Scientists Use DNA Sequencing to Help Diagnose Mystery Brain and Body Disorders in African Children

Scientists in Africa have found a better way to help children with serious developmental disorders get a real diagnosis. The study, called DDD-Africa, looked at the DNA of 505 children from South Africa and the Democratic Republic of Congo. These children had problems with how their brains or bodies developed, but no one had been able to explain why. By using a special type of DNA testing called exome sequencing, researchers hoped to find hidden changes in the children's genes.

Developmental disorders, or DDs, affect how children grow, think, move, and learn. Some of the most important DNA changes linked to these disorders are called copy number variants, or CNVs. A CNV happens when a piece of DNA is accidentally copied too many times or is missing altogether. Finding these tiny changes can be the key to understanding why a child has a developmental disorder.

The DDD-Africa team tested children from two countries. South Africa provided 358 of the children, while 147 came from the Democratic Republic of Congo. The average age of the children was about seven years old, and about 62 percent were boys. The scientists also collected DNA from parents when they were available, which helped them figure out whether a genetic change was inherited or brand new.

To find CNVs in the DNA data, the scientists used two computer programs called CANOES and XHMM. These tools work in different ways, and together they were better at finding important DNA changes than either one alone. CANOES is good at finding medium and large DNA changes, while XHMM is especially useful for finding rare changes in big groups of people. Before using these tools on all the children, the team ran tests to make sure the two programs together gave the best results.

The DNA testing was done at the Wellcome Sanger Institute in the United Kingdom. Scientists read the order of DNA letters in each child's exome, which is the part of DNA that holds instructions for making proteins. The machine read each section about 40 times over to make sure the results were accurate. While this is a bit less than what some labs use, researchers showed it was still good enough to find important DNA changes.

After the computer tools found possible CNVs, doctors and scientists carefully reviewed each one. They used a set of rules from a major medical genetics group to decide whether each CNV was likely to cause disease. They also compared each child's DNA changes to the child's symptoms to see if the two matched up. Any important results were shared in an international database called DECIPHER, so scientists around the world could compare notes.

To make sure the computer results were correct, the team also used a different test called array CGH on 19 of the children who had important findings. This second test confirmed whether the DNA changes found by the computer were real. Labs in South Africa and Belgium helped run these confirmation tests, and most of the results were confirmed. This showed that the computer tools were doing a good job.

One key finding was that children in South Africa were much more likely to have had genetic testing before joining the study. About 95 percent of South African children had prior testing, compared to only 8 percent of children from the DRC. This shows that access to genetic medicine is very unequal across Africa. The DDD-Africa study hopes to help change that by showing that exome sequencing can work even in places where resources are limited.