Clinical Genetics 2 Chromosomal Abnormalities

Question 1

List different types of chromosome abnormality.

Answer 1

• Polyploidy
• Aneuploidy
• Translocations, inversions
• Duplications, deletions
• Ring chromosomes, marker chromosomes, isochromosomes
• Mosaicism

i.e. either change in number or change in structure.

Question 2

1. What is the telomere?
2. What is the centromere?
3. What is the difference between the p arm and the q arm?
4. Give features of light bands?
5. Give features of dark bands?

Answer 2

1. The DNA and protein cap which ensures replication to the tip and tethers to nuclear membrane.
2. Joins sister chromatids, essential for chromosome segregation at cell devision. Made up of 100s of kilo bases of repetitive DNA; some non-specific and some chromosome specific
3. P arm is small (petit) and q arm is the long arm/
4. Replicate early in S phase. Contain less condensed chromatin and are transcriptionally active. Gene and GC rich.
5. G bands, replicate late and contain rich condensed chromatin. AT rich.

Question 3

Down’s Syndrome?

1. What are the clinical features at birth?
2. How does maternal risk increase with age?

Answer 3

1. Decreased muscle tone, single palmar crease, broad flat face with slanting eyes and short nose. Flat back of head.
2. 30 - 1/900
   35 - 1/350
   36 - 1/300
   37 - 1/250
   38 - 1/200
   39 - 1/150
   40 - 1/100
   41 - 1/80
   42 - 1/60
   43 - 1/40 levels out here

Question 4

1. Describe chromosome findings in early miscarriage.

2. Describe the common chromosome abnormalities in Newborns

Answer 4

1. 40% apparently normal

60% abnormal:

• -> Trisomy 30%
• -> 45, X 10%
• -> Triploidy 10%
• -> Tetraploidy 5%
• -> Other 5%

2. (25,000 births a year), chromosome abnormalities per 10,000 births:
   - All 9.1
   - Trisomies 1.4
   - Balanced rearrangements 5.2
   - Unbalanced rearrangements 0.6
   - Sex chromosome abnormalities: male 1.2, female 0.75

Question 5

1. What is the chromosomal abnormality in Patau Syndrome?

2. What are the features of Patau Syndrome?

Answer 5

1. Trisomy of chromosome 13

2. Facial clefts, holoprosencephaly, heart defects, polydactyly, scalp skin defects, renal dysplasia, early death.

Question 6

1. What is the chromosomal abnormality in Edward’s Syndrome?
2. What are the features of Edward’s Syndrome?

Answer 6

1. Trisomy of chromosome 18

2. Arthrogryposis, heart defects, rocker bottom feet, IUGR (small), early death.

Question 7

1. Describe Mosaicism
2. What are the causes of Mosaicism?
3. What percentage of DS individuals are mosaic?

Answer 7

1. An individual or tissue may contain different populations of cells with different numbers of chromosomes.
2. • A post-zygotic mutation
   • Trisomy rescue - trisomic cell line may lose an extra chromosome during mitosis, ‘rescuing’ the karyotyp. May lead to uniparental disomy and some genetic problems (e.g. Prader-Willi).
3. Around 1%

Question 8

1. What is Uniparental Disomy?

2. What do maternal UPD of chromosome 15 and paternal UPD of chromosome 15 cause? Why do they differ?

Answer 8

1. When both copies of a chromosome arise from just one parent.
2. Maternal - Prader-Willi Syndrome (neonatal hypotonia, feeding difficulties, facial dysmorphism, small hands and feet, small genitalia, often pale. hyperphagia in childhood.

Paternal - Angelman Syndrome (mental retardation, little/no speech, jerky movements, spontaneous laughter, characteristic facial features).

Differ because of IMPRITING - some genes show parent-of-origin expression

Question 9

1. What is a translocation?
2. What is a Robertsonian Translocation?
3. Name two other types of translocation.

Answer 9

1. Part of one chromosome becomes detached and re-attaches to another chromosome. Arise during meiosis and may be de novo or inherited.
2. Two acrocentric chromosomes are stuck together and the p arms are lost. Most common is 13;14
3. Balanced translocation, unbalanced translocation (and complex rearrangements)

Question 10

What are the features of a de novo translocation?

