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Abstract
Clinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration of glycomics with genomics has resulted in the elucidation of previously unknown disorders of glycosylation, namely CCDC115-CDG, TMEM199-CDG, ATP6AP1-CDG, MAN1B1-CDG, and PGM1-CDG. This review provides an introduction into protein glycosylation and presents the different glycomics methodologies ranging from gel electrophoresis to mass spectrometry (MS) and from free glycans to intact glycoproteins. The role of glycomics in the diagnosis of congenital disorders of glycosylation (CDG) is presented, including a diagnostic flow chart and an overview of glycomics data of known CDG subtypes. The review ends with some future perspectives, showing upcoming technologies as system wide mapping of the N- and O-glycoproteome, intact glycoprotein profiling and analysis of sugar metabolism. These new advances will provide additional insights and opportunities to develop personalized therapy. This is especially true for inborn errors of metabolism, which are amenable to causal therapy, because interventions through supplementation therapy can directly target the pathogenesis at the molecular level.
Highlights
Technological advances in science are creating a revolution in the world of clinical diagnostics for rare metabolic disorders
A combination of whole exome sequencing (WES) and deep clinical phenotyping was applied to 41 patients with intellectual developmental disorder and unexplained metabolic abnormalities, which resulted in a diagnosis for 28 patients (68%), and a test for targeted intervention on 18 patients (44%) (Van Karnebeek et al 2016)
For congenital disorders of glycosylation (CDG), many cases were unsolved until the inclusion of glycomics into clinical practice, to present the functional defect (Jansen et al 2016a; Jansen et al 2016b; Jansen et al 2016c; Van Damme et al 2016; Van Scherpenzeel et al 2014; Tegtmeyer et al 2014; Carss et al 2013; Iqbal et al 2013)
Summary
Technological advances in science are creating a revolution in the world of clinical diagnostics for rare metabolic disorders. The fact that an omics technique greatly reduces this turnaround time and increases the diagnostic yield has recently been shown for a cohort of 150 patients presenting with complex neurological disorders of suspected genetic origin They compared the number of solved cases applying either whole exome sequencing (WES) alone (29.3%) or the standard care pathway (7.3%). The percentage of solved cases of about 30% is still quite low, which is likely caused by either the lack of sequence coverage of the variant, by disease causes outside the coding sequences, or the presence of too many Bvariants of unknown significance^ In this light, the important connection of genomics with functional -omics methodologies in the diagnosis of metabolic disorders is recognized more and more. This review discusses glycomics, its role in CDG diagnostics, presents different methodologies, and ends with future perspectives, in which the horizon of the diagnostic laboratory needs to be broadened to functionally understand new genetic defects
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