Glycomics in rare diseases: from diagnosis to mechanism

The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) studies rare genetic disorders not only to achieve diagnoses, but to understand human biology. To ascertain the contribution of protein glycosylation to rare diseases, the NIH UDP used mass spectrometry to agnostically identify abnormalities of N-linked and O-linked glycans in plasma and free oligosaccharides in the urine of 207 patients. 60% of UDP patients had a glycome profile that deviated from control values in at least 1 fluid. Additional evaluation of the fibroblast glycome in 66 patients with abnormalities in plasma and/or urine revealed a consistent glycome phenotype in 83% of these cases. Many of these patients may have secondary glycosylation defects, since it is unlikely that they all have congenital disorders of glycosylation (CDGs). In fact, whole exome sequencing revealed only a few patients with CDGs, along with several others having disorders indirectly altering glycosylation. In summary, we describe a biochemical phenotyping screen to identify defects in protein glycosylation that can elucidate mechanisms of disease among NIH UDP patients.