Answer 10

• Often asymptomatic
• May disrupt an important gene
• May mimic autosomal dominant or unmask autosomal recessive disorder

Question 11

What are the consequences of balanced translocations?

Who carries the translocation?

Answer 11

• At risk of unbalanced offspring
• If imbalance is large this may cause miscarriage
• May carry risk of liveborn unbalanced offspring - small translocations associated with a higher risk of live birth.
• Prenatal diagnosis possible

Either the male or female parent.

Question 12

What are the methods of detecting and assessing chromosomal abnormalities and the features of each method?

Answer 12

1. Standard cytogenetics (karyotype)
   - -> Misses subtle abnormalities, imprecise correlation to genes involved, labour intensive and pickup rate Precise location of copy number abnormalities
   - -> Gold standard
   - -> Will not pick up balanced rearrangements
2. FISH (Fluorescence in situ hybridisation)
   - -> Useful for known familial abnormalities or high suspicion of specific syndrome
3. Multiplex Ligand-Mediated Probe Amplification (MLPA)
   - -> PCR technique that is rapid and reliable

Question 13

1. What is Copy Number Variation?

2. What is its importance in disease?

Answer 13

1. The knowledge that not all humans have the same number of genes; approx 10% of the genome may vary in copy number
   - 1 copy: effective deletion
   - 2 copies
   - 3 copies: effective duplication
   Provides basis for phenotypic variation.
2. Basis of some disease susceptibility
   e. g. Macular degeneration - CFH locus chromosome 1

Question 14

What are the advantages of CGH microarrays?

Answer 14

• Detect copy-number abnormalities
• Relies on DNA and not cytogenetics
• Highly specific and can map specific deletions to genes on human genome assembly
• Can help uncover the function of some genes.

Question 15

1. What is the smallest visible deletion?
2. When do deletions arise?
3. List some common deletion syndromes.

Answer 15

1. Around 1 megabase but smaller deletions are detectable by microarray. Easier to spot than duplications.
2. Usually during meiosis
3. • DiGeorge Syndrome (del 22q11 - cardiac abnormalities, thymic hypoplasia –> T cell abnormalities, cleft palate, hypocalcaemia, broad nose, long slender fingers)
     - Williams Syndrome (del 7q11 - hypercalcaemia, developmental delay, executive planning defect, ‘cocktail party’ speech, stellate irides, supravalvular aortic stenosis).
     - Cri du chat (chromosome 5p- microcephaly, wide mouth, hypertelorism, learning disability, facial dysmorphism, cat-like cry)
     - Wolf-Hirschorn
     - Kleefstra syndrome
     - 1p36 deletion syndrome

Question 16

Describe the mechanism and features of Hereditary Motor and Sensory Neuropathy 1A (Charcot-Marie-Tooth 1A)

Answer 16

• Duplication of PMP22 gene on chromosome 17
  (Deletion leads to HNPP - Hereditary Neuropathy with liability to Pressure Palsies).
• Distal neuropathy, wasting of peroneal muscles, clawed feet, sensory disturbances.

Question 17

What features lead you to think about a chromosome problem?

Answer 17

1. Multiple congenital abnormalities/ dysmorphic features
2. Unexplained developmental delay (esp if familial or associated with dysmorphism)
3. Multiple unexplained miscarriages
4. Family history of translocation
5. Clinical similarity to chromosome disorders

Question 18

Name teratogens and the abnormalities caused.

Answer 18

• Thalidomide: limb, heart defects
• Alcohol: growth restriction, mental retardation, microcephaly, behavioural problems, abnormal face
• Anti-epileptics esp Valproate: mental retardation, heart defects, abnormal face
• Warfarin: small, heart and brain malformations
• Vitamin A: small, brain, eye malformations