Medical Genetics

Genetic Mutation

Point, frameshift, splice, copy-number — how DNA changes cause disease

A mutation is any heritable change in DNA sequence. Point mutations alter a single base — synonymous (silent, no amino acid change), missense (different amino acid), nonsense (premature stop codon, often nonsense-mediated decay). Insertions and deletions of non-multiples of 3 cause frameshift mutations that scramble downstream codons. Splice site mutations affect intron-exon junctions. Copy-number variants delete or duplicate large regions (DiGeorge 22q11.2 deletion, Williams 7q11.23). Trinucleotide repeat expansions (Huntington, fragile X). Chromosomal aneuploidy (trisomy 21 Down syndrome, 47,XXY Klinefelter). Mutations arise from replication errors, oxidative damage, UV, ionizing radiation, chemical mutagens. Most are neutral; some cause disease; rarely beneficial.

  • Mutation rate~10⁻⁹ per base per generation in humans
  • New mutations per child~70 de novo single nucleotide variants
  • Point mutation typesSilent, missense, nonsense
  • FrameshiftIndel not multiple of 3 nucleotides
  • Sickle cellGAG to GTG; Glu to Val at position 6 of beta-globin
  • Down syndromeTrisomy 21; ~1/700 live births

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Why mutation types matter

  • Diagnosis. Specific mutation identifies the disease and severity.
  • Prognosis. CFTR genotype predicts CF severity; HTT repeat length predicts age of onset.
  • Treatment. Ivacaftor for CFTR G551D; nusinersen for SMA; ataluren for nonsense Duchenne.
  • Carrier screening. Targets common pathogenic variants in populations.
  • Cancer therapy. EGFR, BRAF, ALK mutations guide targeted therapy.
  • Pharmacogenomics. Drug metabolism varies by genotype.
  • Research. Mechanism of disease informs new drug development.

Common errors

  • Calling all variants pathogenic. Most are benign; ACMG criteria classify as pathogenic, likely pathogenic, VUS, likely benign, benign.
  • Acting on a VUS. Variants of uncertain significance should not drive surveillance or surgery.
  • Karyotype for intellectual disability workup. Microarray is first-line; karyotype only for suspected balanced translocation.
  • Negative panel rules out genetic disease. Coverage gaps; consider exome or genome.
  • Ignoring paternal age effect. Older fathers transmit more de novo mutations.
  • Forgetting mitochondrial heteroplasmy. Tissue-specific mutation load explains variable phenotype.

Frequently asked questions

What's the difference between missense and nonsense?

Missense changes one amino acid to another. Effect ranges from silent (sickle cell trait carriers) to severe (sickle cell disease, MELAS). Nonsense creates a premature stop codon — protein truncated. Often triggers nonsense-mediated mRNA decay, eliminating the message entirely. Duchenne muscular dystrophy frequently nonsense; ataluren can promote read-through of premature stops in some cases. Missense disease examples — sickle cell (Glu6Val in beta-globin), hereditary hemochromatosis (C282Y in HFE), achondroplasia (Gly380Arg in FGFR3).

How do frameshift mutations work?

Insertion or deletion not divisible by 3 shifts the reading frame. Every codon downstream is scrambled. Usually creates a premature stop within ~10-30 codons. Effect typically severe — truncated nonfunctional protein. Tay-Sachs commonly has frameshift in HEXA. BRCA1 5382insC frameshift common in Ashkenazi Jews. CF F508del is a deletion of 3 bases (F508del) — in-frame deletion of phenylalanine, not frameshift, but still highly disruptive.

What are splice site mutations?

Mutations at exon-intron boundaries (canonical GT-AG splice sites) or in branch points or splice enhancers. Cause exon skipping, intron retention, or use of cryptic splice sites. Beta-thalassemia frequently involves splice mutations. Spinal muscular atrophy from SMN1 deletion compensated partly by SMN2 splicing — nusinersen oligonucleotide promotes inclusion of exon 7 in SMN2. Splice-modulating therapies an emerging class.

What is a de novo mutation?

A new mutation present in the child but not detectable in either parent. Average 70 SNVs per child. Achondroplasia 80% de novo (paternal age effect — older fathers, more replication errors in spermatogonia). Apert syndrome, Pfeiffer syndrome, Costello syndrome strong paternal age effects. Other dominant disorders frequently de novo — neurofibromatosis 1, tuberous sclerosis, Marfan. Recurrence risk after a de novo case slightly elevated due to gonadal mosaicism (1-5%).

How do copy number variants cause disease?

Large duplications or deletions affect dosage of multiple genes. 22q11.2 deletion (DiGeorge/velocardiofacial) — cardiac defects, hypocalcemia, immunodeficiency, palatal abnormalities, learning disabilities. 7q11.23 deletion (Williams) — supravalvular aortic stenosis, elfin facies, hypercalcemia, friendly personality. 17p11.2 (Smith-Magenis) — sleep disturbance, intellectual disability, self-injury. Detected by chromosomal microarray, not karyotype. CMA is first-line for unexplained intellectual disability.

What about trinucleotide repeats?

Repeated 3-base sequences expand abnormally. Huntington — CAG repeats in HTT exon 1; >35 disease; >40 fully penetrant; longer = earlier onset (anticipation in paternal transmission). Fragile X — CGG in FMR1 5' UTR; >200 full mutation, methylation silences gene; intellectual disability, autism. Myotonic dystrophy — CTG in DMPK 3' UTR. Friedreich ataxia — GAA in FXN intron 1, recessive. Repeats expand during meiosis or replication.

How are mutations detected?

Karyotype detects aneuploidy and large rearrangements (>5 Mb). Chromosomal microarray detects CNVs as small as ~50 kb. Sanger sequencing for single genes. Next-generation sequencing — gene panels, exome (all coding regions), genome (everything). MLPA detects exon-level deletions/duplications. Triplet repeat-primed PCR for fragile X. Methylation studies for imprinting disorders (Prader-Willi, Angelman). Choice depends on phenotype and pretest probability.