Congenital Disorders of Glycosylation, Type Io Plus Secondary Dystroglycanopathy via the DPM3 Gene

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of disorders caused by defective synthesis of N-linked glycans. Abnormalities in these glycoconjugates cause disturbances in metabolism, cell recognition, cell adhesion, protease resistance, host defense, cell migration, and antigenicity (Marquardt and Denecke. Eur J Pediat 162:359-379, 2003). Clinical presentations are characterized by multisystem involvement. Dystroglycan is the central component of the muscle dystrophin-glycoprotein complex ([DGC] Michele and Campbel.l J Biol Chem 278:15457-15460, 2003). DAG1 encodes the alpha and beta subunits of dystroglycan. Both subunits undergo modification by N- and O-linked glycosylation; however, alpha-dystroglycan undergoes extensive O-linked glycosylation (Ibraghimov-Beskrovnaya et al. Hum Mol Genet 2:1651-1657, 1993). The glycosylation status of dystroglycan is critical for ligand binding and pathogenesis (Barresi and Campbell. J Cell Sci 119:199-207, 2006). A patient with clinical symptoms consistent with muscular dystrophy and a muscle biopsy with immunohistochemical signs of dystroglycanopathy was found to have an abnormal serum transferrin profile, suggesting a CDG type I pattern and reduced dolichol-phosphate-mannose (Dol-P-Man) synthase activity secondary to a homozygous DPM3 (OMIM 605951) variant (Leifeber et al. Am J Hum Genet 85:76-86, 2009). DPM3 encodes a Golgi membrane-spanning protein that binds the catalytic subunit of the Dol-P-Man enzyme. Variants in DPM1, the catalytic subunit of Dol-P-Man, have been shown to cause CDG Ie (OMIM 608799), but no other connections between muscular dystrophy and N-linked glycosylation defects have ever been made. DPM3-associated CDG has been classified as type Io (OMIM 612937).

Congenital disorders of glycosylation and the dystroglycan-associated muscular dystrophies all exhibit autosomal recessive inheritance. Thirteen forms of CDG have been characterized at the molecular level but only three, CDG Ia, CDG Ib, and CDG Ic, have been reported in more than a small number of patients. Congenital and limb girdle muscular dystrophy caused by defective posttranslational processing of alpha-dystroglycan results from variants in six genes that encode known or putative glycosyltransferases. Yet unidentified genes are likely the cause for at least half of all dystroglycanopathy cases. The CDGs result from defective N-linked glycosylation while the dystroglycan-associated muscular dystrophies result from defective O-linked glycosylation. The single patient with apparent dystroglycanopathy and reduced Dol-P-Man synthase activity was found to have a homozygous p.Leu85Ser variant in the DPM3 gene manifesting as reduced binding of the catalytic domain to the Golgi membrane (Leifeber et al. 2009).

Due to the low incidence of this disorder, clinical sensitivity cannot be estimated.

This test provides full coverage of all coding exons of the DPM3 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).