Congenital Disorders of Glycosylation, Type Ii (CDG Ii) via the ALG2 Gene

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. Consequently, the majority of these disorders demonstrate multi-system involvement. 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).

Fewer than 10 cases of CDG Ii, an N-linked glycosylation defect, have been reported in the literature to date (Cossins et al. 2013. PubMed ID: 23404334; Thiel et al. 2003. PubMed ID: 12684507; Asteggiano et al. 2018. PubMed ID: 30397276). Three probands presented with a multisystem disorder characterized by developmental and intellectual disability, bilateral iris colobomas, unilateral cataract, infantile spasms, and hypsarrhythmia (Thiel et al. 2003. PubMed ID: 12684507; Asteggiano et al. 2018. PubMed ID: 30397276). Two of these individuals also presented with additional features, including severe microcephaly, dysmorphism, bilateral epicanthus, bilateral convergent strabismus, and abnormal MRI findings such as hyperintensity in the basal ganglia and periventricular white matter in addition to thinning of the corpus callosum (Asteggiano et al. 2018. PubMed ID: 30397276).

Affected individuals from two other families, however, presented predominantly with a congenital myasthenic syndrome characterized by delayed motor milestones, hypotonia (primarily proximal muscle weakness), mild facial weakness, contractures of the knees, distal joint laxity, bilateral pes planus, and high arched palate (Cossins et al. 2013. PubMed ID: 23404334). Most of the patients never achieved ambulation. In addition, a muscle biopsy taken from one proband exhibited a severe reduction in ALG2 protein.

Congenital disorder of glycosylation type Ii is inherited in an autosomal recessive manner. Most of the causative variants reported in this gene to date are missense; however, one small single basepair deletion and one in-frame indel have been described (HGMD; Asteggiano et al. 2018. PubMed ID: 30397276).

The ALG2 gene encodes a mannosyltransferase that catalyzes the transfer of mannose residues onto Man₁GlcNAc₂-PP-dolichol (Thiel et al. 2003. PubMed ID: 12684507).

Due to the low incidence of this disorder clinical sensitivity cannot be estimated. All coding and non-coding regions of the ALG2 gene that harbor causative variants reported in the Human Gene Mutation Database (HGMD; http://www.hgmd.cf.ac.uk/) as of 08/05/2019 are covered in this test.

This test provides full coverage of all coding exons of the ALG2 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).