VPS54

TUESDAY, Aug. 1, 2023 -- In a study of families that have multiple children with autism, researchers have unearthed new insights into genes that might drive the disorder. “Study design is critical, and not enough attention has been paid to studying families with more than one affected child,” said lead author Dr. Daniel Geschwind , a professor of human genetics, neurology and psychiatry at UCLA in Los Angeles. While past research has mostly focused on families with one child who has autism, few have examined the role of rare inherited variations or their interaction with the combined effect of multiple common genetic variations that contribute to the risk of developing autism, according to this study. At least 50% of genetic risk is predicted by common genetic variation and another 15% to 20% is due to spontaneous mutations or predictable inheritance patterns. The remaining genetic risk is yet to be determined. To study this, researchers did whole genome sequencing in more than 4,550 people from just over 1,000 families with at least two children diagnosed with autism. This group included more than 1,800 children with autism and more than 400 children without an autism diagnosis. The researchers found seven potential genes that are predicted to increase the risk of autism: PLEKHA8, PRR25, FBXL13, VPS54, SLFN5, SNCAIP and TGM1. Most of the new genes were supported by rare inherited DNA variations that were transmitted from parents to children. They also examined what is called polygenic risk, in which a combination of commonly found genetic variations can raise the likelihood of developing autism. Children who inherited rare mutations from unaffected parents in combination with polygenic risk were more likely to have autism, the study showed. The findings help explain why parents who carry a single rare mutation may not show signs of autism even if their children do, according to the study. It also supports the liability threshold model, a concept in behavioral genetics that holds there is an additive effect of genes that influences the probability that someone develops a certain trait. Children who had a language delay had a higher likelihood of inheriting a polygenic score associated with autism. There was not a similar relationship for children without language delays. This pattern was specific to autism. It was not seen in educational attainment, schizophrenia or bipolar disorder, according to the authors, who said this suggests there’s a link between the genetic risk for autism and language delay. "This association of general risk for [autism] that was strongest in those with language delay suggests that language is actually a core component of [autism]," Geschwind said. The findings were published July 28 in the Proceedings of the National Academy of Sciences. Sources University of California, Los Angeles, Health Sciences, news release, July 28, 2023 Posted August 2023