Congenital Disorders of Glycosylation, Type Ic (CDG Ic) via the ALG6 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: 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 Ic, an N-linked glycosylation defect, is the second-most prevalent CDG after CDG Ia (PMM2 deficiency), and generally results in a milder clinical course (Haeuptle et al. 2009. PubMed ID: 19862844; Morava et al. 2016. PubMed ID: 27287710). Approximately 90 cases have been reported in the literature to date (Morava et al. 2016. PubMed ID: 27287710; Medrano et al. 2019. PubMed ID: 30653653). Affected individuals commonly present in infancy or early childhood with a combination of developmental delay, hypotonia (predominantly proximal muscle weakness), speech disability, and epilepsy, while other features such as failure to thrive, ataxia, nystagmus, strabismus, gastrointestinal disturbances, progressive microcephaly, coagulopathy, dysmorphic features, behavioral abnormalities (autistic behavior and/or severe mood swings), abnormal fat distribution, and elevated liver transaminases may be variable (Morava et al. 2016. PubMed ID: 27287710). MRI findings (including vermis hypoplasia and/or cerebellar atrophy) have been described in a subset of patients, as well as skeletal abnormalities such as brachydactyly or arachnodactyly (Morava et al. 2016. PubMed ID: 27287710; Hanefeld et al. 2000. PubMed ID: 10832578; Ichikawa et al. 2013. PubMed ID: 23044053; Drijvers et al. 2010. PubMed ID: 20447155).

Congenital disorder of glycosylation type Ic is inherited in an autosomal recessive manner. Most of the causative variants reported in this gene to date are missense; however, one nonsense variant, three splicing variants, three small in-frame deletions, two single basepair duplications, and one large deletion have also been described (Human Gene Mutation Database). Several in-frame deletions reported in independent patients lead to the removal of the same critical p.Ile299 residue (p.Ile299del) (Haeuptle et al. 2009. PubMed ID: 19862844).

The recurrent p.Ala333Val pathogenic variant has been described in individuals of European, Japanese, and Indian ancestry, and is speculated to have arisen as a founder mutation from an isolated White population (Vuillaumier-Barrot et al. 2005. PubMed ID: 15771971; Dercksen et al. 2013. PubMed ID: 23430515; Ichikawa et al. 2013. PubMed ID: 23044053; Newell et al. 2003. PubMed ID: 12855228). In one study, this common pathogenic variant (p.Ala333Val) was found in the homozygous state in eight of eleven CDG Ic patients, while other pathogenic variants in ALG6 were identified in the remaining three patients (Imbach et al. 2000. PubMed ID: 10914684; Imbach et al. 1999. PubMed ID: 10359825). Another recurrent pathogenic variant is the c.167+5G>A splice site pathogenic variant (Westphal et al. 2000. PubMed ID: 10924277; Imbach et al. 2000. PubMed ID: 10914684; Drijvers et al. 2010. PubMed ID: 20447155; Posey et al. 2017. PubMed ID: 27959697; Dercksen et al. 2013. PubMed ID: 23430515).

The ALG6 gene encodes a glucosyltransferase that catalyzes the transfer of the first glucose (Glc) residue onto the dolichol-linked oligosaccharide precursor for N-linked glycosylation (Haeuptle et al. 2009. PubMed ID: 19862844).

Due to the low incidence of this disorder, clinical sensitivity is difficult to estimate. All of the reported variants in the Human Gene Mutation Database (HGMD; http://www.hgmd.cf.ac.uk/) should be covered in this test, including one gross deletion.

This test provides full coverage of all coding exons of the ALG6 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.