A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type IIw (CDG2W) is caused by a heterozygous mutation in the G6PT1 gene (SLC37A4; 602671), which encodes glucose-6-phosphate translocase, on chromosome 11q23.

Congenital disorder of glycosylation type IIw (CDG2W) is an autosomal dominant metabolic disorder characterized by liver dysfunction, coagulation deficiencies, and profound abnormalities in N-glycosylation of serum specific proteins. All reported patients carry the same mutation (602671.0017) (summary by Ng et al., 2021).

For an overview of congenital disorders of glycosylation, see CDG1A (212065) and CDG2A (212066).

Marquardt et al. (2020) reported a girl who was treated for gastroesophageal reflux and ankyloglossia in infancy; at 10 weeks of age she had developed hepatopathy and failure to thrive. Laboratory tests showed elevated serum transaminases, thrombocytopenia, elevated INR, moderate anemia, prolonged activated partial thromboplastin time (APTT), and multiple clotting factor abnormalities. Liver biopsy at 3 months of age showed steatosis and increased hepatocyte volume. Isoelectric focusing of serum transferrin (190000) showed a CDG type II pattern. She learned to walk at 2 years of age, but development was otherwise normal. At 5 years of age, hepatopathy and coagulopathy had become milder. She was also noted to have a pectus carinatum. Facial dysmorphism included bilateral choanal atresia, low-set ears, broad nose, micrognathia, and facial asymmetry. At 12 years of age, she had normal psychomotor development and was noted to be well, with mild elevation in AST and mild hypercoagulability.

Wilson et al. (2021) reported a patient with CDG2W who had prolonged jaundice, hepatomegaly, mild splenomegaly, anemia, elevated transaminases, elevated APTT, elevated prothrombin time (PT), and decreased fibrinogen (see 134820) in infancy. Liver biopsy at 4 months of age showed fibrosis and bile duct proliferation. She had normal growth and psychomotor development, but during childhood she had persistent hepatomegaly and worsening coagulopathy. At 8 years of age she developed insulin-dependent diabetes. During adolescence she developed progressive scoliosis and membranoproliferative glomerulonephritis.

Ng et al. (2021) reported 7 patients from 4 families, ages 1 month to 42 years, with liver dysfunction, multifactorial coagulation abnormalities, and abnormal N-glycosylation of serum proteins. One patient had ankyloglossia, 3 patients had cardiac abnormalities (including 2 with ventricular septal defects and 1 with tetralogy of Fallot), and 3 patients had scoliosis. All 7 patients had an abnormal type II carbohydrate-deficient transferrin (CDT) and O-glycan apoC-III testing. All 7 patients had decreased coagulation factor II (thrombin) (F2; 176930) and antithrombin (SERPINC1; 107300) activities; 6 of 7 patients had reduced F5 (612309) activity; 6 of 6 patients had reduced F11 (264900) activity; 5 of 7 had reduced protein S (PROS1; 176880); and 4 of 6 had reduced F9 (300746). All 7 patients had elevated aspartate aminotransferase (AST) levels, and none had elevated alanine aminotransferase (ALT).

The transmission pattern of CDG2W in 2 families reported by Ng et al. (2021) was consistent with autosomal dominant inheritance. The heterozygous mutations in the SLC37A4 gene that were identified in patients with CDG2W by Marquardt et al. (2020) and Wilson et al. (2021) occurred de novo.

In a patient with CDG2W, Marquardt et al. (2020) identified a heterozygous mutation (R423X; 602671.0017) in the SLC37A4 gene. The de novo mutation was identified by trio whole-exome sequencing. The mutation was predicted to remove an endoplasmic reticulum retention signal and expose a weak Golgi retention signal. Expression of the mutant protein in HepG2 cells and subsequent immunolocalization studies suggested that it mislocalized to the Golgi. The patient had a CDG type II glycosylation pattern on serum transferrin isoelectric focusing, and HPLC analysis of serum transferrin showed severe hypoglycosylation.

Wilson et al. (2021) identified heterozygosity for the R423X mutation in a patient with CDG2W. The de novo mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing.

Ng et al. (2021) identified heterozygosity for the R423X mutation in 7 patients from 4 families, including a mother and son from one family and a mother, son, and daughter from another family, with CDG2W. Analysis of Huh7 cells expressing SLC37A4 with the R423X mutation showed that the mutant protein likely localized to an undefined intermediate subcompartment between the total ER and the cis-Golgi, leading to lowered Golgi pH.