Congenital Disorders of Glycosylation, Type IIj via the COG4 Gene

Congenital disorders of glycosylation (CDGs) are a group of heterogeneous disorders due to a defect in the linkage of oligosaccharides to proteins. This process involves covalent attachment of carbohydrate chains to the amide group of asparagine (N-glycoprotein) or less commonly to the hydroxyl group of serine/threonine (O-glycoprotein). Congenital disorders of glycosylation result in a wide variety of clinical features due to multisystem involvement, and include defects in nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency (Sparks and Krasnewich 2014; Scott et al. 2014) .

Thus far, only two patients with CDG IIj (COG-CDG) have been described. Onset occurs before one year of age with failure to thrive in infancy. The first patient with CDG IIj presented at 4 months of age with fever, irritability, and complex seizures after vaccination (Reynders et al. 2009). He also exhibited axial hypotonia, peripheral hypotonia, and hyperreflexia along with mild dysmorphic features such as down-sloping frontal area and thick hair. This patient also developed recurrent respiratory infections. By 3 years of age he had microcephaly, cerebral atrophy, ataxia, absence of speech, and psychomotor retardation. A second patient presented at 11 months of age with failure to thrive, recurrent diarrhea, and recurrent respiratory and gastrointestinal infections with sepsis (Ng et al. 2011). Other features included developmental delay, hypotonia, nystagmus, hepatosplenomegaly, and poor growth. Seizures developed at 16 months and an infection was ultimately fatal around 2 years of age. Both patients showed deficiencies in sialylation and galactosylation.

All CDGs exhibit autosomal recessive inheritance. More than 40 genes have been found to be involved with CDGs, but the majority of these have only been reported in a small number of individual patients (Sparks and Krasnewich 2014). The COG4 gene encodes a subunit of the conserved oligomeric Golgi (COG) complex which is composed of eight subunits. It functions as a vesicular tether during retrograde Golgi trafficking which is important for the recycling of Golgi resident proteins (such as glycosylation enzymes) that are essential for the proper glycosylation of secretory proteins (Willett et al. 2013). Defects in COG subunits that lead to aberrant glycosylation are likely a result of abnormal transport or distribution of glycosylation enzymes. Patients with COG4 pathogenic variants are considered to present with a milder phenotype in comparison to the other COG gene deficiencies (Reynders et al. 2009). Missense variants, a nonsense variant, and a small deletion are thus far the only pathogenic variants reported.

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. Analytical sensitivity should be high because all reported causative mutations thus far are detectable by sequencing.

This test provides full coverage of all coding exons of the COG4 gene 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 full 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).