Intellectual disability (ID) is a neurodevelopmental condition characterized by significant limitations in intellectual functioning (such as reasoning and learning) and adaptive behavior (the conceptual, social, and practical skills needed for daily life). The onset occurs before adulthood. ID is a common developmental disability, but its highly variable causes often make diagnosis challenging.
ID is complex and multifactorial, arising from a wide range of biological and environmental influences. A significant portion of cases are rooted in genetic factors, involving alterations in an individual’s genes. However, non-genetic factors can also disrupt brain development and lead to the condition.
Genetic Mechanisms That Cause Intellectual Disability
Genetic changes contribute substantially to intellectual disability by disrupting the complex processes of brain development and function. These changes are broadly categorized based on the scale of the alteration within the genome.
One category involves large-scale changes to entire chromosomes or significant portions of them, known as chromosomal abnormalities. This includes aneuploidy, where there is an incorrect number of chromosomes, such as having an extra copy of a specific chromosome. These alterations affect thousands of genes simultaneously, profoundly altering developmental pathways.
Smaller, but equally significant, disruptions occur at the level of individual genes. A single-gene mutation involves a change in the DNA sequence of one particular gene. This change may lead to the production of a non-functional protein or prevent the protein from being made at all. Since many genes are responsible for building and maintaining brain cells, a change in even one gene can interrupt neural communication and cognitive development.
Another type of alteration is a Copy Number Variation (CNV), which refers to the deletion or duplication of a large segment of DNA spanning multiple genes. CNVs are a major contributor to ID and are essentially sub-microscopic chromosomal changes. A deletion removes genetic material, while a duplication adds extra copies, both of which upset the balance of gene expression required for normal neurological development.
The Role of Non-Genetic and Environmental Factors
While genetic factors account for many cases of intellectual disability, a substantial number of cases are attributed to non-genetic or environmental causes that impact the developing brain. These factors are typically grouped according to the time point at which the brain is affected.
Prenatal factors involve exposures or conditions that occur while the fetus is developing in the womb. Exposure to teratogens, such as maternal consumption of alcohol or certain prescription drugs, can directly interfere with the formation of the fetal brain structure. Maternal infections like rubella or cytomegalovirus, if contracted during pregnancy, can cross the placenta and damage developing neural tissue.
Complications during the birthing process itself are classified as perinatal factors. The most common perinatal cause is birth asphyxia, a complication that results in a lack of oxygen to the baby’s brain. This oxygen deprivation can cause irreparable damage to sensitive brain cells, leading to long-term neurological consequences.
After birth, postnatal factors can also lead to intellectual disability, often through direct injury or severe illness. Severe head trauma, such as from an accident or abuse, can cause brain damage resulting in cognitive impairment. Exposure to environmental toxins, like high levels of lead, can also damage the developing nervous system. Severe, untreated infections, such as meningitis or encephalitis, are additional acquired causes of intellectual disability.
How Genetic Intellectual Disability is Inherited
The way a genetic cause of intellectual disability is transmitted through a family depends on the specific pattern of inheritance associated with the gene or chromosome involved. Some conditions follow classic Mendelian inheritance patterns, while others arise spontaneously.
Autosomal dominant inheritance occurs when only one copy of an altered gene, located on a non-sex chromosome, is enough to cause the condition. A person with an autosomal dominant form of ID has a 50 percent chance of passing the altered gene to each of their children.
In contrast, autosomal recessive inheritance requires both copies of a specific gene to be altered for the condition to manifest. Parents of an affected individual may be carriers, meaning they each possess one altered copy of the gene but do not show symptoms. When two carriers reproduce, there is a 25 percent chance with each pregnancy that the child will inherit two altered copies and be affected.
X-linked inheritance involves genes located on the X chromosome, one of the two sex chromosomes. Since males have only one X chromosome, they are often more severely affected by a condition caused by an altered gene on the X chromosome. Females have two X chromosomes and can have a compensating normal copy.
Many genetic causes are the result of de novo mutations, meaning the genetic change is new and occurred for the first time in the affected individual. These mutations arise during the formation of the egg or sperm or shortly after conception, and are typically not present in the DNA of either parent. De novo changes, including many chromosomal abnormalities and gene mutations, account for a large percentage of ID cases where there is no family history.
Identifying Genetic Causes Through Screening
Modern medical technology offers several tools to pinpoint the specific genetic cause of intellectual disability. Identifying the cause is important for understanding prognosis and recurrence risk, and diagnostic techniques have improved the rate at which a molecular diagnosis can be established.
Karyotyping is a technique used to visualize and examine the entire set of chromosomes to detect large-scale structural changes, such as extra or missing chromosomes. This test is effective for identifying conditions involving whole-chromosome abnormalities, though it cannot detect smaller changes within a chromosome.
Chromosomal Microarray Analysis (CMA) has largely replaced karyotyping as a first-tier test for unexplained intellectual disability because it provides much higher resolution. CMA can detect tiny deletions or duplications of DNA segments, known as copy number variations (CNVs), that are too small to be seen on a standard karyotype. This test is highly effective in finding the underlying cause in a significant percentage of individuals.
The most comprehensive genetic testing methods are Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS). WES focuses on the exome, the protein-coding region of all genes where the majority of disease-causing mutations are found. WGS sequences the entire DNA sequence, including both coding and non-coding regions, offering the most detailed view of an individual’s genetic makeup. These sequencing technologies are capable of detecting single-gene mutations that might be missed by other methods, continually improving the diagnostic yield.