Congenital Disorders of Glycosylation, Type Ia (CDG-Ia) via the PMM2 Gene

Congenital disorders of glycosylation (CDG) are a genetically heterogeneous group of disorders caused by defective synthesis of asparagine (N)-linked glycans. Abnormalities in these glycoconjugates result in disturbed metabolism, cell recognition, cell adhesion, protease resistance, host defense, cell migration, and antigenicity (Marquardt and Denecke. Eur J Pediat 162:359-379, 2003). Consequently, clinical presentations are characterized by multisystem involvement. Individuals with CDG Ia (OMIM 212065) have cerebellar hypoplasia, dysmorphic facies, coagulopathy, strabismus, psychomotor retardation, and sometimes unusual fat distribution and inverted nipples (de Lonlay et al. J Med Genet 38:14-19, 2001; Sparks and Krasnewich GeneReviews 2008). Presentation and clinical course can be highly variable, and three stages have been delineated. The infantile multisystem stage is characterized by failure to thrive secondary to vomiting, diarrhea, and feeding problems; hypotonia and hyporeflexia; high nasal bridge; prominent jaw and ears; and unusual fat distribution over the buttocks. Some patients who present in this stage exhibit fatal neurological and multi-organ involvement, while others present with a non-fatal neurological form lacking visceral organ involvement (de Lonlay et al. J Med Genet 38:14-19, 2001). The late-infantile and childhood ataxia-mental retardation stage is characterized by developmental delay, (especially language and motor skills), ataxia, joint contractures, and skeletal deformities. During the adult stable disability stage, premature aging is observed along with stable mental capacity, progressive skeletal deformities, and hypogonadism (Drouin-Garraud et al. Am J Med Genet 101: 46-49, 2001).

All CDGs 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 few individual patients. CDG Ia is the most common form with ~400 cases reported worldwide, followed by CDG 1b and CDG Ic, each with approximately 20 cases. The PMM2 gene (OMIM 601785) codes for phosphomannomutase-2, an enzyme involved in the synthesis of GDP-mannose. Variants in PMM2 are distributed throughout the coding region, and missense variants are the most common type.

In cases with demonstrated reduced activity of phosphomannomutase and diagnostic serum transferrin glycoforms, PMM2 sequencing is nearly 100% sensitive (Sparks and Krasnewich, GeneReviews 2008). Among 56 patients with proven enzyme deficiency Matthijs et al. found variants on 99% of the affected alleles, and one variant (p.Arg141His) accounted for almost 40% of all causative variants  (Matthijs et al. Am J Hum Genet 62:542-550, 1998). The p.Arg141His homozygous genotype has never been observed, presumably because it is embryonic lethal (Matthijs et al. Molec Genet Metab 68:220-226, 1999). The relatively common European p.Arg141His/p.Phe119Leu and p.Arg141His/p.Asp188Gly genotypes are associated with severe phenotypes, including a high mortality rate for the latter.

This test provides full coverage of all coding exons of the PMM2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.