NeuroDev study maps previously unseen genetic variation in Africa

Data from children in Africa have helped uncover emerging, novel links between neurodevelopmental conditions and more than 30 genes, according to a new preprint.

The findings are among the first from the NeuroDev study, which recruits participants from families in South Africa and Kenya and aims to map the genetics of child development, with an emphasis on autism and other neurodevelopmental conditions. 

“There is a lot of previously unseen variation in the NeuroDev cohort,” says study investigator Elise Robinson, an institute member at the Broad Institute of MIT and Harvard. Incorporating such variation into clinical databases could improve health outcomes for people around the world with African ancestry, she says.

Africa’s population is the world’s most genetically diverse, but it is largely missing from clinical databases, which skew heavily European. The field’s grasp on the genetics of neurodevelopmental conditions is incomplete without data from diverse populations, says Maria Chahrour, associate professor of neuroscience at the University of Texas Southwestern Medical Center, who was not involved in the new work but created the first cohort of African children with autism.

“We’re actually generating essential data that will give us new insights into the genetic architecture of neurodevelopmental diseases,” Chahrour says. “I love to see studies like that, and NeuroDev is one of those.” 

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Each child underwent a four-hour evaluation, and all participants provided genetic samples for whole-exome sequencing. Many South African families also shared photos of their children. For some conditions, these pictures are the first photographed cases in people with African ancestry. 

The NeuroDev children with neurodevelopmental conditions had more rare genetic variants than people with the same conditions in other ancestral groups, the results show, likely due to Africa’s greater genetic diversity and underrepresentation in databases.

Nearly all of the children with neurodevelopmental conditions met the criteria for intellectual disability or developmental delay, and roughly half met the criteria for autism. Children in about 22 percent of families had a genetic diagnosis, with known pathogenic or likely pathogenic variants. An additional 4 percent had variants of uncertain significance in genes linked to neurodevelopmental conditions. 

Another 16.5 percent had variants of uncertain significance with no known links to neurodevelopmental conditions. The lack of population-level data makes it difficult to know whether the variants are pathogenic or benign, says Emily O’Heir, a NeuroDev investigator and genomic variant analyst at the Broad Institute.

The team submitted those 80 cases to the database MatchMaker Exchange. The database matched 32 of them to other reported cases, and the NeuroDev team is now collaborating on multiple reports describing new potential gene-disease links. 

“That was a very good move,” says Daniel Geschwind, professor of neurology, psychiatry and human genetics at the University of California, Los Angeles, who was not involved in the work. “These may or may not be pathogenic. Time will tell.” 

Geschwind says it would be interesting to compare the NeuroDev results with available data on African Americans with autism, including his own work. Even the groups from Kenya and South Africa were strikingly different from each other, he says, likely because of how participants were recruited.

“What they’re doing is an extraordinary, heavy lift and is very interesting,” Geschwind adds.

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In Cape Town, children with neurodevelopmental conditions were more likely to have had hypoxic-ischemic encephalopathy and neonatal jaundice than neurotypical children. In Kilifi, labor and birth complications, maternal infection during pregnancy, and childhood cerebral malaria were also linked with neurodevelopmental conditions. 

How much such environmental factors matter in autism risk likely depends on each population, says Joseph Buxbaum, director of the Seaver Autism Center for Research and Treatment at the Icahn School of Medicine at Mount Sinai, who wasn’t involved in the study. “Here, you’re seeing these other environmental factors that we have some control over,” he says. “That’s a pretty big deal.”

Still, Robinson cautions that more data are needed to confirm and interpret the environmental results. 

The team also shared genetic diagnostic results with some of the families, offering information on their child’s prognosis and potential interventions. “When we do these studies, we do get the answers,” says study investigator Patricia Kipkemoi, a research fellow in psychiatry at Massachusetts General Hospital, who led the Kilifi fieldwork. “That we’ve played a little part in supporting the families and the communities that we work in, it’s important.”