Genetic Determinants of Learning Disability

Question 1

What is learning disability

Answer 1

Significantly reduced ability to understand new or complex information and learn new skills, leading to reduce ability to function independently

Question 2

Causes of learning disability

Answer 2

• Prenatal (chromosomal, maternal infection, teratogens)
• Perinatal (prematurity, trauma)
• Postnatal (serious illness, head injury, poor nutrition, exposure to toxins)

Environmental causes: e.g. spinal bifida due to lack of folic acid intake

Question 3

Autism

Answer 3

1% of UK population 
Not apparent until 1 year
Characterised by:
-impaired social interaction
-impaired social communication 
-impaired imagination

Question 4

Why make a diagnosis?

Answer 4

• Helps understand aetiology
• Discuss genetic aspects of condition (e.g. future children)
• Advise if there are investigations needed for diagnosis
• Think about prognosis
• Give advice about therapeutics
• To access services and support

Question 5

How to make a diagnosis?

Answer 5

• Family history (consanguinity, other members affected)
• Pregnancy history (drug/alcohol, scans, any results of screening tests)
• Perinatal period (adverse events at delivery)
• Developmental milestones
• Vision/hearing
• Seizure history
• Physical examination (dysmorphic changes, malformation, neurological signs, neurocutaneous stigmata)
• Special investigations (biochemical tests, imaging, genetic tests)

Question 6

Wolf-hirschhorn syndrome

Answer 6

4p- (end of chromosome 4 missing)

Characterised by greek helpmeet nose, flat facial profile

Question 7

Di-George syndrome

Answer 7

22q11 micro-deletion
Cleft palette, congenital heart disease, mild to moderate learning disability, renal abnormality
90% de novo

Question 8

Angelman syndrome

Answer 8

Maternal micro-deletion of 15q11-13

Epilepsy, severe learning disability, ataxia, happy

Question 9

Prader-Willi syndrome

Answer 9

Paternal micro-deletion of 15q11-13

Short stature, obesity, hypotonia, learning disability, hypergonadism

Question 10

What is used to look for microdeletions

Answer 10

FISH

Question 11

What test tells you whether deletion is maternal or paternal

Answer 11

Methylation specific PCR

Question 12

What test is used for single gene disorders

Answer 12

Sanger sequencing is gold standard

Question 13

DDX3C mutation

Answer 13

Only affects girls
Causes no LD
Ataxia, seizures
de-novo

Question 14

Tuberous sclerosis complex

Answer 14

Single gene disorder which is autosomal dominant
This affects reproductive fitness
60% de novo
If you have seizures with this condition you will have LD
In order to make diagnosis you need 1 major and 2 minor traits

Question 15

Phenylketonuria

Answer 15

Autosomal recessive single gene disorder
Screen in new born, pick them up, put on diet- this prevents LD
If not managed can lead to microcephaly
Patients have musty breath caused by too much protein intake
Missing enzyme causing a build-up of Phenylalanine =musty smell
Causes developmental delay, behavioural problems and seizures

Question 16

Fragile X syndrom

Answer 16

X linked recessive single gene disorder

High forehead, long ears, long face, prominent jaw

Question 17

2 conditions caused by environmental factors/teratogens

Answer 17

Fetal alcohol syndrome: small head, thin upper lip, difficult behaviour

Fetal valporate sundrome: sodium valporate used for treatment of epilepsy, causes LD and behavioural problems

Question 18

Cytogenic abnormality

Answer 18

Large scale changes to DNA
examples:
-Microdeletions
-Reciprocal translocation
-Robertsonian translocation