Chromosome Defects

• May be
• Abnormal structure
• Abnormal number (aneuploidy): most common (3-4% of all pregnancies)

Aneuploidy

• Usually due to meiotic nondisjunction in meiosis I
• Gamete contains 24 chromosomes but has both copies of one pair

Chromosome structural defects

• Structural abnormalities result from chromosomal breakage
• Can be
• Balanced: normal amount of information

• These don’t usually cause an abnormal phenotype but can create a carrier status with unbalanced gametes and problems for future generations

• Unbalanced: additional or missing information
• Single breaks may be repaired
• Multiple breaks may lead to random rejoining of incorrect ends
• Triggers for breakage
• Chemicals
• Ionizing radiation
• Examples
• Translocation (balanced): exchange of segments between non-homologous chromosomes

• Robertsonian translocation: breaks occur near the centromere in two acrocentric chromosomes. The short arms are lost but generally this is not damaging. In this case the karyotype is 45 chromosomes (one being a combination of two)

• Inversion (balanced): segments are inverted in sequence
• Requires at least two breaks with the intervening segment being inverted 180 degrees
• If involves centromere: pericentric
• If within an arm: paracentric
• Deletion (unbalanced): segments are lost
• Phenotype depends on size of lost segment and its function
• Duplications (unbalanced): tend to be less harmful
• Ring chromosomes (unbalanced): two breaks occur and the two ends unite
• Isochromosomes (unbalanced): one arm is missing and the other is duplicated

Gene mutations

• Can range from a single base pair to deletion of large segments
• Point mutation (nucleotide substitution)

• Missense mutation: different amino acid is transcribed, altering the “sense” of the code (eg. haemoglobinopathies)

• Nonsense mutation: mutation leads to a premature stop codon (eg. Neurofibromatosis type 1)

• Splice site mutation: mutation alters a critical splice junction
• Deletions and insertions

• Frameshifts: deletion or insertion alters the reading frame of translation leading to an inappropriate amino acid sequence

• Codon insertions/deletions (bases lost/gained in multiples of three) eg. repeat expansions

• Gene deletions/duplications

Contiguous gene (or micro-deletion) syndromes

• Prader-Willi
• Williams syndrome
• Di George
• Rubinstein-Taybi