Pathology Chapter 5 pg 137 – 140
50% of spontaneous abortuses during the early months of gestation have a demonstrable chromosomal abnormality
~1% of all newborn infants possess a gross chromosomal abnormality
Approximately 5% of individuals under the age of 25 develop a serious disease with a significant genetic component
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These mutations cause a disease or predispose to a disease
Typically not present in normal population
Such mutations and their associated disorders are highly penetrant, meaning that the presence of the mutation is associated with the disease in a large proportion of individuals. [High Penetrance = Most people with the mutation get the disease]
These diseases are caused by single gene mutations, and usually follow the classic
Mendelian pattern of inheritance.
A great deal of what we know about several physiologic pathways (such as cholesterol transport, chloride secretion) has been learned from analysis of single gene disorders.
Although informative, these disorders are generally rare unless they are maintained in a population by strong selective forces (e.g., sickle cell anemia in areas where malaria is endemic) [Heterozygotes may have evolutionarily advantage etc]
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These arise from structural or numerical alteration in the autosomes and sex chromosomes. [Examples: Translocations, duplications, deletion ]
Like monogenic disease they are uncommon but associated with high penetrance.
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These are far more common than the previous two categories.
They are caused by interactions between multiple variant forms of genes and environmental factors.
Common variants in genes within the population are also called polymorphisms
Each such variant gene confers a small increase in disease risk, and no single susceptibility gene is necessary or sufficient to produce the disease.

It is only when several such polymorphisms are present in an individual that disease occurs, hence the term multigenic or polygenic.
Even normal traits such as height and weight are governed by polymorphisms in several genes.
Each polymorphism has a small effect and is of low penetrance.
Since environmental interactions are important in the pathogenesis of these diseases, they are also called multifactorial disorders. In this category are some of the most common diseases that afflict humans, including atherosclerosis, diabetes mellitus,
hypertension, and autoimmune diseases.
To these three well-known categories must be added a heterogeneous group of single-gene
disorders with nonclassic patterns of inheritance. This group includes disorders resulting from triplet-repeat mutations, those arising from mutations in mitochondrial DNA (mtDNA), and those in which the transmission is influenced by genomic imprinting or gonadal mosaicism.
A mutation is defined as a permanent change in the DNA.
Mutations that affect germ cells are transmitted to the progeny and can give rise to inherited diseases.
Mutations that arise in somatic cells understandably do not cause hereditary diseases but are important in the genesis of cancers and some congenital malformations.
Mutations may result in partial or complete deletion of a gene or, more often, affect a single base.
A point mutation = a single nucleotide base substituted by a different base.
Frameshift mutations = one or two base pairs may be inserted into or deleted from the DNA, leading to alterations in the reading frame of the DNA strand (Less common).
A missense mutation = point mutation that alters the code in a triplet of bases and leads to the replacement of one amino acid by another in the gene product. These mutations alter the meaning of the sequence of the encoded protein
A “conservative” missense mutation = the substituted amino acid causes little change in the function of the protein

A “nonconservative” missense mutation = the substituted amino acid replaces the normal amino acid with a very different one.
An excellent example of this type is the sickle mutation affecting the β-globin chain of hemoglobin. Here the nucleotide triplet CTC (or GAG in mRNA), which encodes glutamic acid, is changed to CAC (or GUG in mRNA), which encodes
valine. This single amino acid substitution alters the physicochemical properties of hemoglobin, giving rise to sickle cell anemia.
A nonsense mutation = a point mutation that changes an amino acid codon to a chain terminator, or stop codon.
Taking again the example of β-globin, a point mutation affecting the codon for
glutamine (CAG) creates a stop codon (UAG) if U is substituted for C. This change leads to premature termination of β-globin gene translation, and the short peptide that is produced is rapidly degraded. The resulting deficiency of βglobin chains can give rise to a severe form of anemia called β 0 -thalassemia
Deleterious effects may also result from mutations that do not involve the exons. Recall that transcription of DNA is initiated and regulated by promoter and enhancer sequences.
Point mutations or deletions involving these regulatory sequences may interfere with binding of transcription factors and thus lead to a marked reduction in or total lack of transcription. Such is the case in certain forms of hereditary anemias.
In addition, point mutations within introns may lead to defective splicing of intervening sequences. This, in turn, interferes with normal processing of the initial mRNA transcripts and results in a failure to form mature mRNA. Therefore, translation cannot take place, and the gene product is not synthesized.
Abnormal mRNA processing may result from mutations affecting introns or splice
junctions or both.
Frameshift mutations = small deletions or insertions involving the coding sequence lead to alterations in the reading frame of the DNA strand.
If the number of base pairs involved is three or a multiple of three, frameshift does not occur; instead an abnormal protein lacking or gaining one or more amino acids is synthesized.
These mutations are characterized by amplification of a sequence of three nucleotides. Although the specific nucleotide sequence that undergoes amplification differs in various disorders, almost all affected sequences share the nucleotides guanine (G) and cytosine (C).
For example, in fragile-X syndrome, prototypical of this category of disorders, there are 250 to 4000 tandem repeats of the sequence CGG within a gene called familial mental retardation 1
(FMR1). In normal populations the number of repeats is small, average = 29. Such expansions of

the trinucleotide sequences prevent normal expression of the FMR1 gene, thus giving rise to mental retardation.
Trinucleotide-repeat mutations are dynamic (i.e., the degree of amplification increases
during gametogenesis) this influences the pattern of inheritance and the phenotypic manifestations of the diseases caused by this class of mutation.
Some Known Beneficial Mutations:
The Human Immunodeficiency Virus (HIV) uses a chemokine receptor, CCR5, to enter cells; a deletion in the CCR5 gene thus protects from HIV infection.
Hereditary disorders, by definition, are derived from one’s parents and are transmitted in the germ line through the generations and therefore are familial.
The term congenital simply implies “born with.” Some congenital diseases are not genetic; for example, congenital syphilis. Not all genetic diseases are congenital; individuals with Huntington disease, for example, begin to manifest their condition only after their 20s or
30s.
Single-base deletion at the ABO
(glycosyltransferase) locus, leading to a frameshift mutation responsible for the O allele.
Four-base insertion in the hexosamindase A gene, leading to a frameshift mutation. This mutation is the major cause of Tay-Sachs disease in Ashkenazi Jews.

Point mutation leading to premature chain termination. Partial mRNA sequence of betaglobin chain of hemoglobin showing codons for amino acids 38-40. A point mutation (C-
>U) in codon 39 changes glutamine (Gln) codon to a stop codon, and hence protein synthesis stops at amino acid 38.
Three-base deletion in the common cystic fibrosis (CF) allele results in synthesis of a protein that lacks amino acid 508
(phenylalanine). Because the deletion is a multiple of three, this is not a frameshift mutation.