Mutation Types in DMD

Mutation Types in DMD

Mutation type Frequency
Exon deletions ~60–70% (most common)
Exon duplications ~5–10%
Point mutations (nonsense, frameshift, splice) ~20–30%
Small indels Small percentage

In De Novo DMD

  • About 1/3 of DMD cases are de novo

Among de novo mutations:

Mutation Relative frequency
Deletions Most common
Point mutations Next most common
Duplications Less common

Deletions Are So Common in DMD

The DMD gene is:

  • The largest gene in the human genome
  • Located on Xp21
  • Contains 79 exons
  • Extremely mutation-prone

Deletion hotspots:

  • Exons 45–55 (most common)
  • Exons 2–20 (secondary hotspot)
  • Unequal recombination → deletions

Carrier Status Distribution

Status Frequency
Carrier mother ~2/3
De novo mutation ~1/3

Germline Mosaicism Risk

If mother tests negative:

Recurrence risk is still: ~4–15%

Due to: Germline mosaicism

DMD Be Suspected Prenatally Without Family History?

Typical DMD:

  • Normal fetal anatomy
  • Normal movements
  • No structural abnormalities

Prenatal suspicion without family history is difficult.

Rare Prenatal Clues

  • Reduced fetal movements (late)
  • Mild polyhydramnios
  • Muscle hypotonia features

But: These are nonspecific and unreliable.

Genetic Testing Strategy

The DMD gene has:

  • Large size (79 exons)
  • High deletion/duplication rate
  • Significant proportion of point mutations

MLPA + NGS together give full coverage.

MLPA (Multiplex Ligation-dependent Probe Amplification)

Best for:

  • Exon deletions
  • Exon duplications

Detection rate: ~70–75% of DMD mutations

Limitation:

  • Cannot detect:
  • Point mutations
  • Small insertions/deletions
  • Splice variants

NGS (Next Generation Sequencing)

Best for:

  • Point mutations
  • Small indels
  • Splice-site variants
  • Nonsense mutations

Detection rate: ~20–30%

Strength:

Detects mutations MLPA misses.

Prenatal Diagnosis Without Known Mutation

Both MLPA and NGS should be used.

MLPA → then NGS; Sequential approach.