Day 4, Lecture 3: Genetics VI: Down Syndrome Flashcards Preview

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Flashcards in Day 4, Lecture 3: Genetics VI: Down Syndrome Deck (20):

Down syndorme (DS) is a particular combination of phenotypic features that include

intellectual disability and characteristic facies 


Down Syndrome is caused by

  • The presence of an extra copy of chromosome 21 
    • as a free chromosome
    • as a Robertsonian translocation
      • A special type of translocation that involves two acrocentric chromosomes. In this type of translocation the satellite material is lost on both chromosomes and the two “q arms” are joined together 
    • As a recprocal translocation involving part of chromosome 21


Dysmorphic findings in DS


Approximately 95% of DS cases result from 

  • non-disjunction during parental meiosis 
    • (DNA molecular techniques can elucidate whether the additional chromosome21 is paternal or maternal in origin, and also whether non-disjunction occured in meiosis I or meiosis II)
    • non-disjunciton was found to be maternal in 95% of cases
    • Maternal non-disjunction was found to be during meiosis I in 77% of cases 


The preponderance of meiosis I non-disjunciton is likely due to 

prolonged meiotic arrest in prophase I of the female oocyte


When does the female oocyte complete meiosis I 

  • Ovulation
    • proceeding to metaphase in meiosis II, which is only completed if fertilization occurs 


difference in nondisjunction in meiosis I vs. Meiosis II


Effect of maternal age on DS risk

  • The Risk of having a child with Down syndrome increases with advancing maternal age 
    • Applies to non-disjunction in both meiosis I and meiosis II, but effect is greater in meiosis I
  • The risk increases in a gradual, linear fashion until about age 30 and increases exponentially thereafter
  • For example, the risk of having a live born with Down Syndrome is 
    • 25-year old woman: 1/1,300
    • 35-year old woman: 1/365
    • 45-year old woman: 1/30


Recurrence risk of Trisomy 21

  • Affected by 
    • maternal age
    • Parental germline mosaicism
  • After 1 DS pregnancy, generally quoted as 1-2%, but higher if age-biased risk is higher
  • After 2 DS pregnancies, may be as high as 10%


What is the most likely reason for the increased incidence of DS 

  • Maternal age at time of first birth is increasing world-wide form 24.9 years old in 2000 to 26.3 years old in 26.3 
  • this in turn means that following pregancies are later than in previous generations 



% of DS that occur bc one parent carries a translocation involving chromosome 21

  • this occurs in about 5% of cases 
    • The risk to the offspring is dependent on the gender of the carrier parent
      • if father carrier: <1%
      • if mother carrier: 10-15%
  • (note the situation is different if t(21:21) in one parent) 
    • in this case all viable pregnancies will result in DS


Robertsonian Translocation (14:21) gamete formation, and consequence for offspring


 21;21 Robertsonian Translocation gamete formation, and offspring consequence


Can DS occur as a result of mitotic non-disjunction event after zygote formation?

  • Yes
    • this may result in clinically significant mosaicism, often with milder phenotype


Prenatal screening and diagnosis of DS

  • The American College of Medical Genetics (ACMG) has issued technical standards and guidelines for prenatal screening for Down syndrome
  • The guidelines distinguishes screening from diagnostic testing
  • The distinction is important, because the goals and expectations differ for clinical sensitivity and specificity, costs, and acceptable level of invasiveness
  • Screening includes measuinrg mutliple second trimester maternal serum markers
  • Asking a woman her age, and offering amniocentesis if she is aged 35 or older is also considered a screening test
  • Other screening methods include fetal ultrasonography
    • looking for nuchal translucency thickness and/or absence of the nasal bone 


Diagnosis of DS

  • The 'standard' diagnositc test for DS is the karyotyping of fetal cells, usually obtained by amniocentesis
    • chorionic villus sampling may also be used
  • postnatally, karyotyping of lymphocytes from peripheral blood is usually done
  • Rapid diagnostic tests are available for emergency situations, prenatally and postnatally
    • Fluorescent in-situ hybridization (FISH)
    • Such result should be followed by routine karyotyping


Complications of DS

  • Individuals with Down Syndrome almost universally have developmental and growth delay and hypotonia
  • Other complications as cardiac, gastrointestinal and hematologic occur with less but considerable frequency
  • These complications are thought to occur because of effects of 'gene dosage'
  • Cardiac complications
    • Congenital structural heart disease
      • atrioventricular septal defects (60% of CHD)
      • Ventricular septal defect (VSD) 
      • Atrial Septal Defect
      • Patent ductus arteriosus
      • Other complex heart disease
        • ex.
          • Tetralogy of Fallot
          • Hypoplastic left heart
    • Gastrointestinal Complications
      • Duodenal atresia or stenosis 
      • Hirschsprung disease (<1%) 
      • Tracheo-esophageal fistula
      • Imperforated anus 
    • Hematological complications
      • Transient myeloproliferative disorder
      • Leukemia
        • 200 to 400 times more frequently in the Down Syndrome 
        • Acute Myeloid leukemia (AML) 
          • outcome generally favorable
          • associated with somatic mutation in GATA1 (on chr X)
        • Acute lymphoblastic leukemia
          • Outcome not as favorable
    • Eye and ENT complications
      • Eye
        • Myopia
        • Cataract
      • ENT
        • Recurrent otitis media (horizontal Eustachian tubes)
        • Conductive hearing loss
        • Protruding tongue, likely due to small mid-face 
    • other issues to be monitored
      • Acquired hypothyroidism
      • Atlanto-axial subluxation
      • Obesity
      • Celiac disease
      • Obstructive sleep apnea
      • Seizures


Critical region for DS

  • Located in a region on 21q, known as syndrome critical region (or DSCR, 21q22-21qter) 


Management/Intervention of DS

  • Postnatal issues 
    • estabishing diagnosis
      • DS is a clinical diagnosis
    • Karyotyping/FISH tsting to confirm and to rule out other causes than trisomy 21
    • Inform family, and arrange for support system, esp. if diagnosis not anticipated
  • Evaulate for congenital heart disease
  • Evaluate hearing loss (through NBS)
  • Evaluate for hypothyroidism (through NBS)
  • Be aware of gastrointestinal complications
  • Be aware of hematological complications
  • Age-specific management guidelines exist, issued by AAP


Early emphasis of DS is on

  • family support and managing life-threatening complications
    • focus is then replaced by optimizing health and educational attainment 

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