Neurodevelopmental Disorders Flashcards
What is a locus
Physical location of a gene
Additive phenotype?
Can be partially expressed if partially present (e.g. Aa)
Humans have ___ of rare miss-sense variance (which can cause functional variety and natural selection)
___ rare protein-truncating variants (intolerant genes)
Humans have 100 of rare miss-sense variance (which can cause functional variety and natural selection)
5 rare protein-truncating variants (intolerant genes)
Describe the Model of Waddington
Start as a “ball” at top of landscape. Genetics define landscape (inherited risk). As the ball descends, it is subjected to various valleys and turns.
These represent:
Environmental “epigenetic” factors
Random developmental fluctuations
Final phenotype reached
How to categorise neurodevelopmental disorders?
Disorders of:
- proliferation
- migration
- cortical organisation
- connectivity
Defects in cortical organisation
Polymicrogyria
neurons migrate to the cortex but don’t organise themselves, ARX mutation, associated w/epilepsy
Defects in neuronal proliferation
Focal Cortical Dysplasia
mutations of the mTOR pathway, abnormal neuron shape -> abnormal electrical firing->epilepsy
Defects in neuronal migration
Lissencephaly: doublecortin mutation (X-linked), smooth brain]- males
Subcortical Banding Heterotopia: doublecortin mutation (X-linked)]- females
Periventricular Nodular Heterotopia (PNH): Mutation in Filamin-1, neurons stuch in ventricles and don’t migrate
Disorders of connectivity
- Autism
- Intellectual disability
- Schizophrenia
Genetic causes of epilepsy?
- Autoimmune
- Focal epilepsy with MRI detectable lesions (resulting from infection, stroke or trauma)
- Genetic susceptibilty
Genetic susceptibilty’s role in the cause of epilepsy?
- Mendelian Inheritance (autosomal dominant/recessive)
- Rare Variant Common Disease: many different genes each confer a small risk, mutations in each of these genes have the overall effect of producing a high risk of diesease
- Common Variant Rare Disease: a genetic variant confers a small risk but this variant is so common (>5%) that epilepsy is more likely
Define genetic heterogeneity
Different genes may cause the same epilepsy
Define phenotypic heterogeneity
Mutations in the same gene may cause different epilepsies (+ different drug responses)
Genetics of epilepsy:
List some ion channel subunit genes that are affected
Voltage-gated (Na+, K+) and ligand gated (nAChR, GABA)
Genetics of epilepsy:
List some non-ion channel genes
LGI1, GLUT1, PCDH19, DEPDC5
