22q11.2 deletion syndrome (22q11.2DS) is a condition caused by the loss of a small fragment of chromosome 22, affecting multiple organ systems. Clinical features include congenital anomalies, cardiac and palatal abnormalities, autoimmune diseases, endocrine, immune, renal, and gastrointestinal problems, speech and language delays, and variable cognitive deficits and neuropsychiatric illnesses. The syndrome has an estimated prevalence of 1 in 1,000 fetuses, with higher rates in those with abnormal ultrasonographic findings or developmental disabilities. Most cases are de novo, but there is a 50% chance of transmission to offspring. Initially identified in patients with DiGeorge syndrome, 22q11.2DS is now recognized as a common cause of congenital heart disease, syndromic palatal anomalies, and developmental delay. The high clinical variability is attributed to various mechanisms, including dosage-sensitive genes, allelic variation, modifier genes, and epigenetic phenomena. The frequent deletion of the 22q11.2 region is due to the complexity of the long-range chromatin interactions (LCRs) in this area, which have not been fully elucidated.22q11.2 deletion syndrome (22q11.2DS) is a condition caused by the loss of a small fragment of chromosome 22, affecting multiple organ systems. Clinical features include congenital anomalies, cardiac and palatal abnormalities, autoimmune diseases, endocrine, immune, renal, and gastrointestinal problems, speech and language delays, and variable cognitive deficits and neuropsychiatric illnesses. The syndrome has an estimated prevalence of 1 in 1,000 fetuses, with higher rates in those with abnormal ultrasonographic findings or developmental disabilities. Most cases are de novo, but there is a 50% chance of transmission to offspring. Initially identified in patients with DiGeorge syndrome, 22q11.2DS is now recognized as a common cause of congenital heart disease, syndromic palatal anomalies, and developmental delay. The high clinical variability is attributed to various mechanisms, including dosage-sensitive genes, allelic variation, modifier genes, and epigenetic phenomena. The frequent deletion of the 22q11.2 region is due to the complexity of the long-range chromatin interactions (LCRs) in this area, which have not been fully elucidated.