GeneticsTier 1Medical Sciences concept

Genetic mutation terminology (aneuploidy, dynamic mutation, nonsense mutation, imprinting, uniparental disomy, heteroplasmy, linkage disequilibrium)

Core concept

Point mutations (single base substitution)

Term	Effect	Example
Silent (synonymous)	Same amino acid (degenerate code)	May still matter if it disrupts splicing
Missense	One amino acid changed	Sickle cell (Glu6Val), C282Y, JAK2 V617F
Nonsense	Codon -> premature STOP -> truncated protein, usually degraded by nonsense-mediated decay	DMD, CF (G542X)
Splice site	Exon skipping / intron retention	Beta-thalassaemia, many

Frameshift = insertion/deletion not a multiple of 3 -> reading frame lost -> downstream nonsense -> null allele
In-frame indel = multiple of 3 -> internal residues lost, protein still made -> milder (CF F508del, Becker MD)

Key detail

Term	Definition
Aneuploidy	Chromosome number not a multiple of 23 - trisomy 21, monosomy X. From non-disjunction
Polyploidy	Whole extra haploid set (69,XXX) - non-viable
Dynamic mutation	Unstable trinucleotide/short-repeat expansion growing between generations -> anticipation. HD (CAG), DM1 (CTG), fragile X (CGG), Friedreich ataxia (GAA, AR and does not show anticipation)
Premutation	Expanded but sub-threshold allele - FMR1 55-200 CGG -> FXTAS and primary ovarian insufficiency, and expands in the female germline
Imprinting	Parent-of-origin monoallelic expression, set by DNA methylation, erased and reset in the germline. PWS/Angelman, Beckwith-Wiedemann
Uniparental disomy	Both homologues from one parent. Isodisomy can unmask a recessive mutation; heterodisomy cannot
Heteroplasmy	Mixture of mutant and wild-type mitochondrial genomes in one cell. Phenotype appears above a threshold (often 60-90%), and varies by tissue and over time
Mosaicism	Two cell lines from a post-zygotic mutation - somatic (segmental phenotype) or germline/gonadal (recurrence risk without a detectable parental mutation)
Linkage disequilibrium	Alleles at nearby loci inherited together more often than chance. Why a GWAS "hit" is usually a tag SNP, not the causal variant; also why extended HLA haplotypes (A1-B8-DR3) travel intact
Penetrance	Proportion with the genotype who show any phenotype
Expressivity	Severity/features among those who do
Pleiotropy	One gene, multiple unrelated systems (Marfan, NF1)
Locus heterogeneity	Different genes -> same phenotype (Alport, retinitis pigmentosa)
Allelic heterogeneity	Different mutations in one gene -> same or different phenotype (CFTR)
Anticipation	Earlier onset and greater severity down generations
Loss of heterozygosity	Second hit inactivating the remaining wild-type tumour suppressor allele (Knudson two-hit)

Clinical relevance

Mutation type predicts therapeutic strategy
- Nonsense -> read-through agents, ataluren (DMD); CFTR class I is not modulator-responsive
- Frameshift out-of-frame in DMD -> exon-skipping antisense oligonucleotides convert it to an in-frame, Becker-like allele (eteplirsen, golodirsen)
- In-frame missense CFTR F508del -> elexacaftor/tezacaftor/ivacaftor
Heteroplasmy explains why mitochondrial disease severity cannot be predicted from blood - test urinary epithelium or muscle
Variant classification (ACMG): pathogenic / likely pathogenic / VUS / likely benign / benign
- A VUS must not be used to change management or to guide cascade testing

Correlations

Pedigree analysis; inheritance patterns of named syndromes
Duchenne muscular dystrophy - mutation types
Complex/polygenic disease genetics and GWAS
CFTR modulator mechanisms
Hardy-Weinberg equilibrium

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.

Get premium access