Measuring mutations in sperm may reveal risk for autism in future children

Providing a more accurate assessment of ASD risk in future children.

Autism spectrum disorder (ASD) is a condition that affects social interaction, communication, interests, and behavior. The exact cause of ASD is unknown, but it’s thought that several complex genetic and environmental factors are involved.

It is widely believed that the disorder is linked to de novo mutations that appear only in the child and are not inherited from either parent’s DNA.

In a new study by the University of California, San Diego School of Medicine, scientists depict a strategy to measure disease-causing mutations found distinctly in the sperm of the father, giving a progressively accurate appraisal of ASD risk in future children.

Co-senior author Jonathan Sebat, Ph.D., professor and chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at UC San Diego School of Medicine said, “Autism afflicts 1 in 59 children, and we know that these de novo DNA mutations cause a significant portion, yet we are still blind to when and where these mutations will occur. With our new study, we can trace some of these mutations back to the father, and we can directly assess the risk of these same mutations occurring again in future children.”

Co-senior study author Joseph Gleeson, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and director of neuroscience research at the Rady Children’s Institute for Genomic Medicine said, “However, such estimates are not based on actual knowledge of the risk in an individual family, but instead are based on frequencies in the general population. When a disease-causing mutation occurs for the first time in a family, the probability that it could happen again in future offspring is not known. Thus families must decide with a great deal of uncertainty.”

Scientists analyzed the sperm of eight fathers who were already parents of children with ASD. They wanted to look for the presence of multiple, genetically different material in cells in the same person; a phenomenon called mosaicism. Using deep whole-genome sequencing, they found variants in offspring that were matched only in the fathers’ sperm.

First author Martin Breuss, Ph.D., an assistant project scientist in Gleeson’s lab, said, “While medical textbooks teach us that every cell in the body has an identical copy of DNA, this is fundamentally not correct. Mutations occur every time a cell divides, so no two cells in the body are genetically identical. Mosaicism can cause cancer or can be silent in the body. If a mutation occurs early in development, then it will be shared by many cells within the body. But if a mutation happens just in sperm, then it can show up in a future child but not cause any disease in the father.”

Up to 15 percent, disease-causing mutations were present in fathers’ sperm cells, information that could not be determined through other means, such as blood samples.

Gleeson said, “My laboratory has a long-standing interest in understanding the origins of pediatric brain disease and how mutations contribute to disease in a child. We previously showed that mosaicism in a child could lead to diseases like epilepsy. Here, we show that mosaicism in one of the parents is at least as important when thinking about genetic counseling.”

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