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trisomy 21

Friday 12 November 2004

Definition: Down syndrome caused by chromosome 21 trisomy is the most common genetic cause of mental retardation in humans. Disruption of the phenotype is thought to be the result of gene-dosage imbalance.

Trisomy 21, also known as Down syndrome (DS), is a complex developmental disorder that affects many organs, including the brain, heart, skeleton and immune system.

A working hypothesis for understanding the consequences of trisomy 21 is that the overexpression of certain genes on chromosome 21, alone or in cooperation, is responsible for the clinical features of DS.

There is now compelling evidence that the protein products of two genes on chromosome 21, Down syndrome candidate region 1 (DSCR1) and dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), interact functionally, and that their increased dosage cooperatively leads to dysregulation of the signaling pathways that are controlled by the nuclear factor of activated T cells (NFAT) family of transcription factors, with potential consequences for several organs and systems that are affected in DS individuals.

Incidence, 1 in 650-1000 live births


- trisomy 21

  • Meiotic origin >95% maternal, mostly meiosis I - Increased recurrence risk with parental translocation
  • Full trisomy 21: 94%
  • Mosaic trisomy 21: 2.4%
  • Translocation 21: 3.3%


- systemic anomalies

  • short stature

- head and neck anomalies

  • brachycephaly
  • excess nuchal skin
  • flat facial profile
  • small ears
  • folded helix
  • conductive hearing loss
  • upslanting palpebral fissures
  • epicanthal folds
  • cleft lip/cleft palate
  • cataracts
  • iris brushfield spots
  • protruding tongue

- cardiovascular anomalies (50%)

  • pulmonary hypertension
  • pulmonary capillary dysplasia
  • pulmonary vascular sclerosis
  • coronary periarteritis nodosa

- digestive anomalies

- hepatic anomalies

- renal anomalies

  • renal tubular dysgenesis

- rachis anomalies

  • atlanto-axial instability

- limbs anomalies

  • hypoplastic iliac wings
  • shallow acetabulum
  • joint laxity
  • short hands, broad hands
  • fifth finger mid-phalanx hypoplasia
  • single transverse palmar crease
  • talipes equinovarus

- neurological anomalies

- endocrine anomalies

  • hypothyroidism

- hematological anomalies

- autoimmunity

Animal models

- mouse model (16677859)


- Prandini P, Deutsch S, Lyle R, Gagnebin M, Delucinge Vivier C, Delorenzi M, Gehrig C, Descombes P, Sherman S, Dagna Bricarelli F, Baldo C, Novelli A, Dallapiccola B, Antonarakis SE. Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. Am J Hum Genet. 2007 Aug;81(2):252-63. PMID: 17668376


- de la Luna S, Estivill X. Cooperation to amplify gene-dosage-imbalance effects. Trends Mol Med. 2006 Oct;12(10):451-4. PMID: 16919501

- Antonarakis SE, Epstein CJ. The challenge of Down syndrome. Trends Mol Med. 2006 Oct;12(10):473-9. PMID: 16935027

- Reeves RH. Down syndrome mouse models are looking up.
Trends Mol Med. 2006 Jun;12(6):237-40. PMID: 16677859

- Patterson D, Costa AC. Down syndrome and genetics - a case of linked histories. Nat Rev Genet. 2005 Feb;6(2):137-47. PMID: 15640809

- Hitzler JK, Zipursky A. Origins of leukaemia in children with Down syndrome. Nat Rev Cancer. 2005 Jan;5(1):11-20. PMID: 15630411

- Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S. Chromosome 21 and down syndrome: from genomics to pathophysiology. Nat Rev Genet. 2004 Oct;5(10):725-38. PMID: 15510164

- Hernandez D, Fisher EM. Down syndrome genetics: unravelling a multifactorial disorder. Hum Mol Genet. 1996;5 Spec No:1411-6. PMID: 8875245