Cytogenetics And Learning Disorders Part 1

Question 1

What is better tolerated in humans, gain or loss of autosomal material?

Answer 1

Gain

Question 2

What are the two main ways in which you can have a gain of genetic material?

Answer 2

1. Primary trisomy (meiotic non-disj, mitotic non-disj and mosaicism)
2. Segmental duplication (interstitial dup, insertions, additional marker chromosomes)

Question 3

What are the three autosomal trisomy syndromes that are viable to term in non-mosaic form?

Answer 3

1. Trisomy 21: Down syndrome (15 per 10,000 births; 80% of pregnancies are lost prior to term)
2. Trisomy 18: Edwards syndrome (3 per 10,000 births; 95% are lost)
3. Trisomy 13: Patau syndrome (2 per 10,000 births; 95% are lost)

Question 4

As well as downs, Edwards and Patau syndrome, a number of other autosomal trisomies are viable in mosaic form. What are the most common two?

Answer 4

Mosaic trisomy 8 and 9

Question 5

What is the commonest genetic cause of mental retardation?

Answer 5

Down syndrome

Question 6

How can Down syndrome arise?

Answer 6

1. Trisomy 21 (94%): majority of these arise through non-disj at maternal meiosis I
2. Unbalanced Robertsonian translocation (4%)
3. Mosaic (2%): post-zygotic mitotic non-disj event (can also result from trisomy rescue)

Question 7

What are the physical features of Down syndrome?

Answer 7

• Flat facial profile with flattened nose
• Palpebral fissures (eyes) slant upwards and have epicanthic folds
• small ears
• flat back of the head (brachycephaly)
• protruding tongue (macroglossia)
• bilateral single palmar crease
• shorter than average with poor muscle tone
• other clinical features include mild to moderate mental retardation, ASD, cardiac defects and increased risk of leukaemia (can be transient)

Question 8

Provide some details on Patau syndrome

Answer 8

• Majority = Trisomy 13 - some arise through unbalanced Robertsonian translocation
• severe mental retardation
• clinical features = scalp defect and holoprosencephaly, polydactyly, cleft palate
• reduced life expectancy (~80% die within first year)

Question 9

Provide some details on Edwards syndrome

Answer 9

• Majority = Trisomy 18 - some arise through Trisomy 18q (usually isochromosome)
• associated with IUGR/failure to thrive/severe mental retardation
• > 90% die by 1yr
• common clinical features = clenched hand and rockerbottom feet

Question 10

A duplicated segment of a chromosome can either be?

Answer 10

1. Direct: red green goes to red green red green

2. Inverted (mirror image): red green goes to red green green red

Question 11

Provide some info on additional marker chromosomes

Answer 11

• Supernumerary
• Small and often mosaic
• clinical significance is dependent on their genetic composition

Question 12

Give two examples of syndromes arising through mosaicism for an extra marker chromosome

Answer 12

• Pallister Killian syndrome: isochromosome containing 2 copies of 12p (tetrasomy 12p)
• Cat eye syndrome: isochromosome containing 2 copies of proximal part of 22q

Question 13

Provide some details on Pallister Killian syndrome

Answer 13

• mosaic Tetrasomy 12p arising through isochromosome
• expressed in tissue specific way: rarely seen in metaphase blood preparations but can be found in skin and through interphase FISH
• clinical features include mental retardation, epilepsy, hypo/hyperpigmented patches of skin, distinctive coarse facial features, sparse temporal hair

Question 14

What gametes arise from a non-disj event at

(a) meiosis I
(b) meiosis II

Answer 14

(a) 2 disomic gametes and 2 nullosomic gametes

(b) 1 disomic gamete, 1 nullosomic gamete and 2 normal monosomic gametes

Question 14

Provide some details on Cat eye syndrome

Answer 14

• Mosaicism for an additional small isochromosome consisting of two copies of the proximal part of 22q
• often tissue specific
• vertical colobomas in the eye (hence its name)