Congenital Disorders of Glycosylation (CDG) Panel (Types Ia, Ib, and Ic)

Congenital disorders of glycosylation (CDG) are a genetically heterogeneous group of disorders caused by defective synthesis of asparagine (N)-linked glycans. Abnormalities in these glycoconjugates cause disturbances in metabolism, cell recognition, cell adhesion, protease resistance, host defense, cell migration, and antigenicity (Marquardt and Denecke. Eur J Pediat 162:359-379, 2003). Consequently, clinical presentations are characterized by multisystem involvement. Individuals with CDG Ia (OMIM #212065) have cerebellar hypoplasia, dysmorphic facies, coagulopathy, strabismus, psychomotor retardation, and sometimes unusual fat distribution and inverted nipples (de Lonlay et al. J Med Genet 38:14-19, 2001; Sparks and Krasnewich GeneReviews 2005). Presentation and clinical course can be highly variable, and three stages (infantile multisystem stage, late infantile and childhood ataxia-mental retardation stage, adult stable disability stage) have been delineated. Individuals with CDG Ib (OMIM #602579) exhibit diarrhea, protein-losing enteropathy, profound hypoglycemia, coagulopathy, and fibrotic liver disease (Jaeken et al. Am J Hum Genet 62:1535-1539, 1998). Patients are not dysmorphic and do not have cerebellar hypoplasia or unusual fat distribution. CDG Ib is treatable with oral mannose (Niehues at al. J Clin Invest 101:1414-1420, 1998). Individuals with CDG Ic (OMIM #603147) exhibit neurological symptoms including hypotonia, developmental delay, strabismus, and seizures. Clinical features of CDG Ic overlap both types Ia and Ib; however, symptoms are generally not as severe as in type Ia, and multi-organ involvement is not observed. Minimal protein-losing enteropathy and minimal liver disease of CDG Ic can often differentiate this type from CDG Ib. Cerebellar hypoplasia, a consistent finding in type Ia, is not seen in type Ic patients (Grunewald et al. Pediat Res 52:618-624, 2002).

All CDGs exhibit autosomal recessive inheritance. Thirteen forms of CDG have been characterized at the molecular level, but only three, CDG Ia, CDG Ib, and CDG Ic, have been reported in more than a few individual patients. CDG Ia is the most common form with ~400 cases reported worldwide, followed by CDG 1b and CDG Ic, each with approximately 20 cases. Variants in these three genes are most commonly missense variants, and they are distributed throughout the coding regions.

In cases with demonstrated reduced phosphomannomutase or mannosephosphate isomerase activity plus diagnostic serum transferrin glycoforms, PMM2 and MPI sequencing, respectively, is nearly 100% sensitive (Sparks and Krasnewich, GeneReviews 2005). Due to the low incidence of CDG Ic and lack of enzyme assay, test sensitivity for ALG6 sequencing is difficult to estimate.

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

This panel provides 100% 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).