subset of the human glycome in large numbers of various biological samples. The ultimate goal in high-throughput glycomics is to gain better knowledge and understanding of the complete human glycome, using methods that are easy to adapt and implement in (basic) biomedical research. Aiming to promote wider use and development of high-throughput glycomics, here we present currently available, emerging and prospective methods and some of their applications, revealing a largely unexplored molecular layer of the complexity of life.

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“…Although proteomics and metabolomics are quite universal approaches, the utility and yield of other ‐omics techniques (e.g., lipidomics and glycomics) 135,142,143 require further evaluation. Fluxomics using stable isotope labeling, to study the flux of metabolites through a metabolic pathways, is a relatively new technique 144 .…”

Section: The Added Value Of Functional Datamentioning

confidence: 99%

How to proceed after “negative” exome: A review on genetic diagnostics, limitations, challenges, and emerging new multiomics techniques

Wortmann

Oud

Alders

et al. 2022

J of Inher Metab Disea

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Exome sequencing (ES) in the clinical setting of inborn metabolic diseases (IMDs) has created tremendous improvement in achieving an accurate and timely molecular diagnosis for a greater number of patients, but it still leaves the majority of patients without a diagnosis. In parallel, (personalized) treatment strategies are increasingly available, but this requires the availability of a molecular diagnosis. IMDs comprise an expanding field with the ongoing identification of novel disease genes and the recognition of multiple inheritance patterns, mosaicism, variable penetrance, and expressivity for known disease genes. The analysis of trio ES is preferred over singleton ES as information on the allelic origin (paternal, maternal, “de novo”) reduces the number of variants that require interpretation. All ES data and interpretation strategies should be exploited including CNV and mitochondrial DNA analysis. The constant advancements in available techniques and knowledge necessitate the close exchange of clinicians and molecular geneticists about genotypes and phenotypes, as well as knowledge of the challenges and pitfalls of ES to initiate proper further diagnostic steps. Functional analyses (transcriptomics, proteomics, and metabolomics) can be applied to characterize and validate the impact of identified variants, or to guide the genomic search for a diagnosis in unsolved cases. Future diagnostic techniques (genome sequencing [GS], optical genome mapping, long‐read sequencing, and epigenetic profiling) will further enhance the diagnostic yield. We provide an overview of the challenges and limitations inherent to ES followed by an outline of solutions and a clinical checklist, focused on establishing a diagnosis to eventually achieve (personalized) treatment.

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Clinical glycomics in the diagnostic laboratory

Cited by 7 publications

References 16 publications

Dissecting Total Plasma and Protein-Specific Glycosylation Profiles in Congenital Disorders of Glycosylation

Dissecting Total Plasma and Protein-Specific Glycosylation Profiles in Congenital Disorders of Glycosylation

Developments and perspectives in high-throughput protein glycomics: enabling the analysis of thousands of samples

How to proceed after “negative” exome: A review on genetic diagnostics, limitations, challenges, and emerging new multiomics techniques

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