Children with rare disease CDG don’t have mutation in every cell type

By Heather Buschman, Ph.D.
May 10, 2013

Children born with rare, inherited conditions known as Congenital Disorders of Glycosylation, or CDG, have mutations in one of the many enzymes the body uses to decorate its proteins and cells with sugars. Properly diagnosing a child with CDG and pinpointing the exact sugar gene that’s mutated can be a huge relief for parents—they better understand what they’re dealing with and doctors can sometimes use that information to develop a therapeutic approach. Whole-exome sequencing, an abbreviated form of whole-genome sequencing, is increasingly used as a diagnostic for CDG.

But researchers at Sanford-Burnham recently discovered three children (pictured above) with CDG who are mosaics—only some cells in some tissues have the mutation. For that reason, standard exome sequencing initially missed their mutations, highlighting the technique’s diagnostic limitations in some rare cases. These findings were published April 4 in the American Journal of Human Genetics.

“This study was one surprise after another,” said Hudson Freeze, Ph.D., director of Sanford-Burnham’s Genetic Disease Program and senior author of the study. “What we learned is that you have to be careful—you can’t simply trust that you’ll get all the answers from gene sequencing alone.”

Searching for a rare disease mutation

Complicated arrangements of sugar molecules decorate almost every protein and cell in the body. These sugars are crucial for cellular growth, communication, and many other processes. As a result of a mutation in an enzyme that assembles these sugars, children with CDG experience a wide variety of symptoms, including intellectual disability, digestive problems, seizures, and low blood sugar.

To diagnose CDG, researchers will test the sugar arrangements on a common protein called transferrin. Increasingly, they’ll also look for known CDG-related mutations by whole-exome sequencing, a technique that sequences only the small portion of the genome that encodes proteins. The patients are typically three to five years old.

A cautionary tale for genomic diagnostics

In this study, our researchers observed different proportions and representations of sugar arrangements depending on which tissues were examined. In other words, these children have the first demonstrated cases of CDG “mosaicism”—their mutations only appear in some cell types throughout the body, not all. As a result, the usual diagnostic tests, like whole-exome sequencing, missed the mutations. It was only when Freeze’s team took a closer look, examining proteins by hand using biochemical methods, did they identify the CDG mutations in these three children.

The team then went back to the three original children and examined their transferrin again. Surprisingly, these readings, which had previously shown abnormalities, had become normal. Freeze and his team believe this is because mutated cells in the children’s livers died and were replaced by normal cells over time. However, better transferrin did not reverse all symptoms.

“If the transferrin test hadn’t been performed early on for these children, we never would’ve picked up these cases of CDG. We got lucky in this case, but it just shows that we can’t rely on any one test by itself in isolation,” Freeze said.


This research was funded by The Rocket Fund at Sanford-Burnham and the U.S. National Institutes of HealthNational Institute of Diabetes and Digestive and Kidney Diseases grant R01DK55615 and National Human Genome Research Institute grant 1U54HG006493.

Ng, B., Buckingham, K., Raymond, K., Kircher, M., Turner, E., He, M., Smith, J., Eroshkin, A., Szybowska, M., Losfeld, M., Chong, J., Kozenko, M., Li, C., Patterson, M., Gilbert, R., Nickerson, D., Shendure, J., Bamshad, M., & Freeze, H. (2013). Mosaicism of the UDP-Galactose Transporter SLC35A2 Causes a Congenital Disorder of Glycosylation The American Journal of Human Genetics, 92 (4), 632-636 DOI: 10.1016/j.ajhg.2013.03.012

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About Author

Heather Buschman, Ph.D.

Heather was an SBP Communications staff member.



  1. Oliver is my grandson and I just want to thank Hud Freeze and Bobby Ng and the whole team for their spectacular work in identifying the defect in these three special young people! You guys are the best! Thank you for your hard work and dedication!

  2. It is so exciting to learn that our little Rocket’s fund continues to provide knowledge and unlock more of the secrets associated with CDG. Amazing breakthrough.

  3. Thank you for all the information and encouraging research you are doing on CDG. Our 15 month old grand-daughter has been recently diagnosed with CDG 1A. We are overwhelmed with the details of this disorder and her doctors are at a loss in how to help her. We live in Southern California, can you recommend a doctor or children s hospital that is familiar with CDG 1A?


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