2 Neuroscience2.9 Genetics
2.9 Genetics
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Written by Resident Doctor Committee · Published
Inheritance
Mendelian patterns are dominant, recessive, X-linked and mitochondrial; fathers do not transmit mitochondrial variants.
Penetrance is the proportion of carriers expressing a defined phenotype; 40 or more CAG repeats in HTT are fully penetrant.
Expressivity is the form and severity the phenotype takes.
Heritability describes variance in a population, not the causal share in one person.
Finding genes
Method | Establishes | Limit |
|---|---|---|
Family, twin and adoption studies | Heritability; schizophrenia concordance 40 to 50% in monozygotic, 10 to 15% in dizygotic twins | Shared environment, assortative mating, non-random placement |
Linkage | A chromosomal region; a logarithm of the odds (LOD) score of 3 is significant | Weak for small effects |
Genome-wide association study | Common variants at p below 5 x 10 to the minus 8 | Tags a locus, not a cause; needs huge samples |
Adoption studies separate inheritance from rearing. Polygenic scores predict poorly for individuals and across ancestries.
Types of abnormality
Level | Example | Detection |
|---|---|---|
Numerical | Trisomy 21 | Karyotyping |
Structural | 22q11.2 copy number variant | Chromosomal microarray, first line in unexplained learning disability with dysmorphism |
Sequence | Single nucleotide variants | Panels, exome or genome sequencing |
Repeat expansion | CGG in FMR1, CAG in HTT | Targeted assays, because sequencing reads repeats poorly |
Expanding repeats can produce anticipation; HTT expansion is especially paternal.
FMR1 full mutations exceed about 200 CGG repeats and silence the gene.
15q11-13 imprinting | Lost copy | Features |
|---|---|---|
Prader-Willi | Paternal | Hypotonia, hyperphagia |
Angelman | Maternal | Severe learning disability, ataxia, paroxysmal laughter |
Prenatal testing
Cell-free DNA screening from about 10 weeks samples mainly placental DNA.
Chorionic villus sampling at 11 to 14 weeks and amniocentesis from 15 weeks are diagnostic but carry procedure-related miscarriage risk.
Heterogeneity and endophenotypes
Locus heterogeneity means different genes give a similar phenotype; allelic heterogeneity means different variants within one gene.
Pleiotropy means one variant affects several traits.
Endophenotypes are measurable intermediate traits that are heritable, illness-associated, familial and relatively state-independent, such as P50 gating, prepulse inhibition and smooth pursuit.
Epigenetics
Epigenetic regulation changes expression without changing sequence: promoter methylation often represses, and acetylation often opens chromatin.
Peripheral epigenetic marks do not establish brain mechanisms.