Inherited Accumulation of Rare Mutations Affects Severity of Neurodevelopmental Disorders

Techniques such as high-throughput genome sequencing have allowed scientists to identify hundreds of genetic variants that are linked with increased risk of different neurodevelopmental or neuropsychological disorders, such epilepsy, schizophrenia, intellectual disability, and autism spectrum disorder (ASD). However, two people with the same known risk variant won’t necessarily present with the same symptoms.

A major international research effort headed by a team at the Pennsylvania State University now reports study data indicating that while the primary risk variant may make an individual more susceptible to developing a particular disorder, such as ASD, the variability and severity of symptoms will depend on their genetic background of accumulated rare mutations—such as deletions and duplications—which have been inherited from parents and grandparents.

“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, Ph.D., associate professor of biochemistry and molecular biology and of anthropology at Penn State. Girirajan is senior author of the team’s published paper in Genetics in Medicine. “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 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.”

The authors report on their studies in a paper entitled, “Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.”

About 10% to 30% of autism cases are now attributed to rare disruptive genetic variants, including copy number variants (CNVs) and single nucleotide variants (SNVs), the authors write. However, not all individuals who carry a particular risk variant will exhibit the same disorder, let alone the same severity of symptoms. A deletion at location 16p11.2 in the genome, for example, was first described in children with autism, but has since been linked with intellectual disability and developmental delay (ID/DD), obesity, epilepsy, cardiac disease, and scoliosis.

“Only about 24% of cases manifest an autism phenotype,” the authors pointed out. Similarly, different people who carry the same pathogenic variant of a single gene may also present with different type of disorder or symptoms. “While some of these effects could be due to allelic heterogeneity, phenotypic variability among carriers of the same molecular lesion suggests a strong role for variants in the genetic background.”

To investigate the importance of genetic background in neurodevelopmental disease the Penn State team and colleagues analyzed and compared data, including clinical information and protein coding gene sequences, from 757 individuals with deletions at either 16p12.1 or 16p11.2, and 233 family members, including parents and siblings. “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,” Girirajan noted.

The results showed that even when the same primary genetic variant was present, the variability and severity of neurodevelopmental disease was still dependent upon the number of other inherited rare variants. Individuals with one or more of the primary mutations who demonstrated clinical features had greater numbers of background genetic mutations than other members of the family who had the same primary mutation, but who didn’t exhibit the same clinical features. 

“This suggests that a child with a higher number of mutations in their genetic background is more likely to develop intellectual disabilities,” continued Girirajan. “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.”

In fact, what the results suggest, the authors noted, is that noncarrier parents with a strong family history of neurodevelopmental and psychiatric disease demonstrated a much higher mutational burden than those with a mild family history. “In families with a strong history of neurodevelopmental and psychiatric disease, a higher number of rare variants in the genetic background are more likely to be transmitted to the proband from the noncarrier parent, potentially contributing to a more severe manifestation of the disorders.”

“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,” Girirajan stated. “This tells us that getting information about family history, about the parents' genetic profile, is incredibly useful when trying to make a diagnosis.”

Interestingly, the number of mutations in the patient’s genetic background was also linked with head size, which correlated with cognitive development, in individuals with the 16p11.2 deletion, and to IQ scores in individauls with one of the two primary mutations, or one of several other disease-associated primary mutations.

The overall findings indicate that a large number of disease-associated variants that are deemed to be solely causative for a disorder are, more likely, accompanied by a substantial amount of rare genetic variation, the authors point out. But how much additional genetic variation needs to be present to change the severity of disease appears to be variable. “Some primary variants more tolerant to changes in the genetic background, such as the 16p12.1 deletion, are transmitted through generations and only surpass the threshold for severe disease with the accumulation of several additional rare pathogenic variants,” they commented. “Other primary variants that are often de novo, such as the 16p11.2 deletion, push the genetic background closer to the threshold for severe manifestation and therefore require a lesser contribution from other hits.”

“Some primary mutations may sensitize an individual to a lesser degree, requiring large numbers of mutations in the genetic background to produce symptoms associated with the disorder,” said Lucilla Pizzo, a graduate student in the molecular medicine program at Penn State and first author of the published paper. “For example, an inherited mutation that has been passed on for many generations may not have produced strong symptoms in the parents or grandparents, but large numbers of mutations in the genetic background of the child could lead to clinical features. Other primary mutations may sensitize the genome to a greater degree, with fewer additional mutations required to produce symptoms associated with the disorder.”

The authors say it is important that the genetic background of a patient is analyzed even after clinicians have identified a likely diagnostic pathogenic variant, so that the best course of conseling and disease management can be decided for each individual. “We need more-thorough screens when a patient comes into a clinic so that we can consider more than just one mutation,” said Girirajan. “With knowledge about the family history and genetic background, we can get closer to a more accurate prognosis and provide rehabilitation sooner. For example, a patient could start speech therapy or physical rehabilitation before the developmental delay hits.”