Congenital Disorders of Glycosylation, Type Ih (CDG Ih) via the ALG8 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).

CDG type Ih, an N-linked glycosylation defect, has been described in approximately 20 individuals to date (Höck et al. 2015. PubMed ID: 26066342; Bastaki et al. 2018. PubMed ID: 28940310). Patients generally present at birth or during the neonatal period, and disease progression is often rapid. Symptoms include dysmorphic features, which are characterized by retrognathia, low-set ears, hypertelorism, and/or pes equinovarus; muscular hypotonia; hepatomegaly; coagulopathy, often notably thrombocytopenia; edema and ascites, which may include fetal hydrops; cardiorespiratory problems; gastrointestinal signs including diarrhea, vomiting, feeding problems, and protein-losing enteropathy; and occasionally congenital cataracts (Höck et al. 2015. PubMed ID; 26066342). Patients often show signs of brain involvement, such as psychomotor delays, seizures, ataxia, and/or structural abnormalities. Additionally, affected individuals may also display fat pads, wrinkly skin, cutis laxa, and/or inverted nipples. Plasma isoelectric focusing of transferrin of these patients demonstrates a type I pattern (CDG-I).

Congenital disorder of glycosylation type Ih is inherited in an autosomal recessive manner. The ALG8 gene encodes a protein (dolichyl-phosphate-glucose 1-mannose 9-N-acetylglucosamine glucosyltransferase) required for the addition of the second glucose residue onto lipid-linked oligosaccharides (Chantret et al. 2003. PubMed ID: 12480927). The majority of causative variants reported in this gene to date are missense; however, one nonsense, three splicing, three small frameshift deletions, and one single basepair duplication have also been reported (Human Gene Mutation Database).

Due to the low incidence of this disorder clinical sensitivity cannot be precisely estimated. However, all coding and non-coding regions of the ALG8 gene that harbor causative variants reported in the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/) as of 06/20/2019 are covered in this test.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV-calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This test provides full coverage of all coding exons of the ALG8 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.

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).