Session 16: Genetic disorders

Session 16: Genetic disorders

• Alex Simon (MD)

1

Back to top

Learning tasks

Learning tasks

At the end of this session, students are expected to be able to:

Describe genetic mutations.

Classify genetic diseases.

Describe genetic diseases related to gene mutation.

Describe genetic diseases related to chromosomal abberation.

Describe genetic diseases related to multifactorial inheritance.

2

Back to top

Mutations

Mutations

Refers to permanent changes in the DNA.

Mutations that affect germ cells are transmitted to the progeny and may give rise to inherited diseases.

Mutations in somatic cells are not transmitted to the progeny but are important in the causation of cancers and some congenital malformations.

Types

Point mutations.

Frameshift mutations.

Trinucleotide repeat mutations.

3

Back to top

Point mutations

Point mutations

Mutations involving a change in a single nucleotide base within a gene e.g. Sickle cell disease.

Types

Silent mutation.

Altered DNA codes for the same amino acid without changing the phenotypic effect.

Missense mutation

Altered DNA codes for a different amino acid, which changes the phenotypic effect.

Nonsense mutation.

Altered DNA codes for a stop codon that causes premature termination of protein synthesis.

4

Back to top

Frameshift mutations

Frameshift mutations

Frameshift mutations occur when the insertion or deletion of one or two base pairs alters the reading frame of the DNA strand.

Two classes of genes, proto-oncogenes and tumour suppressor genes, regulate normal cell growth and differentiation.

Mutations affecting these genes, most often in somatic cells, are involved in the pathogenesis of tumours.

Example: Tay-Sachs disease.

5

Back to top

Trinucleotide repeat mutations

Trinucleotide repeat mutations

Mutations are characterized by amplification of a sequence of three nucleotides.

There is expansion of these normally repeated sequences to more than 100 repeats.

Normally, 3 nucleotides are repeated 20-30 times.

All affected sequences share the nucleotides guanine (G) and cytosine (C).

Cause amplification of a sequence of three nucleotides (e.g., CAG), which disrupts gene function

Example: Fragile X syndrome.

6

Back to top

Major categories of Genetic disorders

Major categories of Genetic disorders

Those related to mutant genes (single gene mutation) of large effect (Mendelian disorders).

Those arising from chromosomal aberrations (Cytogenetic disorders).

Diseases with complex multigenic inheritance (Multifactorial disorders).

7

Back to top

Major categories of Genetic disorders cont…

Major categories of Genetic disorders cont…

Mendelian disorders.

All resulting from single-gene mutations of large effect.

Most of these conditions are hereditary and familial.

Mutations involving single genes follow one of three patterns of inheritance

Autosomal dominant disorders.

Autosomal recessive disorders.

Sex linked (X-linked) disorders.

8

Back to top

Major categories of Genetic disorders cont…

Major categories of Genetic disorders cont…

Genetic disorders due to chromosomal aberrations.

Disorders that are the consequence of numeric or structural abnormalities in the chromosomes.

Multifactorial genetic disorders.

Multifactorial, or complex, inheritance implies that both genetic and environmental influences condition the expression of a phenotypic characteristic or disease.

9

Back to top

Diseases caused by single-gene defects (Mendelian disorders)

Diseases caused by single-gene defects (Mendelian disorders)

Mutations involving single genes follow one of three patterns of inheritance

Autosomal dominant disorders.

Autosomal recessive disorders.

Sex linked (X-linked) disorders.

10

Back to top

Autosomal dominant disorders

Autosomal dominant disorders

Characteristics of Autosomal dominant disorders.

Manifests in the heterozygous state, so at least one parent in an index case usually is affected

Characterised by one faulty copy of gene (i.e. mutant allele) in any autosome and one copy of normal allele

50% chance of passing on the disease to the next generation.

Both males and females are affected.

The gene is situated on autosomes, not sex chromosomes.

Both can transmit the condition.

No carrier state.

11

Back to top

Autosomal dominant disorders cont…

Autosomal dominant disorders cont…

One dominant mutant gene (A) is required to express the disorder.

Heterozygotes (Aa) express the disorder.

Homozygotes (AA) are often spontaneously aborted.

In many cases, structural proteins are affected by the mutation in ADD.

12

Back to top

Examples of Autosomal dominant disorders

Examples of Autosomal dominant disorders

Marfan’s syndrome.

Retinoblastoma.

Osteogenesis imperfecta.

Neurofibromatosis.

Achondroplasia.

Huntington disease.

Polycystic kidney disease.

Ehlers – Danlos syndrome.

Tuberous sclerosis.

Myotonic dystrophy.

Familial hypercholesterolemia.

Hereditary spherocytosis.

Familial polyposis coli.

Von Willebrand disease.

13

Back to top

Autosomal recessive disorders

Autosomal recessive disorders

Characteristics of Autosomal recessive disorders

Individuals must be homozygous for the mutant recessive gene (aa) to express the disorder.

Homozygotes are symptomatic early in life.

Heterozygous individuals (Aa) are asymptomatic carriers.

