Congenital Disorders of Glycosylation, Type If (CDG If) via the MPDU1 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). As defective glycosylation negatively impacts a wide variety of cellular processes, most of these diseases are multi-systemic and early onset in nature.

Only a few cases of CDG type If, an N-linked glycosylation defect, have been reported to date. All individuals presented with initial symptoms during the neonatal or infantile period (Kranz et al. 2001. PubMed ID: 11733556; Schenk et al. 2001. PubMed ID: 11733564; Bastaki et al. 2018. PubMed ID: 28940310; Thiel et al. 2018. PubMed ID: 29721919). Primary clinical features for this disorder include hypotonia, seizures, ichthyosiform changes to the skin, psychomotor retardation, and optical findings such as strabismus or optic atrophy. A subset of patients presented with additional phenotypes, which included brain abnormalities (such as cerebral atrophy), gastrointestinal problems (abdominal pain, vomiting, diarrhea), and/or cardiomyopathy.

Congenital disorder of glycosylation (CDG) type If exhibits autosomal recessive inheritance. MPDU1 is a protein involved in the biosynthesis of dolichylpyrophosphate-linked oligosaccharide (Kranz et al. 2001. PubMed ID: 11733556). Specifically, the MPDU1 gene encodes a protein termed ‘mannose phosphate dolichol utilization defect 1,’ which is required for efficient use of dolichol- P-mannose within this pathway, although the exact molecular mechanism is yet unclear. Several pathogenic MPDU1 missense pathogenic variants and a single base deletion have been reported to date.

Due to the low incidence of this disorder, clinical sensitivity cannot be estimated at this time. There have been no reported large deletions or insertions in this gene to date (Human Gene Mutation Database). Analytical sensitivity should be high as reported pathogenic 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 MPDU1 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).