Genome Sequencing Diagnostics Have Significant Problems, As New Research Demonstrates

Genome sequencing diagnostics has some serious limitations to it, as researchers at the Sanford-Burnham Medical Research Institute recently discovered when they came across three children who had some of the rare inherited conditions collectively known as Congenital Disorders of Glycosylation (CDG), but only in some of the cells of their body, not all. The children are ‘mosaics’ — the term used for people who have different genomes in different parts of their body.

The press release from the Sanford-Burnham Medical Research Institute provides some context:

Children born with rare, inherited conditions known as 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 the Sanford-Burnham Medical Research Institute recently discovered three children 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.

“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.”

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.

In the new research, it was observed that there were “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 researchers then returned “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.”

“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.

The findings were recently published in the American Journal of Human Genetics.

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