Congenital disorders of glycosylation and the challenge of rare diseases

Abstract

The congenital disorders of glycosylation are a diverse group of disorders, which present both common and unique challenges in the diagnosis of rare disorders. These disorders affect a variety of structures and processes in their synthesis. Studies by Himmelreich and by Ng and their coworkers are discussed as they exemplify the extremes of such challenges. These include ascertainment bias associated with the recognition of only extreme phenotypes, variant classification limited by the rarity of the observed variant, limitations in glycan methodology, and expression patterns that can change with time and tissue type. The continuing importance of functional studies to help sort out these challenges is highlighted.

Contribution of a Novel B3GLCT Variant to Peters Plus Syndrome Discovered by a Combination of Next-Generation Sequencing and Automated Text Mining

“…In addition to ocular defects, PPS is characterized by short stature, dysmorphic facial features, and developmental delay [21]. In terms of classification, PPS belongs to genetically heterogeneous congenital disorders of glycosylation, grouping rare congenital, neurometabolic, and malformation syndromes [22,23]. It is caused by changes in B3GLCT, encoding an O -fucose-specific β-1,3-glucosyltransferase (beta-1,3-glucosyltransferase), responsible for attachment of glucose to O -linked fucose ( O -fucose), which is previously added by protein O -fucosyltransferase 2 ( POFUT2 ) to thrombospondin type 1 repeats (TSRs), present in many proteins [24].…”

Fetal phenotype of SLC35A2‐CDG: Enlarged cisterna magna on ultrasound

“…Congenital disorders of glycosylation (CDG) are rare conditions caused by genetic defects in glycan synthesis, processing or transport that are required in formation of glycoproteins and glycolipids 1 . Glycosylation involves an ever growing number of genes, encoding different proteins or enzymes.…”

“…Congenital disorders of glycosylation (CDG) are rare conditions caused by genetic defects in glycan synthesis, processing or transport that are required in formation of glycoproteins and glycolipids. 1 Glycosylation involves an ever growing number of genes, encoding different proteins or enzymes. A defect of one of these genes can lead to a subtype of CDG, potentially affecting multiple organ systems and always including an important neurological component.…”

DDOST‐CDG: Clinical and molecular characterization of a third patient with a milder and a predominantly movement disorder phenotype

“…Congenital disorders of glycosylation (CDG) are a group of clinically and biochemically heterogeneous inherited conditions affecting posttranslational protein modification and causing abnormal glycosylation of several types of macromolecules including glycoproteins, glycolipids, and proteoglycans 1–3 . Over 175 genetic disorders have been identified across several glycosylation pathways, and the list of conditions is ever growing with the identification of new genes implicated in the pathogenesis of these disorders, accelerated by the advent of next‐generation sequencing 3,4 .…”

“…Congenital disorders of glycosylation (CDG) are a group of clinically and biochemically heterogeneous inherited conditions affecting posttranslational protein modification and causing abnormal glycosylation of several types of macromolecules including glycoproteins, glycolipids, and proteoglycans. [1][2][3] Over 175 genetic disorders have been identified across several glycosylation pathways, and the list of conditions is ever growing with the identification of new genes implicated in the pathogenesis of these disorders, accelerated by the advent of nextgeneration sequencing. 3,4 Although the clinical spectrum is variable, impaired glycosylation of different macromolecules can result in overlapping multisystemic manifestations that often begin in infancy, and may include failure to thrive, developmental delay, neurologic abnormalities, hypoglycemia, hepatocellular injury, protein losing enteropathy, dermatologic manifestations, ocular anomalies, and skeletal anomalies.…”