The human genome, the complete set of DNA instructions in nearly every cell, contains billions of building blocks. While the overall blueprint is remarkably similar across individuals, tiny differences exist in our DNA sequences. On average, any two individuals’ genomes are about 99.6% identical, meaning approximately 0.4% of their DNA differs. Most genetic variations are harmless, contributing to unique traits like eye color or height. However, some specific changes within this vast genetic code can have significant implications for health.
Defining Pathogenic Variants
A pathogenic variant is an alteration in the DNA sequence known to cause disease or significantly increase the risk of a particular health condition. In clinical genetics, “variant” is preferred over “mutation” because it describes an allele more precisely without inherently suggesting a negative outcome.
Distinguishing pathogenic variants from other genetic changes is a key process in medical understanding. A “benign variant” is a DNA change that does not lead to any known genetic conditions, essentially a normal version of a gene. Conversely, a “variant of uncertain significance” (VUS) is a genetic variant whose impact on health or gene function is not yet known. VUS classifications require further investigation due to insufficient or conflicting evidence. With more research, a VUS may be reclassified as pathogenic, likely pathogenic, likely benign, or benign.
How Pathogenic Variants Impact Health
Pathogenic variants lead to health problems by altering the normal function of genes or the proteins they produce. Genes contain instructions for cells to make proteins, which perform most cellular work and are necessary for the body’s structure, function, and regulation. A change in the DNA sequence can disrupt these instructions, causing the resulting protein to be non-functional, improperly folded, excessively active, or even completely absent.
For example, a pathogenic variant might introduce a premature “stop codon,” leading to a shortened, non-functional protein. Other variants, known as missense changes, can alter a single amino acid in a protein, potentially destabilizing its structure or changing its interaction with other molecules. These disruptions can interrupt complex cellular processes. The specific impact of a pathogenic variant varies widely, depending on the gene involved and the nature of the DNA change, ranging from mild to severe conditions.
Inheritance of Pathogenic Variants
Pathogenic variants can be passed down through families in several ways. In autosomal dominant inheritance, only one copy of an altered gene is sufficient for a person to be affected. An affected individual has a 50% chance of passing the variant to each child, regardless of sex.
In contrast, autosomal recessive inheritance requires variants in both copies of a gene for the condition to develop. Parents of an individual with an autosomal recessive condition typically carry one altered gene copy but show no symptoms. If both parents are carriers, each child has a 25% chance of being affected and a 50% chance of being a carrier. X-linked inheritance involves genes on the X chromosome. Males, with one X chromosome, are often more frequently and severely affected by X-linked recessive disorders than females, who have two. A “de novo” variant can also occur, which is a new genetic change arising spontaneously in an individual, not inherited from either parent.
Identifying Pathogenic Variants
Identifying pathogenic variants involves genetic testing, using samples such as blood or saliva. These tests employ DNA sequencing technologies to read the order of DNA building blocks in a person’s genes. Once obtained, the DNA sequence undergoes analysis and interpretation.
Genetic professionals, including laboratory scientists and genetic counselors, compare the individual’s sequence to a reference human genome to pinpoint differences. They evaluate these identified variants using established guidelines and extensive databases of known genetic changes and their associated health outcomes. Genetic testing can be performed for various reasons, such as confirming a diagnosis, assessing an individual’s risk for a condition, or informing family planning decisions.