Down syndrome usually results from trisomy 21, a spontaneous chromosomal abnormality in which chromosome 21 has three copies instead of the normal two because of faulty meiosis (nondisjunction) of the ovum or, sometimes, the sperm. This results in a karyotype of 47 chromosomes instead of the normal 46. In about 4% of patients, Down syndrome results from an unbalanced translocation (chromosomal rearrangement) in which the long arm of chromosome 21 breaks and attaches to another chromosome. The disorder may also be due to chromosomal mosaicism, a mixture of two cell types—one with a normal number of chromosomes (46) and some with 47 (an extra chromosome 21).

Down syndrome occurs in 1 in 650 to 700 live births, but the prevalence increases with advanced parental age, especially when the mother is age 34 or older at delivery or the father is older than age 42. At age 20, a woman has about 1 chance in 400 of having a
child with Down syndrome; by age 49, she has 1 chance in 12. If a woman has had one child with Down syndrome, the risk of recurrence is 1% to 2%. This risk varies according to the type of translocation the parents carry, and genetic counseling should be discussed.