Genetic determinants of learning disability

Question 1

Define learning disability

Answer 1

• Significantly reduced ability to understand new or complex information
• Reduced ability to cope independently which starts before adulthood with lasting effects on development

Question 2

Define autisic spectrum disorders

Answer 2

• Developmental conditions present from birth

- Characterised by impaired social interaction, impaired social communication and impaired imagination

Question 3

What is the cause?

Answer 3

• Genetics
• Problems during pregnancy and birth - infections, teratogens, prematurity
• Incidents after birth - serious illness, head injury, poor nutriotion, exposure to toxins

Question 4

Cytogenetic vs molecular genetic abnormalities

Answer 4

• Cytogentic = can be seen under microscope

- Molecular = cannot be seen under microscope

Question 5

What are the main causes of cytogenetic abnormality?

Answer 5

• Aneuploidy - abnormalities in chr number
• Translocations = robertsonian, reciprocal
• Deletions/ duplications

Question 6

What is a Robertsonian translocation?

Answer 6

• Only occurs on 13, 14, 15, 21, 22
• Get 2 acrocentric chromosomes stuck end to end
• Carrier has 45 chromosomes, but normal amount of genetic material
• Affected has 46 chromosomes, but extra copy of one (usually 21)

Question 7

What is a reciprocal translocation?

Answer 7

• Involve any part of any chromosome
• Exchange of material between the 2 chromosomes
• Carrier completely normal
• Can result in offspring with unbalaced amounts of the 2 chromosomes

Question 8

What is 4p-(wolf-Hirschhorn)?

Answer 8

• 4p-9a large chunk of Chr4 is deleted - malformation of kidney, cardiac disease, differential features
• Can see the differences under microscope

Question 9

What is caused by a 22q11 microdeletion?

Answer 9

• Significant speech and language difficulties
• Cleft palate
• Congenital heart disease
• Hypocalcaemia
• Mild to moderate learning difficulties
• Renal abnormalities
• AKA DiGeorge syndrome

Question 10

What is FISH?

Answer 10

• Fluorescent in situ hybridisation
• Uses fluorescent probe complimentary to specific part of the genome you want to look at - if present, it will fluoresce
• can be used when looking for deletions (eg 2 copies of each bit of DNA should be present, will see by 2 separate lights)

Question 11

What is arrayCGH?

Answer 11

• An untargeted test, dont need to know what you are looking for
• Uses probes all along the Chromosome, will pick up any microsatellites
• Array is done to make it less likely to fail, allowing them to hybridise on the slide anywhere, then a computer will arrange it correctly
• Yellow is normal; red = duplication; green = deletion

Question 12

What symptoms does a 7q11.2 deletion cause?

Answer 12

• William’s syndrome
• FISH shows that the elastin gene isnt present on both alleles - deletion
• Learning difficulties and speech delay

Question 13

What symptoms does a 15q11.2 deletion cause?

Answer 13

• often inherited from parent with few problems
• variable phenotype
• no reliably recognisably dysmorphology
• seizures
• mild-moderate delay

Question 14

How do we look for single gene disorders?

Answer 14

• Sanger sequencing if we know what we are looking for

Question 15

What is phenylketonuria?

Answer 15

• have no/ a defect in phenylalanine hydroxylase
• Means that they are unable to turn phenylalanine into tyrosine, causing its accumulation
• Developmental delay
• Beahvioural/ social probs
• seizures
• hyperactivity
• Growth retardation
• Eczema
• Microcephaly
• A musty odour of child

Question 16

What are the characteristics of X-linked recessive diseases?

Answer 16

• Women may be carriers
• Unlikely to produce affected female - more likely male as only have 1 X
• No male to male
• But definitely male to female, as will pass on the disease X

Question 17

What are the synptoms of fragile-X syndrome?

Answer 17

• High forehead
• Long ears
• Long face
• Prominent jaw
• macro-orchidism

Question 18

What are triple repeat expansions?

Answer 18

• Unstable/ dynamic expansions - can increase in size in next generation
• Instability depends on parent of origin
• General correlation between size of expansion and severity of disorder
• Variable in families due to number of repeats

Question 19

What is imprinting?

Answer 19

• Disease is present even though there is no apparent cytogenetic or molecular genetic abnormality
• Certain parts of the genome are imprinted (methylated)
• importance of having both parents’ contribution
• Depends on which parent the gene is inherited from that determines if it is switched on or off

Question 20

Prade-Willi/ Angelman

Answer 20

• Both syndromes are associated with the loss of the chromosomal region 15q11-13
• This region has paternally expressed SNRPN and NDN, and the maternally expressed UBE3A
• Paternal inheritence of a deletion of this region = Prader-Willi (hypotonia, obesity, hypogonadism)
• Maternal inheritence of the same deletion = Angelman (epilepsy, tremors and smiling facial expression)