While one main risk gene may make an individual susceptible to autism or another neurodevelopmental disorder, it is the whole collection of associated changes in their DNA that decides whether they develop it and how severe it becomes.
This was the conclusion that researchers arrived at after analyzing developmental, cognitive, and genome sequencing data of hundreds of people with known risk genes together with that of their parents and siblings.
They suggest that their findings explain why two people carrying the same risk gene, also known as the “primary mutation,” can have very different symptoms of the associated neurodevelopmental disorder.
“For example,” says senior study author Santhosh Girirajan, an associate professor of biochemistry and molecular biology at Pennsylvania State University in University Park, “when a parent and child have the same primary mutation but only the child develops the disorder.”
He explains that when diagnosing a disorder such as autism, the focus on finding the cause tends to be on identifying the “one primary mutation.”
However, this approach does not explain why many people with the same primary mutation can have widely different symptoms.
“Genetic sequencing tools can reveal a large number of mutations in a person’s genome,” he remarks.
The researchers have now published their findings in the journal Genetics in Medicine.
Neurodevelopmental disorders are “common and widespread” conditions that affect movement, language, social skills, communication, and emotions.
Typical examples include autism — or, more accurately, autism spectrum disorder (ASD) — and attention deficit hyperactivity disorder (ADHD).
Such disorders can be traced to early growth and development of the brain. However, the exact causes are unknown. Genetic, environmental, and biological factors are thought to be involved.
People with ASD face challenges in communicating and interacting, as well as understanding and expressing emotions.
They often react, learn, and pay attention differently to others, and they may also repeat particular behaviors and prefer to have the same daily routines. The signs usually start early in life and continue throughout adulthood.
Some people with ASD can manage well on their own, while others might need lots of support with daily living.
The Centers for Disease Control and Prevention (CDC) estimate that about 1 in 59 children have ASD in the United States, and that boys are about four times more likely to be diagnosed with it than girls.
ADHD is “one of the most common” neurodevelopmental disorders in children. It’s often diagnosed in childhood and usually persists until adulthood.
As well as causing children to be “overly active,” ADHD can disrupt their ability to pay attention and control impulsive behavior without thought for the consequences.
A national survey revealed that in 2016, there were around 6.1 million children in the U.S. who had ever been diagnosed with ADHD; this figure represents nearly 1 in 10 of all those aged 2–17 years in the U.S. population.
Girirajan and his colleagues studied individuals who had one of two “disease-associated mutations” that are known to be linked to neurodevelopmental disorders.
The mutations are missing sections of genetic material on chromosome 16. One mutation is called 16p11.2, and the other is called 16p12.1. These are both included on a “global screen for children with developmental delays.”
Girirajan explains that in 95 percent of children who carry 16p12.1, the mutation has been passed on from a parent. This means that “any difference in clinical features between the parent and child is due to what they have in the genetic background,” he notes.
Their analysis found that people with either of the primary mutations who also showed clinical signs of the associated disorder had “significantly more mutations in the genetic background” than parents or siblings who were also “carrier family members.”
The investigators also revealed that there was a link between the number of mutations and certain distinctive features of the associated disorder, such as head size in the case of 16p11.2 deletion, which is a “feature of cognitive development.”
“The more mutations you have,” notes Girirajan, “the more different types of combinations you have that can potentially produce clinical features.”
He goes on to explain that while the primary mutation is likely only passed on by one parent, most of the changes in an individual’s genetic background come from both parents; but the “child ends up having more than what either parent had individually.”
It could even be that the parent who did not pass on the primary mutation is the one that passes on most of the mutations — that end up in the individual’s genetic background — that contribute to disease development and features.
“This tells us that getting information about family history, about the parents’ genetic profile, is incredibly useful when trying to make a diagnosis,” Girirajan urges.
He and his colleagues suggest that the primary mutation is what primes the individual into being susceptible to the particular disorder, and the genetic background sets the course of disease development and how it manifests clinically.
It could also be a more complex situation than a simple on or off. It could be, for instance, that one type of primary mutation makes one individual less sensitive, and another makes another more sensitive to developing the disease.
In that case, the first individual would require many more mutations in their genetic background to produce symptoms as severe as those of the second individual, whose primary mutation would make them more sensitive.
In this way, the primary mutation could be passed on down several generations but the symptoms remain mild until a child happens to also inherit lots of mutations in their genetic background.
The researchers now plan to extend their study into the non-coding areas of the genome. So far, they have focused only on the small percentage that codes for proteins.
They hope that one day, their findings will help clinicians give better information to their patients and reach more accurate prognoses in time for rehabilitation to have impact earlier.
This would mean, for instance, that “a patient could start speech therapy or physical rehabilitation before the developmental delay hits,” Girirajan concludes.
“Our work reveals that the primary mutation likely sensitizes 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.”