The human genome is organized into 23 pairs of chromosomes, which are tightly packed structures of DNA. Errors in this complex arrangement can range from changes in a single DNA base pair to the loss or gain of entire chromosomes. Chromosomal micro deletions represent a specific type of error, where a small segment of DNA is missing from one of these chromosomes. This structural change can have profound effects because even a small missing piece can contain several genes, altering the instructions necessary for normal development and function.
Defining Chromosomal Micro Deletions
A chromosomal micro deletion is the absence of a tiny piece of a chromosome, a segment that is too small to be observed using traditional cytogenetic methods like standard light microscopy, or karyotyping. While a standard karyotype can detect large structural abnormalities, micro deletions are typically submicroscopic, often ranging from one to five Mb. The small segment of missing genetic material is a type of copy number variant (CNV), specifically a loss of genetic material, and is usually estimated to contain multiple genes. The loss of these genes often results in a condition known as a contiguous gene syndrome, as the affected genes are located next to each other on the chromosome.
Genetic Mechanisms of Occurrence
Micro deletions most frequently arise from mistakes that occur during meiosis, the specialized cell division process that creates sperm and egg cells. The primary mechanism responsible for these recurrent deletions is non-allelic homologous recombination (NAHR). This process is caused by the misalignment of homologous chromosomes during crossing over, which is mediated by repetitive DNA sequences called low-copy repeats (LCRs) that flank the affected region. The high degree of sequence similarity in LCRs makes the DNA repair machinery prone to error, resulting in an unequal exchange. When unequal crossing over occurs, one resulting gamete will have a deletion, and the other will have a reciprocal duplication. Most micro deletions are described as de novo, meaning they are a new change in the affected individual and were not present in either parent’s DNA.
Associated Health Conditions and Syndromes
The health effects of a micro deletion depend entirely on the specific genes that have been lost and the resulting change in gene dosage. Many well-known syndromes are caused by the recurrent loss of a particular chromosomal segment, leading to a predictable but highly variable clinical presentation.
DiGeorge Syndrome (22q11.2 deletion)
The loss of genetic material from the long arm of chromosome 22, known as the 22q11.2 deletion, is the cause of DiGeorge syndrome. This deletion often removes 30 to 40 genes. It is associated with a wide spectrum of issues, including congenital heart defects, problems with the immune system, cleft palate, and an increased risk for psychiatric conditions later in life, such as schizophrenia.
Williams Syndrome (Chromosome 7)
Williams syndrome results from a 1.5–1.8 Mb deletion on chromosome 7, involving about 26 to 28 genes, including the ELN gene. Individuals with this deletion often exhibit a distinctive pattern of facial features and supravalvular aortic stenosis (a narrowing of the aorta). Their cognitive profile is characterized by a strong verbal ability but severely impaired visuospatial skills, alongside an overly social, outgoing personality.
Prader-Willi and Angelman Syndromes (15q11-q13)
The same segment of chromosome 15, the 15q11-q13 region, is implicated in two different conditions: Prader-Willi syndrome and Angelman syndrome. This is an example of genomic imprinting, where the expression of the gene depends on which parent it was inherited from. A deletion of the paternal copy causes Prader-Willi syndrome, characterized by hypotonia and feeding difficulties in infancy, followed by hyperphagia leading to morbid obesity. Conversely, the loss of the maternal copy results in Angelman syndrome, which presents with severe developmental delay, lack of speech, intellectual disability, and often seizures.
Tools for Diagnosis and Detection
Because micro deletions are too small to be seen with a standard microscope, specialized genetic testing methods are necessary for their identification. The most comprehensive method used today is Chromosomal Microarray (CMA) analysis, which has become the first-tier diagnostic test for individuals with unexplained developmental delay, intellectual disability, or multiple congenital anomalies. CMA works by comparing the patient’s DNA to a reference sample, allowing for the detection of copy number variants (CNVs), including both micro deletions and micro duplications, across the entire genome with a high resolution. Another method, Fluorescence In Situ Hybridization (FISH), is a more targeted test that is useful when a specific micro deletion syndrome is already clinically suspected. FISH utilizes fluorescently labeled DNA probes that are designed to stick to a particular, known chromosomal region. If the target region is deleted, the corresponding fluorescent signal will be missing in the patient’s cells, confirming the diagnosis for that specific syndrome.