Genetic Disorders – Mutations, Multifactorial, and Single gene disorders

A knowledge of the normal human genetics will facilitate the understanding of genetic diseases or Genetic Disorders. Hence, the student is advised to revise the normal human genetics before reading this chapter. Here, only brief highlights of the normal are given. Genetic diseases are often said to be difficult to students. We have tried to dispel this wrong notion & to make genetic as clear as possible at the cost of brevity. we did in order to facilitate the student’s understanding.

Genetic information is stored in DNA. The typical normal human cell contains 46 chromosomes {i.e. 23 pairs of chromosomes: 22 homologous pairs of autosomes & one pair of sex chromosomes (XX or XY)}. Members of a pair (described as homologous chromosomes or homologs] carry matching genetic information. I.e. they have the same gene loci in the same sequence, though at any specific locus they may have either identical or slightly different forms, which are called alleles. One member of each pair of chromosomes is inherited from the father, the other from the mother.Each chromosome is in turn composed of a very long unbranched molecule of DNA bound to histones & other proteins. This interaction between the long DNA molecule & the histones decreases the space occupied by the long DNA. I.e. this interaction packages the long DNA into the shorter chromosomes.

Each chromosome contains a single continuous DNA molecule. DNA is composed of two very long complementary chains of deoxynucleotides. The 2 chains (strands) of DNA wind around each other i.e. twist about each other forming a double helix – “the twisted ladder model”. Each deoxynucleotide, in turn, is composed of a nitrogenous base {i.e. adenine (A), or guanine (G), or cytosine (C), or thymine (T)} bound to deoxyribose & phosphate.

DNA has two basic functions:

  1. It codes for the proteins which are important for the metabolic & structural functions of the cell. I.e. it provides the genetic information for protein synthesis.
  2. It transmits the genetic information to the daughter cells & to the offsprings of the individual.

Hence, the central dogma of molecular biology is:

DNA → transcription → RNA → translation → PROTEIN.
↓ replication

DNA stores genetic information. This is done by the sequence of the nucleotides in the DNA. The portion of DNA that is required for the production of a protein is called a gene. A gene has exons (coding sequences) & introns (intervening sequences). The transcription of a gene is regulated by a promoter region, enhancer region, etc….

The sequence of nucleotides in a gene determines the sequence of amino acids in a specific protein. Three consecutive nucleotides form a code word or codon. Each codon signifies a single amino acid. Since the number of condons (64) outnumbers the number of amino acids (20), most amino acids are specified by more than 1 condon, each of which is completely specific.

To translate its genetic information into a protein, a segment of DNA (i.e. a gene) is first transcribed into mRNA. The mRNA contains a sequence of nucleotides that is complementary to the nucleotides of the DNA. Each DNA triplet codon is converted into a corresponding RNA triplet codon. Then each mRNA codon codes for a specific amino acid.

Hence, the sequences of the RNA codons is translated into a sequence of amino acids (i.e. protein). Therefore, the sequence of the amino acids in the protein is determined by the sequence of the codons in the mRNA which in turn is determined by the sequence of nucleotides in the DNA .

In summary, the primary sequence of bases in the coding regions of DNA determines the sequence of amino acids in the protein. Hence, any alteration in the sequence of bases in the normal gene causes an alteration of the protein at a specific point in its sequence. Such alteration is called mutation & is the basis of genetic diseases.
Genetic information is transmitted to the daughter cells under two circumstances:

  1. Somatic cells divide by mitosis, allowing the diploid (2n) genome to replicate itself completely in conjunction with cell division.
  2. Germ cells (sperm & ova) undergo meiosis – a process that enables the reduction of the diploid (2n) set of chromosomes to the haploid state (1n).When the egg is fertilized by the sperm, the 2 haploid sets are combined, thereby restoring the diploid state in the zygote.


  • Hereditary (familial) disorders are disorders derived from one’s parents.
  • Congenital means “born with.” It may be genetic, for example Down’s syndrome. Or it may not be genetic, for example congenital syphilis. Not all genetic diseases are congenital, for example patients with Huntington’s disease begin to manifest their disease in the 3rd or 4th decades.
  • Genotype means the genetic constitution (genome).
  • Phenotype means the observed biochemical, physiological, & morphological characteristics of an individual as determined by his/her genotype & the environment in which it is expressed.
  • Allele means one of the alternative versions of a gene that may occupy a given locus.
  • Gene, as already stated, is the portion of DNA that codes for a protein.


Mutations (Genetic Disorders)

In Genetic Disorders, Mutations –

  • are the bases of genetic diseases.
  • are defined as permanent changes in the primary nucleotide sequence of DNA regardless of its functional significance.
  • occur spontaneously during cell division or are caused by mutagens such as radiation, viruses, & chemicals.
  • can occur in germ line cells (sperm or oocytes) or in somatic cells or during embryogenesis. Germline mutations can be passed from one generation to the next & thus cause inherited disease. Somatic mutations do not cause hereditary disease but they may cause cancer (because they confer a growth advantage to cells) & some congenital malformations. Mutations that occur during development (embryogenesis) lead to mosaicism. Mosaicism is a situation in which tissues are composed of cells with different genetic constitutions. If the germ line is mosaic, a mutation can be transmitted to some progeny but not others. This can sometimes lead to confusion in assessing the patterns of inheritance.
  • affect the various levels of protein synthesis.
  • can be classified into the following three categories based on the extent of the genetic damage:

1. Genome mutations (Genetic Disorders)

  • are due to chromosome missegregation.
  • are gain or loss of one or more whole chromosomes.
  • are exemplified by aneuploidy & polyploidy.
  • are often incompatible with survival.