The dominant gene (A) overrides the mutant recessive gene (a).

Both parents must be heterozygous to transmit the disorder.

Both males and female may carry the gene.

14

Back to top

Autosomal recessive disorders cont…

Autosomal recessive disorders cont…

50% risk that the gene will be passed to any child in accordance with Mendel’s first law of segregation.

The trait parents (heterozygous carriers) are usually not affected, but siblings may show the disease.

Associated with consanguineous marriage.

In many cases, enzyme proteins are affected by the mutation in ADR.

15

Back to top

Examples of Autosomal recessive disorders

Examples of Autosomal recessive disorders

Sickle cell anemia.

Thalassemias.

Albinism.

Congenital adrenal hyperplasia.

Wilson disease.

Hemochromatosis.

Phenylketonuria.

Galactosemia.

Homocystinuria.

Lysosomal storage diseases (Gaucher disease).

Alpha 1 antitrypsin deficiency e.g. Cystic fibrosis.

Glycogen storage disease.

16

Back to top

Sex linked (X-linked) disorders

Sex linked (X-linked) disorders

X-linked disorders are caused by mutations in genes on X-chromosome, derived from either

One of the two X-chromosomes in females or

The single X-chromosome of the male.

Therefore, all sex-linked disorders are, in fact, X-linked disorders.

No Y-linked diseases are known as yet.

X-linked disorders can be either recessive (almost all) or dominant (rare).

Most of X-linked disorders are X-linked recessive.

17

Back to top

Characteristics of Sex linked (X-linked) disorders

Characteristics of Sex linked (X-linked) disorders

Transmitted by heterozygous female carriers only to sons (sons are hemizygous for the X chromosome).

Therefore only males are clinically abnormal.

Heterozygous females rarely express the full phenotypic change, because they have the paired normal allele.

However, because of the inactivation of one of the X chromosomes in females (usually the normal allele) permitting full expression of the disease in heterozygous females.

The daughters of a carrier mother have 50% risk of carrying the trait.

18

Back to top

Characteristics of Sex linked (X-linked) disorders cont…

Characteristics of Sex linked (X-linked) disorders cont…

Sons of heterozygous women have one chance in two (50%) of receiving the mutant gene.

They are hemizygous affected 50% of the time (i.e. the sons have 50% chance of being affected)

An affected male does not transmit the disorder to sons, but all daughters are carriers.

Daughters are normal heterozygous carriers 50% of the time & normal homozygotes 50% of the time.

Affected daughters are produced by matings of heterozygous females with affected males.

19

Back to top

Examples of Sex linked (X-linked) disorders

Examples of Sex linked (X-linked) disorders

Haemophilia A.

Duchenne muscular dystrophy.

Diabetes insipidus.

Colour blindness.

Chronic granulomatous disease.

Fragile X syndrome.

Glucose-6-phosphate dehydrogenase deficiency.

Bruton’s agammaglobulinaemia.

Wiskott -Aldrich syndrome.

Lesch-Nyhan syndrome.

20

Back to top

Chromosomal(Cytogenetic) disorders

Chromosomal(Cytogenetic) disorders

Cytogenetic disorders may result from alterations in the number or structure of chromosomes and may affect autosomes or sex chromosomes.

These disorders are divided into two (2) types

Numerical abnormalities

Structural abnormalities.

21

Back to top

Characteristics of Chromosomal (Cytogenetic) disorders

Characteristics of Chromosomal (Cytogenetic) disorders

Chromosomal disorders may be associated with absence (deletion, monosomy), excess (trisomy), or abnormal rearrangements (translocations) of chromosomes.

In general, loss of chromosomal material produces more severe defects than does gain of chromosomal material.

Excess chromosomal material may result from a complete chromosome (as in trisomy) or from part of a chromosome (as in robertsonian translocation).

22

Back to top

Characteristics of Chromosomal (Cytogenetic) disorders

Characteristics of Chromosomal (Cytogenetic) disorders

Imbalances of sex chromosomes (excess or loss) are tolerated much better than autosomes imbalances.

Sex chromosomal disorders often produce subtle abnormalities, sometimes not detected at birth.

Infertility, a common manifestation, cannot be diagnosed until adolescence.

In most cases, chromosomal disorders result from de novo changes (i.e., parents are normal, and risk of recurrence in siblings is low).

Uncommon but important exception to this principle is exhibited by the translocation form of Down syndrome.

23

Back to top

Numerical abnormalities

Numerical abnormalities

In humans, the normal chromosome count is 46.

Somatic cell is diploid or 2n (46 chromosomes)

Germ cells have haploid or 1n (23 chromosomes).

Any exact multiple of the haploid number (n) is called euploid.

Haploid, diploid or polyploid are euploids.

24

Back to top

Numerical abnormalities cont…

Numerical abnormalities cont…

Polyploidy is a multiple of haploid number e.g. triploid or 3n (69 chromosomes), tetraploid or 4n (92 chromosomes).

Occurs in megakaryocytes and dividing liver cells.

Polyploidy in somatic cells results in a spontaneous abortion.

