Family genetics play an important role in severity of autism

A new research has shown that the total amount of rare mutations in a person's genetics can explain why mental health in individuals with a disease-associated mutation have different symptoms.

A new research has been done to prove that developing a neurodevelopmental disorder like autism or ADHD and the severity of the mental health disease depends on genetic changes that are beyond a single supposedly disease-causing mutation. Led by the researchers from Penn State, the research revealed that the total number of rare mutations -- deletions, duplications, or other changes in the DNA sequence in the genome can explain why individuals with a disease-associated mutation can have vastly different symptoms.

Published in in the journal Genetics in Medicine, Santhosh Girirajan, associate professor of biochemistry and molecular biology and of anthropology at Penn State and senior author of the paper, said, "Genetic sequencing tools can reveal a large number of mutations in a person's genome, but diagnosis typically focuses on identifying one primary mutation as the cause of a disorder. However, this strategy does not explain why many individuals with the same primary mutation have very different features or symptoms. For example, when a parent and child have the same primary mutation but only the child develops the disorder. Our work reveals that the primary mutation likely sensitises a person to a disorder, but the amount of other mutations elsewhere in the genome is what actually determines the cognitive ability and developmental features in that person."

For the research, the team took genetic, cognitive, and developmental information from individuals who had one of two known disease-associated mutations, and of their families. The team believed that both the mutations are deletions of genetic material on chromosome 16 16p11.2 and 16p12.1 and are spotted during the screening for children with developmental delays.

But the team noticed that other than those primary mutations, there are additional mutations that make up an individual's genetic background. "Ninety-five percent of children who have the 16p12.1 mutation inherit it from their parents, so any difference in clinical features between the parent and child is due to what they have in the genetic background," added Girirajan in the study.

The team went on to find that the individuals who had one of the primary mutations had significantly more mutations in the genetic background than their parents who did not express clinical features.

"This suggests that a child with a higher number of mutations in the genetic background is more likely to develop intellectual disabilities," said Dr. Girirajan in the study. "The more mutations you have, the more different types of combinations you have that can potentially produce clinical features. Most of these mutations in the genetic background are passed on by the parents, and when the parents' mutations come together in a combinatorial way, the child ends up having more than what either parent had individually. The primary mutation is usually only passed on by one of the parents, and it turns out that the parent who does not pass on the primary mutation actually passes on more mutations in the genetic background. This tells us that getting information about family history, about the parents' genetic profile, is incredibly useful when trying to make a diagnosis."

In the end of the study, the team suggested that the primary mutation sensitises an individual to a disorder and that the genetic background sets the trajectory for potential clinical structures.