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A protein glycosylation screen to diagnose rare genetic disorders and unravel disease mechanisms

Friday, September 18, 2015 — Poster Session IV

12:00 p.m. – 1:30 p.m.
FAES Terrace


  • MS Kane
  • M Davids
  • X Li
  • M Raihin
  • M He
  • WA Gahl
  • CF Boerkoel


The NIH Undiagnosed Diseases Program (UDP) concentrates its efforts on the most puzzling medical cases, focusing on disease discovery and patient diagnosis using both genomic data and basic research. Some UDP patients could have Congenital Disorders of Glycosylation (CDGs), whose phenotypes lack consistent clinical features or biomarkers, and are difficult to diagnose. Therefore, we undertook an agnostic screen of plasma and urine to identify abnormalities of protein glycosylation in UDP patients. Plasma and urine screens were completed for 110 patients, and included profiling of plasma N-linked glycans by MALDI-TOF, plasma O-linked glycans by LC-MS/MS and MALDI-TOF, and urine free oligosaccharides by MALDI-TOF/TOF. Over 75% of UDP patients had a glycosylation profile that deviated from a healthy control population in at least one specimen. Additional evaluation of the N-linked and O-linked glycosylation profiles in primary dermal fibroblasts of 56 patients with glycome abnormalities resulted in a tractable glycome phenotype in ~50% of these cases. Using this approach, we identified different CDGs, lysosomal storage disorders (affecting glycoprotein degradation), and rare disorders in which glycosylation is affected indirectly. We also added abnormal glycosylation findings to the phenotypical spectrum of a known rare disease, shedding light on a potential factor of the underlying pathogenic mechanism. In summary, we described a comprehensive screening approach to identify primary protein glycosylation abnormalities and provide a useful tool for biochemically phenotyping patients with unknown diseases and unraveling the underlying mechanisms of diseases.

Category: Genetics and Genomics