Congenital disorders of glycosylation: Still “hot” in 2020

Ondruskova, Nina; Čechová, Anna; Hansı́ková, Hana; Honzík, Tomáš; Jaeken, Jaak

doi:10.1016/j.bbagen.2020.129751

Cited by 98 publications

(96 citation statements)

References 201 publications

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“…Congenital disorders of glycosylation (CDG) are a growing group of metabolic diseases with at least 137 defects ( Ondruskova et al, 2021 ). According to the International Classification of Inherited Metabolic Disorders (ICIMD) database, 32 are classified as N-linked protein glycosylation defects ( Ferreira et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation Across Various Populations Based on Allele Frequencies in General Population Databases

et al. 2021

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Congenital disorders of glycosylation (CDG) are a widely acknowledged group of metabolic diseases. PMM2-CDG is the most frequently diagnosed CDG with a prevalence as high as one in 20,000. In contrast, the prevalence of other CDG types remains unknown. This study aimed to analyze the estimated prevalence of different N-linked protein glycosylation disorders. We extracted allele frequencies for diverse populations from The Genome Aggregation Database (gnomAD), encompassing variant frequency information from 141,456 individuals. To identify pathogenic variants, we used the ClinVar database as a primary source. High confidence loss-of-function variants as defined by the LOFTEE algorithm were also classified as pathogenic. After summing up population frequencies for pathogenic alleles, estimated disease birth prevalence values with confidence intervals were calculated using the Bayesian method. We first validated our approach using two more common recessive disorders (cystic fibrosis and phenylketonuria) by showing that the estimated prevalences calculated from population allele frequencies were in accordance with previously published epidemiological studies. Among assessed 27 autosomal recessive N-glycosylation disorders, the only disease with estimated birth prevalence higher than one in 100,000 was PMM2-CDG (in both, all gnomAD individuals and those with European ancestry). The combined prevalence of 27 different N-glycosylation disorders was around one in 22,000 Europeans but varied considerably across populations. We will show estimated prevalence data from diverse populations and explain the possible pitfalls of this analysis. Still, we are confident that these data will guide CDG research and clinical care to identify CDG across populations.

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Section: Introductionmentioning

confidence: 99%

The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation Across Various Populations Based on Allele Frequencies in General Population Databases

et al. 2021

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“…Approximately 140 inborn errors of metabolism have been classified as congenital disorders of glycosylation (CDG), a rapidly expanding group of diseases caused by defects in the synthesis and attachment of glycans to glycoproteins and glycolipids ( Ondruskova et al, 2021 ). ALG1-CDG is a subtype with severe multiorgan involvement (OMIM 608540) caused by pathogenic variants in ALG1 .…”

Section: Introductionmentioning

confidence: 99%

ALG1-CDG Caused by Non-functional Alternative Splicing Involving a Novel Pathogenic Complex Allele

et al. 2021

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This study reports on a Mexican mestizo patient with a multi-systemic syndrome including neurological involvement and a type I serum transferrin profile. Clinical exome sequencing revealed complex alleles in ALG1, the encoding gene for the chitobiosyldiphosphodolichol beta-mannosyltransferase that participates in the formation of the dolichol-pyrophosphate-GlcNAc2Man5, a lipid-linked glycan intermediate during N-glycan synthesis. The identified complex alleles were NM_019109.5(ALG1): c.[208 + 16_208 + 19dup; 208 + 25G > T] and NM_019109.5(ALG1): c.[208 + 16_208 + 19dup; 1312C > T]. Although both alleles carried the benign variant c.208 + 16_208 + 19dup, one allele carried a known ALG1 pathogenic variant (c.1312C > T), while the other carried a new uncharacterized variant (c.208 + 25G > T) causing non-functional alternative splicing that, in conjunction with the benign variant, defines the pathogenic protein effect (p.N70S_S71ins9). The presence in the patient’s serum of the pathognomonic N-linked mannose-deprived tetrasaccharide marker for ALG1-CDG (Neu5Acα2,6Galβ1,4-GlcNAcβ1,4GlcNAc) further supported this diagnosis. This is the first report of an ALG1-CDG patient from Latin America.

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“…CDG are an expanding group of rare, multisystem, underdiagnosed heterogeneous diseases caused by deficient or improper synthesis or attachment of glycans to proteins and lipids. More than 130 inherited disorders have been identified so far, most of them following an autosomal recessive inheritance pattern (Ondruskova et al, 2021). Glycosylation is a very important post-translational modification, as it is estimated that at least 2% of the human genome codes for proteins involved in this vital biochemical pathway (Ng and Freeze, 2018).…”

Section: Glycosaminoglycan Synthesis-related Disorders Form a Subgroup Of Congenital Disorders Of Glycosylationmentioning

confidence: 99%

Section: Glycosaminoglycan Synthesis-related Disorders Form a Subgroup Of Congenital Disorders Of Glycosylationmentioning

confidence: 99%

Chondrodysplasias With Multiple Dislocations Caused by Defects in Glycosaminoglycan Synthesis

Cormier‐Daire

2021

Front. Genet.

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Chondrodysplasias with multiple dislocations form a group of severe disorders characterized by joint laxity and multiple dislocations, severe short stature of pre- and post-natal onset, hand anomalies, and/or vertebral anomalies. The majority of chondrodysplasias with multiple dislocations have been associated with mutations in genes encoding glycosyltransferases, sulfotransferases, and transporters implicated in the synthesis or sulfation of glycosaminoglycans, long and unbranched polysaccharides composed of repeated disaccharide bond to protein core of proteoglycan. Glycosaminoglycan biosynthesis is a tightly regulated process that occurs mainly in the Golgi and that requires the coordinated action of numerous enzymes and transporters as well as an adequate Golgi environment. Any disturbances of this chain of reactions will lead to the incapacity of a cell to construct correct glycanic chains. This review focuses on genetic and glycobiological studies of chondrodysplasias with multiple dislocations associated with glycosaminoglycan biosynthesis defects and related animal models. Strong comprehension of the molecular mechanisms leading to those disorders, mostly through extensive phenotypic analyses of in vitro and/or in vivo models, is essential for the development of novel biomarkers for clinical screenings and innovative therapeutics for these diseases.

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Congenital disorders of glycosylation: Still “hot” in 2020

Cited by 98 publications

References 201 publications

The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation Across Various Populations Based on Allele Frequencies in General Population Databases

The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation Across Various Populations Based on Allele Frequencies in General Population Databases

ALG1-CDG Caused by Non-functional Alternative Splicing Involving a Novel Pathogenic Complex Allele

Chondrodysplasias With Multiple Dislocations Caused by Defects in Glycosaminoglycan Synthesis

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