Congenital Disorders of Glycosylation (CDG) Panel

Congenital disorders of glycosylation (CDGs) are a clinically heterogeneous group of inborn errors of metabolism that are characterized by defects in protein or lipid glycosylation, a form of post-translational modification. These disorders can be further differentiated into several categories depending upon what part of the glycosylation pathway has been disrupted: protein N-linked protein glycosylation defects, which are the most common; O-linked protein glycosylation defects; glycolipid and glycosylphosphatidylinositol (GPI) anchor defects; or multi-pathway defects (Brasil et al. 2018. PubMed ID: 29702557; Jaeken. 2017. PubMed ID: 28484880; Scott et al. 2014. PubMed ID: 24831587). Analysis via serum transferrin isoelectrofocusing is often considered the standard first screen test for N-linked protein glycosylation disorders; however, normal results with this test do not preclude the possibility of a CDG diagnosis (N-linked or otherwise), and therefore, molecular testing is often advised if a CDG is part of the differential (Jaeken. 2017. PubMed ID: 28484880).

As defective glycosylation negatively impacts a wide variety of cellular processes, most of these diseases are multi-systemic and early onset in nature. However, varying degrees of severity and age at onset have been described, even in patients with defects in the same gene (Sparks and Krasnewich. 2015. PubMed ID: 20301289; Sparks and Krasnewich. 2017. PubMed ID: 20301507). The majority of N-linked CDGs present in infancy, and symptoms may include failure to thrive, developmental delay, liver dysfunction, seizures, hypotonia, hypoglycemia, protein-losing enteropathy, eye dysfunction (such as strabismus or retinitis pigmentosa), immunologic dysfunction, skin abnormalities, or skeletal abnormalities (Sparks and Krasnewich. 2017. PubMed ID: 20301507).

CDG type Ia (PMM2-CDG) due to pathogenic variants in PMM2 is the most common N-linked CDG described to date. The clinical spectrum of PMM2-CDG may range from a severe infantile-onset multi-system disease to an adult stable disability disorder (Sparks and Krasnewich. 2015. PubMed ID: 20301289).

O-linked CDGs, in contrast, typically present as muscular dystrophies with additional phenotypes such as hypotonia, brain malformations, intellectual disability, cardiac involvement, or ocular dysfunction (Martin. 2005. PubMed ID: 16584074).

GPI anchor defects are characterized by intellectual disability, hyperphosphatasia, or paroxysmal nocturnal hemoglobinuria (Witters et al. 2017. PubMed ID: 29112118). Lastly, defects that result in multi-pathway dysfunction, such as those that involve the dolichol phosphate mutase (DPM) complex that is essential for all three glycosylation pathways, often result in severe multi-system phenotypes. Clinical features may overlap with symptoms seen in both N- and O-linked glycosylation disorders (Witters et al. 2017. PubMed ID: 29112118).

At this time, treatment is available for MPI-CDG (oral mannose or liver transplantation) (Jaeken. 2017. PubMed ID: 28484880). Partial treatments exist for SLC35C1-CDG (oral fucose); DOLK-CDG (heart transplantation); PGM1-CDG, SLC35A2-CDG, and SLC39A8-CDG (galactose); and DPAGT1-CDG and ALG2-CDG (cholinesterase inhibitors; Jaeken. 2017. PubMed ID: 28484880).

The great majority of CDGs tested in this panel exhibit autosomal recessive inheritance, with a few exceptions: notably, ALG13, ATP6AP1, MAGT1, PIGA, SLC35A2, and SSR4 exhibit X-linked inheritance (Sparks and Krasnewich. 2017. PubMed ID: 20301507; Evers et al. 2017. PubMed ID: 28688840; Tarailo-Graovac et al. 2015. PubMed ID: 25885527). See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Note that the most common pathogenic variant in PMM2, p.Arg141His, has a very high carrier rate in certain populations (up to ~0.8% in European continental populations, http://gnomad.broadinstitute.org/), yet homozygotes for this variant have not yet been documented. Homozygosity for this variant is therefore strongly suspected to result in embryonic lethality (Matthijs et al. 1998. PubMed ID: 9497260; Thiel et al. 2006. PubMed ID: 16847317).

Clinical sensitivity for this panel is difficult to estimate at this time, as this specific group of genes has not previously been tested in a large cohort to date. The majority of CDGs have only been reported in a handful of individuals; some exceptions include CDG caused by defects in the PMM2 gene, which has been reported in over 700 individuals to date, and CDG due to pathogenic variants in the MPI, ALG6, SRD5A3, and COG6 genes (Sparks and Krasnewich. 2017. PubMed ID: 20301507).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.9% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).