Congenital Disorders of Glycosylation, Type Id (CDG Id) via the ALG3 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).

Approximately 25 cases of CDG Id, an N-linked glycosylation defect, have been reported worldwide to date. This disorder is characterized by a slowly progressive encephalopathy that is usually diagnosed in utero or early infancy. Seizures, hypotonia, microcephaly, hypertelorism, large ears, long fingers/toes, psychomotor retardation, progression of white matter atrophy, and/or dysmorphic features are some of the primary phenotypes that may be associated with this disorder (Rimella-Le-Huu et al. 2008. PubMed ID: 18679822; Alsubhi et al. 2017. PubMed ID: 28742265; Santos-Cortez et al. 2018. PubMed ID: 30167849; Lepais et al. 2015. PubMed ID: 26126960). Additional clinical features that have been reported in multiple patients include hepatomegaly, skeletal dysplasia, optic atrophy, a flat nasal bridge, absent or poor speech, feeding difficulties, hypoplastic and/or inverted nipples, short neck, ambiguous genitalia, pulmonary hypertension, and/or heart defects such as patent ductus arteriosus (Riess et al. 2013. PubMed ID: 23791010; Lepais et al. 2015. PubMed ID: 26126960; Alsubhi et al. 2017. PubMed ID: 28742265).

Congenital disorder of glycosylation type Id is inherited in an autosomal recessive manner. The majority of causative mutations reported in this gene to date are missense; however, one splicing, one small inframe deletion, and one indel have also been reported (HGMD).

The ALG3 gene encodes a mannosyltransferase that catalyzes the transfer of mannose from dolichyl-phosphate mannose to a lipid-linked oligosaccharide intermediate (Körner et al. 1999. PubMed ID: 10581255).

Due to the low incidence of this disorder clinical sensitivity cannot be estimated. All coding and non-coding regions of the ALG3 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 ALG3 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).