20th February 2024

Genetic abnormalities

Chromosomal abnormalities or base-pair mutations can cause genetic mutations. Chromosomal abnormalities can be broadly divided into numerical abnormalities and structural abnormalities.

Numerical abnormalities are caused by the failure of chromosomal separation during meiosis and can manifest as:

• Error in ploidy – Failure of the division of the entire set of homologous chromosomes during anaphase I or failure of the division of all sister chromatids during anaphase II, resulting in a diploid gamete. Fertilisation with a normal gamete results in a triploid cell and is usually incompatible with life.
• Aneuploidy – Occurs due to a failure to separate a single chromosome pair during anaphase, resulting in monosomic or trisomic cells following fertilisation.

Structural abnormalities occur during prophase I as chromosomes undergo crossing over. This can manifest as:

• Reciprocal translocation – 2 non-homologous chromosomes swapped segments. This can result in trisomy or monosomy of the translocated segments.
• Robertsonian translocation – Translocation affects acrocentric chromosomes (chromosomes with centromeres close to the end of the chromosome), forming fusion chromosomes. Carriers of such translocations can be asymptomatic due to the balanced nature of the translocation. Increased risk of monosomy or trisomy for their offspring.
• Deletion – Segments of chromosomes are lost during crossing-over, which usually results in significant abnormalities.
• Insertion – Chromosome segments are added during crossing-over, usually resulting in less significant abnormalities.
• Inversion – Error in chromosomal rearrangement where a segment within the chromosome is reversed.

Base-pair mutations occur during DNA replication errors or by environmental factors, resulting in a change in the DNA sequence, and can result in single-gene disorders. This manifests in several ways:

• Base-pair substitution – Single substitution of a nucleotide with a different base-pair. This does not typically result in a phenotype change due to nonsense DNA and redundancies within the codons that encode amino acids. This can result in a missense mutation, resulting in the premature termination of a polypeptide sequence.
• Frame-shift mutation – Occurs following insertion or deletion of a nucleotide, resulting in alteration of the amino acid sequence downstream from the mutation.
• Trinucleotide expansion mutation – Characterised by amplification of a sequence of 3 nucleotides. Dynamic mutations can increase with gametogenesis, affecting the phenotypic presentation.