13 - Molecular Cytogenetics 2

Question 1

Monosomy

Answer 1

• Loss of single chromosome
• Autosomal monosomy not compatible with life
• Sex chromosomal monosomy X is compatible

Question 2

Trisomy

Answer 2

• Gain of single chromosome
• Some autosomal trisomies are compatible with life (13,18,21)
• Trisomy X is mild

Question 3

Whole chromosome aneuploidy

Answer 3

• Major cause of foetal death as most aneuploidies are incompatible with life
• Some aneuploidies do result in viable offspring with a spectrum of developmental disorders

Question 4

Trisomy 21

Answer 4

• Majority have 3 free copies of chromosome 21
• Some have 1 copy translocated to another acrocentric chromosome (e.g. 14)
• Most cases arise from error at maternal meiosis
• Minority of cases from error during spermatogenesis

Question 5

Clinical features of trisomy 21

Answer 5

• Intellectual disabilities
• Congenital heart disease
• Thyroid disorders
• Poor immune function
• Increased risk of leukemia

Question 6

Trisomy 18

Answer 6

• Severe, most infants die in first year of life
• Dysmorphic facial features
• Rocker bottom feet and clenched hands
• Organ malformations (most cardiovascular)

Question 7

Syndrome name of trisomy 18

Answer 7

Edwards syndrome

Question 8

Trisomy 13

Answer 8

• Severe, high postnatal mortality
• Heart defects
• Brain or spinal cord abnormalities
• Rocker bottom feet
• Extra fingers or toes

Question 9

Syndrome name of trisomy 13

Answer 9

Patau syndrome

Question 10

Klinefelter syndrome 47 (XXY)

Answer 10

• Males have 47, XXY are always infertile
• Some have poor development of secondary sexual characteristics and female fat distribution
• Breast tissue
• Developmental delay
• Behavioural issues
• Learning disabilities

Question 11

Turner syndrome 45 (X)

Answer 11

• One X is the only sex chromosome
• Short stature
• Swelling of hands and feet
• Webbed neck
• Reproductive sterility

Question 12

Diagnosis of whole chromosome copy number changes

Answer 12

• QF-PCR (prenatal detection, cheap and fastest)
• NIPT
• FISH
• Karyotype (can detect translocations)
• Microarray

Question 13

Microdeletion and microduplication syndromes

Answer 13

• Small deletions or duplications that cannot be seen by conventional cytogenetics (karyotype)
• Detected by microarray, MLPA or FISH
• Occur in same location in the genome in many different patients
• Low copy repeat (LCRs) predispose the region to recurrent genomic rearrangements by non-allelic homologous recombination

Question 14

Non allelic homologous recombination

Answer 14

• Misalignment and recombination between LCR sequences
• Gives rise to reciprocal duplication & deletion

Question 15

Examples of recurrent microdeletion and microduplication syndromes

Answer 15

1. 22q11.2 deletion syndrome
2. 22q11.2 duplication syndrome
3. Williams syndrome
4. Prader Willi / Angelman syndrome (15q11.2 deletion syndrome)
5. 15q11.2 duplication syndrome

Question 16

22q11.2 deletion syndrome

Answer 16

• Most common microdeletion syndrome
• CATCH 22 clinical features
• Best detected by MLPA
• Occur within region of complex genomic architecture

Question 17

CATCH 22

Answer 17

C: Cardiac defects
A: Abnormal faces
T: Underdeveloped thymus, immunodeficiency
C: Cleft palate
H: Hypocalcemia, hypoparathyroidism

Question 18

22q11.2 duplication syndrome

Answer 18

• Milder than deletion
• Mild intellectual disability
• Growth retardation
• Also found in parents (carriers)

Question 19

Williams syndrome

Answer 19

• 7q11.23 deletion
• Distinctive facial features
• Developmental delay
• ADHD
• Heart defects

Question 20

Prader Willi Syndrome

Answer 20

• 15q11q13 deletion (paternal deletion OR maternal UPD)
• Floppy at birth
• Developmental delay
• Obesity after 2 years
• Intellectual disability and other behavioural problems

Question 21

Angelman syndrome

Answer 21

• 15q11q13 deletion (maternal deletion OR paternal UPD)
• Developmental delay, minimal use of words
• Movement disorder
• Frequent laughter/smiling, short attention span
• Delayed growth
• Seizures

Question 22

15q11q13 duplication syndrome

Answer 22

• Autism
• Intellectual disability
• Seizures
• Developmental delays
• Duplications mostly maternally inherited
• Paternally inherited duplication have mild phenotype

Question 23

Diagnosis of 15q11q13 PWS/AS region

Answer 23

• Methylation-specific MLPA can identify the deletions and duplications of 15q11q13
• Also reveals inheritance pattern

Question 24

Charcot Marie Tooth Type 1A (CMT1A)

Answer 24

• Caused by 17p12 duplications including the PMP22 gene
• Adult onset progressive peripheral neuropathy
• Characterised by distal symmetrical muscle weakness
• Dose senstitive

Question 25

PMP22 protein

Answer 25

• Produced in schwann cells
• Critical to myelination in the PNS
• PMP-22 duplication gives an increase in the protein that causes CMT1A
• PMP-22 deletion gives a decrease in the protein which causes a milder peripheral neuropathy

Question 26

Pelizaeus-Merzbacher disease

Answer 26

• Caused by duplication of the PLP1 gene on Xq22.2
• Boys with duplication have dysmyelination
• Deletion of PLP1 causes mild myelin disorder
• No production of PLP1 protein is less severe than over production.
• Example of dosage sensitive gene

Question 27

Pathogenic partial deletion of IL1RAPL1 gene

Answer 27

• Intragenic deletion (exons 4,5,6)
• IL1RAPL1 expressed in brain that is responsible for X linked intellectual disability
• Facial features in males
• Detected by microarray, MLPA or gene sequencing