Neurodevelopmental Disease Flashcards
Understand the principle modes of inheritance Understand how germline and somatic mutations can contribute to neurodevelopmental disease Understand how neurodevelopmental disease can originate from genetic defects in neuronal proliferation, neuronal migration, and neuronal connectivity Understand how precision medicine can be applied to neurodevelopmental disease
What is a gene locus?
The physical location of a gene
Name three ways in which diploid genotypes can be expressed in a phenotype
With dominant, recessive, or additive effects
How much of the human genome codes for proteins?
2%
How many protein coding genes are there approximately?
20,000
How many genetic variants does the average person differ from others by?
2 million
How many rare protein truncating genetic variants does the average individual have?
5 - but in most people these fall in a protein that is non-essential for development
How did Waddington define the epigenetic landscape model in 1957?
The precise developmental pathway is determined by environmental influences (epigenetics) and random developmental fluctuation (chance)
When does the migration of neurons take place in utero?
Gestation weeks 10-20
When does myelination of axons occur in development?
Childhood
Name a developmental defect in cortical organisation, and the genes involved
Polymicrogyria - an excess number of gyri which can occur from germline mutations in ARX and TBB2B
Name a developmental defect in cortical proliferation, and the pathway involved
Focal cortical dysplasia - caused by somatic mutations in the mTOR pathway, which regulates growth
Name a developmental defect in cortical migration, and the genes involved
Lissencephaly - caused by DCX mutations in males (X-linked gene) or SCBH in females (less severe), or by a mutation on LIS1 on chromosome 17
What proportion of epilepsy is caused by brain damage?
1/5
Define the common variant common disease hypothesis of complex inheritance
Alleles individually confer a relatively small risk of developing a disorder, but one individual having many of these genes has a high risk of developing the disease
Define the rare variant common disease hypothesis of complex inheritance
A newly arising mutation, or a rare gene variant, confers a very high risk of developing a disease. Many of these rare variants confer risk for the same disease, making the disease appear common despite each variant being rare
What proportion of epilepsies are Mendelian?
1-2%
Why are most de novo mutations inherited from the father?
Mioisis in males carries on throughout life, and is not perfect - so for each round of spermatogenesis there is a risk of a mistake entering the new sperm
What are epileptic encephalopathies?
Severe epilepsies developed during the first year of life with neurodevelopmental decline and a high risk of sudden death
Name at least two genes implicated in monogenic epileptic encephalopathies
GABRB3, STXBP1, DNM1, SCN1A
What is the difference between fluid and crystallised cognitive abilities?
Fluid cognitive abilities are general abilities and include things like reasoning, processing speed, and memory. Crystallised cognitive abilities are specific skills, such as reading or riding a bicycle
At what age does fluid cognitive ability start to decline?
40
