Our bodies are made of billions of cells, each containing 46 chromosomes organized into 23 pairs. These thread-like structures are composed of tightly packaged DNA, which holds our genetic instructions. A chromosomal microdeletion occurs when a very small piece of genetic material is missing from a chromosome. Though often too small for standard microscopic techniques, these deletions can significantly impact an individual’s health and development.
Understanding Chromosomal Microdeletions
A microdeletion is the loss of a small DNA segment from a chromosome. This segment can contain one or more genes, which provide instructions for building and operating our bodies. Microdeletions are defined as deletions smaller than 5 million base pairs (5 megabases or Mb). They are considered a type of copy number variant (CNV), meaning the usual two copies of a DNA segment are reduced to one. The impact of a microdeletion depends on its location and the specific genes that are missing.
How Microdeletions Occur
Most chromosomal microdeletions arise spontaneously as new genetic changes, known as “de novo” events. These happen during the formation of reproductive cells, such as sperm or egg, or in the very early stages of embryonic development after fertilization. One common mechanism for these spontaneous deletions is unequal crossing over during meiosis, the process of gamete formation. If the chromosomes misalign during this exchange due to similar repetitive DNA sequences, a segment can be deleted from one chromosome.
While many microdeletions are de novo, some can be inherited from a parent. A parent carrying a balanced translocation, where pieces of chromosomes have swapped without any net loss or gain of genetic material, might pass on an unbalanced version to their child, resulting in a microdeletion or microduplication. In such inherited cases, the parent typically shows no symptoms because their genetic material is complete, even if rearranged. If a microdeletion is identified as de novo, the chance of it recurring in future pregnancies is less than 1%, but if inherited, the recurrence risk can be as high as 50% in each subsequent pregnancy.
Recognizing Common Microdeletion Syndromes
DiGeorge syndrome, also known as 22q11.2 deletion syndrome, results from a missing piece on the long arm of chromosome 22. Individuals with DiGeorge syndrome can include congenital heart problems, an impaired immune system, low calcium levels, and developmental delays. Physical features may include small, low-set ears, hooded eyes, and a broad nasal tip; some individuals may also have a cleft palate. The severity of symptoms can vary widely among affected individuals.
Prader-Willi syndrome is caused by a deletion in the 15q11-q13 region of the paternally inherited chromosome 15. Infants with Prader-Willi syndrome exhibit weak muscle tone and feeding difficulties, leading to poor growth. In childhood, this typically transitions to excessive eating and obesity if food intake is not controlled. Other common features include mild to moderate intellectual disability, developmental delays in motor skills and language, distinctive facial features like a narrow forehead and almond-shaped eyes, and underdeveloped genitals. Behavioral problems, including temper outbursts and compulsive behaviors like skin picking, are also common.
Angelman syndrome, also involving the 15q11-q13 region, arises from a deletion or other genetic change on the maternally inherited chromosome 15. This condition primarily affects the nervous system, leading to severe developmental delay, intellectual disability, and significant speech impairment, often with minimal or no word use. Individuals with Angelman syndrome typically exhibit movement and balance problems, characterized by an unsteady gait and tremulous limbs. A unique behavioral pattern includes frequent laughter, smiling, an excitable demeanor with hand-flapping movements, hyperactivity, and a short attention span.
Williams syndrome is linked to a deletion on chromosome 7q11.23, affecting 25 to 27 genes. Individuals with Williams syndrome often present with distinctive facial features like a broad nasal bridge, full cheeks, and a wide mouth, sometimes described as “elfin facies”. Cardiovascular issues, particularly supravalvular aortic stenosis (narrowing of the aorta), are common. Developmental delays, mild to moderate intellectual disability, and a unique personality of extreme friendliness, talkativeness, and musical interest are also frequently observed. Feeding problems in infancy, dental abnormalities, and elevated calcium levels in the blood also occur.
Diagnosing Chromosomal Microdeletions
Detecting chromosomal microdeletions requires advanced genetic testing methods due to their small size. Traditional karyotyping, examining stained chromosomes under a microscope, identifies larger changes (typically >5-10 megabases), but its resolution is insufficient for microdeletions. For this reason, chromosomal microarray analysis (CMA) is the primary method for diagnosing these subtle genetic changes.
CMA scans DNA at a much higher resolution than karyotyping, capable of detecting changes as small as 27 kilobases (Kb). This allows CMA to identify microdeletions and microduplications that would be missed by conventional methods. Samples for CMA can be obtained from blood (child or adult) or prenatal sources like amniotic fluid or chorionic villus tissue. While CMA is highly effective for detecting copy number variants, it generally does not detect balanced chromosomal rearrangements, like translocations or inversions, where no genetic material is lost or gained. For targeted detection of known microdeletions, Fluorescence In Situ Hybridization (FISH) can be used, which employs fluorescent probes that bind to particular DNA sequences.
Living with a Microdeletion Diagnosis
A chromosomal microdeletion diagnosis has various implications, often requiring a comprehensive and coordinated approach to care. Early intervention helps maximize developmental potential and manage associated symptoms. This often involves supportive therapies tailored to individual needs. These therapies may include physical therapy to address motor skill delays and muscle tone issues, speech therapy to improve communication abilities, and occupational therapy to enhance daily living skills.
Genetic counseling helps families understand the diagnosis, its potential health implications, and the chances of recurrence in future pregnancies. Counselors provide information about the microdeletion, including its location, size, genes involved, and whether it was inherited or occurred spontaneously. They also discuss family planning options and provide support. Ongoing medical management, often involving specialists, is common to address health issues, ensuring continuous support and care throughout life.