What Causes Down Syndrome?

Down syndrome is a genetic disease caused by an extra copy of an autosome, chromosome 21. The disorder is named after the physician John Langdon Down, who first published his observations in 1866. Like all other genetic disorders, there is no cure for the chromosomal change. But early intervention, medical care, education, and therapies greatly improve health and quality of life.

Causes of Down Syndrome

Aneuploidy is the condition in which there is a variation in the number of chromosomes that results in the addition or loss of one or more chromosomes. The aneuploidy related to the gain of one chromosome to an otherwise diploid genome is known as trisomy. Trisomy of 21 causes Down Syndrome, and the disease is also known as trisomy 21 (designated 47,XX,+21 (female) or 47,XY,+21 (male)).

Prevalence varies by population and reporting; commonly cited estimates are about 1 in 700 live births (range ≈1 in 700–1000 depending on region and data source).

The extra chromosome 21 most often arises from nondisjunction during maternal meiosis, when chromosome pairs fail to separate properly.
Nondisjunction is the failure of chromosomes to separate during anaphase (either homologous chromosomes in meiosis I or sister chromatids in meiosis II), often due to improper spindle/kinetochore attachments established at metaphase.
In Anaphase I, it is the failure of homologous chromosomes to disjoin.
In Anaphase II, it is the failure of sister chromatids. Either error can produce gametes with n+1 or n−1.
The majority of trisomy 21 cases arise from maternal meiotic errors, predominantly meiosis I. Estimates vary, but ~75–90% of nondisjunction events are of maternal meiotic I origin.
Subsequent fertilisation of the (n+1) chromosome containing gamete with a normal one results in the trisomic condition.

Nondisjunctional Events Increase with Maternal Age

Even though the additional chromosome might be derived from any one of the parents, chromosome analysis has shown that the ovum is the source for about 95% of trisomy 21 cases. Moreover, the increased maternal age is also directly related to Down Syndrome births.

Meiosis initiates in the eggs of a human female in her foetal state, and the oocyte development is arrested in Meiosis I.
During puberty, as ovulation begins, meiosis is initiated when one egg continues into Meiosis II during each ovulatory phase. The process is again arrested and not completed until fertilisation occurs.
As a consequence, older women produce significantly older ova that have been arrested longer.
In these older ova, cohesion between sister chromatids deteriorates, and they are susceptible to missegregation.

Other Types of Down Syndrome

Besides the random nondisjunction of chromosome 21 before gamete formation, the other types of the syndrome and their causes are as follows-

Mosaicism

After fertilisation, nondisjunction occurs during the mitotic division in the zygote, resulting in some normal cells and some cells with trisomy 21. It is a rare form (~1–2% of cases) and often presents with milder or variable features depending on the proportion and distribution of trisomic cells.

Familial Down Syndrome or Translocation Down Syndrome

Nondisjunction of chromosome 21 is a random error, which is not expected to be inherited. Nevertheless, the syndrome occasionally runs in families and is referred to as familial Down syndrome.

It mostly involves translocation and is also known as translocation down syndrome. It might not be expressed in the parent due to balanced translocation, but it can pass the unbalanced translocation to the child.

Most familial (translocation) cases involve translocations, commonly 14;21 or 21;21 (also sometimes 13;21). A parent can be a balanced carrier and be phenotypically normal, but risk passing an unbalanced translocation to offspring.

Frequently Asked Questions (FAQs)

Q1. Can Down syndrome be inherited?

Most cases of Down syndrome are not inherited and occur due to random nondisjunction. However, in rare cases (about 3–4%), it can be inherited through a Robertsonian translocation from a parent.

Q2. Does maternal age affect the risk of Down syndrome?

Yes. The likelihood of having a baby with Down syndrome increases significantly with maternal age, especially after age 35.

Q3. Are all individuals with Down syndrome affected in the same way?

No. The severity and specific symptoms vary. While most people have some degree of intellectual disability and characteristic physical features, health challenges, and developmental outcomes can differ widely.