Neurogenetics
What You'll Learn
Classification of Mutations
| Mutation Type |
Description |
Example |
| Silent |
Nucleotide change but same amino acid (codon degeneracy) |
No clinical effect |
| Missense |
Single nucleotide change → different amino acid |
Sickle cell disease (Glu → Val); CADASIL (NOTCH3 cysteine mutations) |
| Nonsense |
Single nucleotide change → premature stop codon |
Duchenne muscular dystrophy (truncated dystrophin) |
| Frameshift |
Insertion or deletion NOT a multiple of 3 → shifts reading frame |
Duchenne (out-of-frame deletion) vs. Becker (in-frame deletion) |
| In-frame insertion/deletion |
Insertion or deletion of 3n nucleotides; reading frame preserved |
Becker muscular dystrophy (shortened but partially functional dystrophin) |
| Splice-site mutation |
Disrupts intron-exon boundary → abnormal mRNA splicing |
Some forms of SMA, familial dysautonomia (IKBKAP) |
| Trinucleotide repeat expansion |
Dynamic mutation; repeat length increases across generations |
Huntington (CAG), Fragile X (CGG), Friedreich ataxia (GAA) |
| Chromosomal deletion |
Loss of a chromosome segment |
DiGeorge (22q11.2 deletion), Williams (7q11.23) |
| Chromosomal duplication |
Extra copy of a chromosome segment |
CMT1A (PMP22 duplication) |
| Gene fusion |
Two genes fused by translocation or deletion |
BCR-ABL in CML; KIAA1549-BRAF in pilocytic astrocytoma |
Functional Consequences of Mutations
| Pattern |
Key Features |
Board-Relevant Examples |
| Autosomal dominant |
50% offspring affected; vertical transmission; male-to-male transmission possible; variable penetrance and expressivity; de novo mutations common |
Huntington, NF1, NF2, TSC, myotonic dystrophy, CADASIL, most SCAs, CMT1A |
| Autosomal recessive |
25% affected offspring; horizontal transmission (siblings affected); carriers asymptomatic; consanguinity ↑ risk; typically loss-of-function mutations |
Friedreich ataxia, Wilson disease, SMA, most metabolic diseases, ataxia-telangiectasia |
| X-linked recessive |
Males affected; carrier females usually asymptomatic; NO male-to-male transmission; affected father → all daughters are carriers, no sons affected |
Duchenne/Becker, Kennedy disease (SBMA), Fragile X, Fabry disease, adrenoleukodystrophy |
| X-linked dominant |
Affects both sexes; often lethal in males; affected females show variable expression due to X-inactivation |
Rett syndrome (MECP2), incontinentia pigmenti (IKBKG), Aicardi syndrome (presumed X-linked dominant; gene not yet identified) |
| Mitochondrial |
Maternal inheritance only (mtDNA-encoded disorders); affected mother → all children at risk; affected father → no children affected; heteroplasmy (variable mutation load); threshold effect. Caveat: many mitochondrial diseases (e.g., POLG, most Leigh syndrome) are nuclear-encoded and follow Mendelian (often AR) inheritance. |
MELAS, MERRF, LHON, Kearns-Sayre, NARP |
| Genomic imprinting |
Gene expression depends on parent of origin; same chromosomal deletion → different disease depending on which parent it came from |
Prader-Willi: paternal 15q11–13 deletion (~70%), maternal UPD (~25%), imprinting defect (~5%). Angelman: maternal 15q11–13 deletion (~70%), paternal UPD (~5%), imprinting defect (~5%), UBE3A mutation (~10%) |
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