Aneuploidy is the number of chromosomes which is not an exact multiple of haploid number

Examples

Hypodiploid or 2n-1 (45 chromosomes) monosomy,

Hyperdiploid or 2n+1 (47 chromosomes) trisomy.

25

Back to top

Numerical abnormalities cont…

Numerical abnormalities cont…

The chief causes of aneuploidy is

Nondisjunction of a homologous pair of chromosomes at the first meiotic division or

Failure of sister chromatids to separate during the second meiotic division or during mitosis in somatic cells, leading to the production of two aneuploid cells.

Failure of pairing of homologous chromosomes followed by random assortment (anaphase lag) can also lead to aneuploidy.

26

Back to top

Numerical abnormalities cont…

Numerical abnormalities cont…

When nondisjunction occurs at the time of meiosis, the gametes formed have either an extra chromosome (n + 1) or one less chromosome (n − 1).

Fertilization of such gametes by normal gametes would result in two types of zygotes:

Trisomic: with an extra chromosome (2n + 1).

Monosomic: with a less chromosome (2n − 1).

27

Back to top

Numerical abnormalities cont…

Numerical abnormalities cont…

Mosaicism

Describes the presence of two or more populations of cells with different complements of chromosomes in the same individual.

Two chromosomally different cell lines are derived from a single fertilized egg.

Occurs due to nondisjunction of chromosomes during mitotic division in the early embryonic period.

Mosaicism affecting sex chromosomes is common, whereas autosomal mosaicism is not.

28

Back to top

Structural abnormalities

Structural abnormalities

Structural changes in the chromosomes usually result from chromosomal breakage followed by loss or rearrangement of material.

During cell division (meiosis as well as mitosis), certain structural abnormalities of chromosomes may appear.

These may occur during gametogenesis and then transmitted to all somatic cells and cause hereditary transmissible disorders.

May produce somatic cell mutations and result in changes varying from no effect to some forms of cancers.

29

Back to top

Patterns of chromosomal rearrangement after breakage

Patterns of chromosomal rearrangement after breakage

Translocation.

Reciprocal.

Robertsonian.

Isochromosomes.

Deletion.

Inversions.

A ring chromosome.

30

Back to top

Examples of Chromosomal disorders involving autosomes

Examples of Chromosomal disorders involving autosomes

Down's syndrome.

Trisomy 21, Karyotype: 47XX, 47XY.

Maternal age has a strong influence.

The most common cause of trisomy.

Due to meiotic nondisjunction.

Edward's syndrome.

Trisomy 18 type, Karyotype: 47XX or 47XY.

Patau's syndrome.

Trisomy 13, Karyotype: 47XX, 47XY.

31

Back to top

Examples of Chromosomal disorders involving sex chromosomes

Examples of Chromosomal disorders involving sex chromosomes

Turner's syndrome.

Monosomic, Karyotype: 45X0.

Due to nondisjunction.

Klinefelter's syndrome.

Trisomic, Karyotype: 47XXY.

Due to nondisjunction.

Phenotypically male.

XYY syndrome.

Caused by paternal nondisjunction.

Associated with aggressive (sometimes criminal) behavior.

32

Back to top

Multifactorial genetic disorders

Multifactorial genetic disorders

Result from the combined actions of environmental factors & two or more mutant genes having additive effects.

The greater the number of inherited mutant genes, the more severe the phenotypic expression of the disease.

The disease clinically manifests only when the combined influences of the genes & the environment cross a certain threshold.

33

Back to top

Examples of multifactorial genetic disorders

Examples of multifactorial genetic disorders

Hypertension.

Diabetes mellitus.

Congenital heart disease.

Cleft lip and cleft palate.

Pyloric stenosis.

Schizophrenia.

Bipolar disorders.

Neural tube defects.

Coronary heart disease (Ischemic heart disease).

Gout.

34

Back to top

Key points

Key points

Mutations are permanent change in DNA.

Single-gene mutations of large effect is seen in Mendelian disorders.

Autosomal dominant disorders are characterized by expression in heterozygous state.

Both copies of a gene are mutated in Autosomal recessive disorders.

Sex linked disorders are transmitted by heterozygous females to their sons, who manifest the disease.

Combined effect of genetic and environmental influences in multigenic genetic disorders.

35

Back to top

Review questions

Review questions

Explain three (3) types of mutations.

List (3) categories of genetic diseases.

Mention five (5) examples of autosomal recessive disorders.

List five (5) characteristics of sex linked disorders.

Explain five (5) patterns of chromosomal rearrangement after breakage.

36

Back to top

References

References

Bezabeh M.; Tesfaye A.; Ergicho B. et al (2004): General pathology lecture notes for Health Sciences students. Ethiopia Public Health Training Initiative. Pg. 98-136.

Goljan E.;(2007): Rapid Review Pathology (2th Ed.) Elsevier Saunders, USA. Pg. 85-97.

Kumar V. ; Abbas A. K. ; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, USA. Pg. 216-220, 234-241.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India. Pg. 257-263.

37

Back to top