Congenital Disorders of Glycosylation, Type Ie (CDG Ie) via the DPM1 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. 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 Ie, an N-linked glycosylation defect, has been described in approximately fifteen individuals to date (Kim et al. 2000. PubMed ID: 10642597; Bursle et al. 2017. PubMed ID: 27481510; Yang et al. 2013. PubMed ID: 23856421; Vuillaumier-Barrot et al. 2005. PubMed ID: 15771971; Garcia-Silva et al. 2004. PubMed ID: 15669674; Dancourt et al. 2006. PubMed ID: 16641202; Imbach et al. 2000. PubMed ID: 10642602; Medrano et al. 2019. PubMed ID: 30653653; Perez-Cerda et al. 2017. PubMed ID: 28139241). Patients typically presented during the neonatal or infantile stages with hypotonia, retinopathy, progressive microcephaly, seizures, and developmental delays. Other common symptoms included facial dysmorphism and abnormal findings upon neuroimaging, such as delayed myelination and/or cerebellar atrophy. Biochemically, many patients were reported to have elevated creatine kinase and antithrombin III deficiency. Less commonly-reported symptoms included knee contractures, strabismus, nystagmus, and/or hepatosplenomegaly. Clinically less severely-affected patients have also been reported. Two siblings with enzymatic, cellular, and molecular-confirmed CDG Ie were found to have ataxia as the dominant phenotype (Dancourt et al. 2006. PubMed ID: 16641202).

Congenital disorder of glycosylation (CDG) type Ie is inherited in an autosomal recessive manner. The DPM1 gene encodes a mannosyltransferase that catalyzes the transfer of the sixth mannose to a lipid-linked oligosaccharide precursor (Gandini et al. 2017. PubMed ID: 28743912). Several missense pathogenic variants, one splice site pathogenic variant, two small frameshift deletions, and one large deletion have been reported in this gene to date (Human Gene Mutation Database).

Due to the low incidence of this disorder, clinical sensitivity cannot be estimated at this time. Only one large deletion has been reported in this gene (Human Gene Mutation Database). Analytical sensitivity should be high as the great majority of reported variants are detectable by sequencing.

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 DPM1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions where 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).