Page 205 - Concise Pathology for Exam Preparation ( PDFDrive )

190 SECTION I General Pathology

Q. What are the different categories of genetic disorders?

Ans. Different categories of genetic disorders include the following:
1. Those related to single-gene mutations of large effect (Mendelian disorders).
2. Diseases with multifactorial (polygenic) inheritance, which involve both genetic and
environmental influences (complex multigenic disorders). They are caused by
interaction between multiple variant forms of genes and environmental factors. These
variations in genes are referred to as ‘polymorphisms’. Each variant gene causes a
small increase or decrease in the risk of a disease. No single susceptibility gene is
individually sufficient for inducing the disease. Several polymorphisms are required
for the disease to occur.
3. Those arising from structural and numeric aberrations in autosomes and sex
chromosomes (chromosomal disorders).

Q. Define mutation.

Ans. Mutation refers to a permanent change in DNA. Mutations which affect germ cells
are transmitted to the progeny and may give rise to inherited diseases. Mutations in the
somatic cells are not transmitted to the progeny and may give rise to cancers and
congenital malformations.
• Genome mutations involve loss or gain of whole chromosomes giving rise to monosomy
or trisomy.
• Chromosome mutations result from the rearrangement of genetic material to give rise
to visible changes in the chromosome.
• The most common mutations associated with genetic disease are gene mutations,
which involve partial or complete deletion of a gene or often a single base.
Examples:
• Point mutations: These can occur within coding sequences as well as noncoding
sequences. The latter involve the regulatory sequences in the promoter/enhancer
regions and not the exons. Point mutations result from the substitution of a single
nucleotide base by a different base, resulting in the replacement of one amino acid by
the other in the protein, eg, sickle cell anaemia. Such mutations alter the meaning of the
genetic code and are thus called missense mutations.
• Certain point mutations may change an amino acid codon to a chain termination codon
or stop codon. Nonsense mutations interrupt translation, leading to the formation of
truncated proteins which are rapidly degraded.
• Point mutations or deletions involving regulatory sequences interfere with the binding
of transcription factors leading to a gross reduction or complete absence of transcription
(as seen in thalassaemias).
• Point mutations involving introns lead to defective splicing of intervening sequences.
• Frame shift mutations occur when the insertion or deletion of one or two base pairs
alter the reading frame of the DNA strand.
• Trinucleotide repeat mutations are characterized by amplification of a sequence of
three nucleotides; all affected sequences share guanine and cytosine, eg, in fragile
X syndrome, there are 200–400 tandem repeats of the sequence CGG within a gene
called FMR1 (familial mental retardation-1), which prevents the normal expression of
FMR1 gene leading to mental retardation.

Q. Define pleiotropy.
Ans. The phenomenon in which a single gene mutation leads to many phenotypic effects
is called pleiotropism, eg, Marfan syndrome is associated with widespread involvement
of the connective tissue component of skeleton, eye, cardiovascular system, etc. all of
which result from a single mutation in the gene fibrillin.

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