Day 4, Lecture 3: Genetics VI: Down Syndrome

Question 1

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

Answer 1

intellectual disability and characteristic facies

Question 2

Down Syndrome is caused by

Answer 2

• 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

Question 3

Dysmorphic findings in DS

Answer 3

Question 4

Approximately 95% of DS cases result from

Answer 4

• 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

Question 5

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

Answer 5

prolonged meiotic arrest in prophase I of the female oocyte

Question 6

When does the female oocyte complete meiosis I

Answer 6

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

Question 7

difference in nondisjunction in meiosis I vs. Meiosis II

Answer 7

Question 8

Effect of maternal age on DS risk

Answer 8

• 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

Question 9

Recurrence risk of Trisomy 21

Answer 9

• 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%

Question 10

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

Answer 10

• 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

Question 11

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

Answer 11

• 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

Question 12

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

Answer 12

Question 13

21;21 Robertsonian Translocation gamete formation, and offspring consequence

Answer 13

Question 14

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

Answer 14

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

Question 15

Prenatal screening and diagnosis of DS

Answer 15

• 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

Question 16

Diagnosis of DS

Answer 16

• 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

Question 17

Complications of DS

Answer 17

• 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

Question 18

Critical region for DS

Answer 18

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

Question 19

Management/Intervention of DS

Answer 19

• 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

Question 20

Early emphasis of DS is on

Answer 20

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