What causes Down syndrome?

Updated: Apr 30, 2018
  • Author: Gratias Tom Mundakel, MBBS, DCH; Chief Editor: Maria Descartes, MD  more...
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Down syndrome is caused by the following 3 cytogenic variants:

  • Three full copies of chromosome 21

  • Chromosomal translocation that results in 3 copies of the critical region for Down syndrome

  • Mosaicism

In 94% of patients with Down syndrome, full trisomy 21 is the cause; mosaicism (2.4%) and translocations (3.3%) account for the remaining cases. Approximately 75% of the unbalanced translocations are de novo, and approximately 25% result from familial translocation.

A free trisomy 21 results from nondisjunction during meiosis in one of the parents. This occurrence is correlated with advanced maternal and paternal age. About 95% of the time, the error is maternal nondisjunction, with meiosis I errors occurring three times as frequently as meiosis II errors. The remaining 5% cases are paternal in origin, and meiosis II errors predominate.

Advanced maternal age remains the only well-documented risk factor for maternal meiotic nondisjunction. However, understanding of the basic mechanism behind the maternal age effect is lacking.

Translocation occurs when genetic material from chromosome 21 becomes attached to another chromosome, resulting in 46 chromosomes, with 1 chromosome having extra material from chromosome 21 attached. It may occur de novo or be transmitted by one of the parents. Translocations are usually of the centric fusion type. They frequently involve chromosome 14 (14/21 translocation), chromosome 21 (21/21 translocation), or chromosome 22 (22/21 translocation).

Mosaicism is considered a postzygotic event (ie, one that occurs after fertilization). Most cases result from a trisomic zygote with mitotic loss of one chromosome. As a result, two cell lines are found: one with a free trisomy and the other with a normal karyotype. This finding leads to great phenotypic variability, ranging from near normal to the classic trisomy 21 phenotype.

Cytogenetic and molecular studies suggest that dup21(q22.1-22.2) is sufficient to cause Down syndrome. The DSCR contains genes that code for enzymes, such as superoxide dismutase 1 (SOD1), cystathionine beta-synthase (CBS), glycinamide ribonucleotide synthase-aminoimidazole ribonucleotide synthase-glycinamide formyl transferase (GARS-AIRS-GART).

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