Washington DC: Turns out, the severity of a neurodevelopmental disorder like autism or ADHD in an individual depends on genetic changes beyond a single, supposedly disease-causing mutation.
A new study led by researchers at Penn State revealed that the total amount of rare mutations -- deletions, duplications, or other changes to the DNA sequence -- in a person's genome can explain why individuals with a disease-associated mutation can have vastly different symptoms.
"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," said Santhosh Girirajan, senior author of the study. "However, this strategy does not explain why many individuals with the same primary mutation have very different features or symptoms."
Girirajan explained, "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."
The research team considered genetic, cognitive, and developmental information from individuals who contained one of two known disease-associated mutations, and of their families. Both mutations are deletions of genetic material on chromosome 16 -- one in a region referred to as 16p11.2 and the other 16p12.1 -- and are detected in a global screen for children with developmental delays. These primary mutations provide a frame of reference to study the additional mutations that make up an individual's "genetic background."
Individuals with one of the primary mutations who expressed clinical features had significantly more mutations in the genetic background than their parents or siblings who did not express clinical features. The researchers also linked the number of mutations in the genetic background to head size, a feature of cognitive development, in individuals with the primary 16p11.2 deletion and to IQ scores in individuals with one of the two primary mutations or one of several other disease-associated primary mutations.
This suggested that a child with a higher number of mutations in the genetic background is more likely to develop intellectual disabilities. 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.
The researchers suggested that the primary mutation sensitises an individual to a particular disorder and that the genetic background sets the trajectory for potential clinical features.
Some primary mutations may sensitise an individual to a lesser degree, requiring large numbers of mutations in the genetic background to produce symptoms associated with the disorder.
This study focused solely on genetic changes that occurred in the protein-coding portions of the genome.
The findings appeared in the Journal of Genetics in Medicine.