What is the role of genetics in the pathophysiology of Down syndrome?

Updated: Apr 30, 2018
  • Author: Gratias Tom Mundakel, MBBS, DCH; Chief Editor: Maria Descartes, MD  more...
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The extra chromosome 21 affects almost every organ system and results in a wide spectrum of phenotypic consequences. These include life-threatening complications, clinically significant alteration of life course (eg, intellectual disability), and dysmorphic physical features. Down syndrome decreases prenatal viability and increases prenatal and postnatal morbidity. Affected children have delays in physical growth, maturation, bone development, and dental eruption.

Two different hypotheses have been proposed to explain the mechanism of gene action in Down syndrome: developmental instability (ie, loss of chromosomal balance) and the so-called gene-dosage effect. [11] According to the gene-dosage effect hypothesis, the genes located on chromosome 21 have been overexpressed in cells and tissues of Down syndrome patients, and this contributes to the phenotypic abnormalities. [12]

The extra copy of the proximal part of 21q22.3 appears to result in the typical physical phenotype, which includes the following:

  • Intellectual disability - Most patients with Down syndrome have some degree of cognitive impairment, ranging from mild (intelligence quotient [IQ] 50-75) to severe impairment (IQ 20-35); patients show both motor and language delays during childhood

  • Characteristic facial features

  • Hand anomalies

  • Congenital heart defects - Almost half of affected patients have congenital heart disease, including ventricular septal defect and atrioventricular canal defect

Molecular analysis reveals that the 21q22.1-q22.3 region, also known as the Down syndrome critical region (DSCR), appears to contain the gene or genes responsible for the congenital heart disease observed in Down syndrome. A new gene, DSCR1, identified in region 21q22.1-q22.2, is highly expressed in the brain and the heart and is a candidate for involvement in the pathogenesis of Down syndrome, particularly with regard to intellectual disability and cardiac defects.

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