A new Cell study led by Penn State researchers suggests that the genetic background surrounding a key variant may be just as important as the variant itself in determining how a disorder develops. The work shows that secondary genetic variants, or changes scattered throughout the genome, can shape the effects of a primary variant linked to conditions such as autism and developmental delay.
“Some genetic diseases are relatively simple, with an essentially one-to-one relationship between the presence of a genetic variant—or a change in a person’s DNA that differs across people—and the manifestation of the trait,” said Santhosh Girirajan, corresponding author of the study and head of biochemistry and molecular biology at Penn State. “However, many traits are more complex. We know, for example, that most disease-causing variants contribute to a variety of clinical outcomes, even among individuals carrying the same variant. In this study, we looked for patterns of secondary variants that could help explain this and eventually guide the development of more effective—potentially personalized—therapies.”
The researchers analyzed whole genome sequences from 442 individuals across 124 families, each carrying a deletion on chromosome 16 (16p12.1) associated with neurodevelopmental and psychiatric conditions. They examined 17 classes of secondary variants and found that specific variant types correlated with distinct clinical outcomes. For example, children with an expanded short tandem repeat, a DNA sequence repeated multiple times, showed a higher risk for nervous system features in addition to developmental delay.
The study also revealed how research design can influence genetic interpretations. Patterns of primary and secondary variants differed depending on whether participants came from general population biobanks or clinical cohorts selected for developmental conditions.
“Our results suggest that treatment strategies need to consider more than just the primary variant,” said Girirajan. “Instead, we’ll need to take a more complete approach that considers each individual person’s characteristics and their unique set of secondary variants.”
Publication Details
Jensen M, Smolen C, Tyryshkina A, et al. Genetic modifiers and ascertainment drive variable expressivity of complex disorders. Cell. 2025. doi:10.1016/j.cell.2025.09.012
“Some genetic diseases are relatively simple, with an essentially one-to-one relationship between the presence of a genetic variant—or a change in a person’s DNA that differs across people—and the manifestation of the trait,” said Santhosh Girirajan, corresponding author of the study and head of biochemistry and molecular biology at Penn State. “However, many traits are more complex. We know, for example, that most disease-causing variants contribute to a variety of clinical outcomes, even among individuals carrying the same variant. In this study, we looked for patterns of secondary variants that could help explain this and eventually guide the development of more effective—potentially personalized—therapies.”
The researchers analyzed whole genome sequences from 442 individuals across 124 families, each carrying a deletion on chromosome 16 (16p12.1) associated with neurodevelopmental and psychiatric conditions. They examined 17 classes of secondary variants and found that specific variant types correlated with distinct clinical outcomes. For example, children with an expanded short tandem repeat, a DNA sequence repeated multiple times, showed a higher risk for nervous system features in addition to developmental delay.
The study also revealed how research design can influence genetic interpretations. Patterns of primary and secondary variants differed depending on whether participants came from general population biobanks or clinical cohorts selected for developmental conditions.
“Our results suggest that treatment strategies need to consider more than just the primary variant,” said Girirajan. “Instead, we’ll need to take a more complete approach that considers each individual person’s characteristics and their unique set of secondary variants.”
Publication Details
Jensen M, Smolen C, Tyryshkina A, et al. Genetic modifiers and ascertainment drive variable expressivity of complex disorders. Cell. 2025. doi:10.1016/j.cell.2025.09.012