Congenital Disorders of Glycosylation, Type Ig (CDG Ig) via the ALG12 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).

Approximately 10 cases of CDG Ig, an N-linked glycosylation defect, have been reported in the literature to date, and all were diagnosed in early infancy (Haeuptle et al. 2009. PubMed ID: 19862844; Normand et al. 2018. PubMed ID: 30266093; Retterer et al. 2016. PubMed ID: 26633542; Murali et al. 2014. PubMed ID: 25019053). Affected individuals commonly present with feeding difficulties, psychomotor delay, short stature, hypotonia, microcephaly, facial dysmorphism, inverted nipples, thrombocytopenia, low IgG, and/or intermittent elevation of liver transaminases. Males may exhibit micropenis and/or hypospadias (Kranz et al. 2007. PubMed ID: 17506107; Eklund et al. 2005. PubMed ID: 15639192).

In the most severe cases, skeletal involvement and/or structural brain abnormalities have been reported. Several probands presented with talipes equinovarus and ulnar deviation at the wrists (Kranz et al. 2007. PubMed ID: 17506107; Murali et al. 2014. PubMed ID: 25019053). Clinical features of other affected individuals included hypoplasia of the corpus callosum or ventricle enlargement (Kranz et al. 2007. PubMed ID: 17506107; Di Rocco et al. 2005. PubMed ID: 16435218).

Congenital disorder of glycosylation type Ig is inherited in an autosomal recessive manner. Most of the causative variants reported in this gene to date are missense; however, one nonsense variant and four small frameshift deletions have also been described (Human Gene Mutation Database).

The ALG12 gene encodes a mannosyltransferase that catalyzes the transfer of the eighth mannose from dolichol-P-Man to the dolichol-linked oligosaccharide (Haeuptle et al. 2009. PubMed ID: 19862844).

Due to the low incidence of this disorder clinical sensitivity cannot be estimated. All coding and non-coding regions of the ALG12 gene that harbor causative variants reported in the Human Gene Mutation Database (HGMD; http://www.hgmd.cf.ac.uk/) as of 08/06/2019 are covered in this test.

This test provides full coverage of all coding exons of the ALG12 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).