2. Chromosome mutations (Genetic Disorders)

  • are due to rearrangement of genetic material in a chromosome which results in structural changes in the chromosome.
  • can be seen by the microscope.
  • are exemplified by translocations.
  • are infrequently transmitted because most are incompatible with survival (like genome mutations).

3. Gene mutations (Genetic Disorders)

  • cause most of the hereditary diseases.
  • are submicroscopic (i.e. cannot be seen by the microscope).
  • may affect a single base (more common) or they may affect a larger portion of a gene.
  • have the following types:
    • Single base pair change (Point Mutation)
    • Deletions & Insertions
    • Expansions of repeat sequences

A. Point mutation (Single base pair change)

Is the substitution of one base for another. Includes the following types:-

  1. Silent mutations
  2. Missense mutations
  3. Nonsense mutations

1. Silent (Synonymous) mutation (Genetic Disorders)

In Genetic Disorders, The genetic code is redundant (i.e. there is more than one codon for most amino acids) & therefore a change in one base may result in no change in the amino acid sequence of the protein. The base replacement does not lead to a change in the amino acid but only to the substitution of a different codon for the same amino acid. For example, the change of the codon UUU which codes for phenylalanine to UUC (i.e. the replacement of U by C) is a silent mutation because the new codon (UUC) also codes the same amino acid (phenylalanine).

2. Missense mutations (Genetic Disorders)

In Genetic Disorders, Changes the codon for one amino acid to the codon for another amino acid. Is exemplified by the mutation which causes sickle cell anemia. Hemoglobin is composed of a heme, two α-globin polypeptide chains, & two β-globin polypeptide chains. In normal individuals, the codon GAG codes for glutamic acid in the 6th position of the β-globin polypeptide chain. But in sickle cell anemia this codon is changed to GUG which codes valine. Hence, as a result of this single base substitution, valine substitutes glutamic acid in the β-globin chain. This amino acid substitution alters the physicochemical properties of hemoglobin, which is now called Hemoglobin S. This leads to sickle cell anemia.

3. Nonsense mutation (Genetic Disorders)

In Genetic Disorders, Changes the codon for an amino acid to a stop codon, leading to termination of translation of the mRNA transcript & a truncated protein. Is exemplified by the mutation which causes βo – thalassemia. In this, a substitution of U for C in the codon 39 of the β globin chain of hemoglobin (i.e. the change of CAG to UAG) converts the codon for glutamine to a stop codon. This results in premature termination of the β globin gene translation. I.e. protein synthesis stops at the 38th amino acid. This results in short peptide which is rapidly degraded leading to the absence of β- globin chains. This leads to βo – thalassemia.


B. Deletions & insertions (Genetic Disorders)

In Genetic Disorders, Can occur within coding sequences or within noncoding sequences.

  • Deletions & insertions of one or two bases within coding sequences lead to frameshift mutations because they alter the reading frame of the triplet genetic code in the mRNA so that every codon distal to the mutation in the same gene is read in the wrong frame. This leads to altered amino acid sequence & usually premature termination of the peptide chain because of the occurrence of a termination codon in the altered reading frame.
  • Deletion or insertion of three or a multiple of three base pairs within coding sequences does not cause frameshift mutation, instead it results in abnormal protein missing one or more amino acid.
  • Deletions affecting the promoter/enhancer sequences (i.e. in the noncoding regions) leads to promoter / enhancer mutations.

C. Expansion of repeat sequences (trinucleotide repeat mutations)

  • show expansion of a sequence of 3 nucleotides. Normally, 3 nucleotides are repeated 20-30 times. Trinucleotide repeat mutation is when there is expansion of these normally repeated sequences to more than 100 repeats.
  • The mechanism leading to an increase in the number of repeats is not clear. It is also not clear how the increase leads to disease.
  • cause myotonic dystrophy, Huntington’s disease, fragile X syndrome, etc…are not stable (i.e. they are dynamic) (i.e. the degree of amplification increases during gametogenesis). This leads to the phenomenon of anticipation (i.e. the disease worsens during the subsequent generations).

Summary of Mutation

In Genetic Disorders, Mutations can interfere with normal protein synthesis at various levels:-

  • Promoter/enhancer mutations → No transcription/ increased transcription → No protein/increased protein.
  • Missense mutation → Abnormal protein with a different amino acid → A protein altered with function or loss of function
  • Nonsense mutation → Affects translation → Truncated protein → Rapidly degraded protein → Absence of the protein.

Many different proteins are synthesized in each cell of the body. These proteins include enzymes & structural components responsible for all the developmental & metabolic processes of an organism. Mutation can result in abnormality in any of these protiens. Mutation → Abnormal protein/No protein/ Increased protein → Abnormal metabolic processes → Tissue injury →Genetic diseases.


Categories of genetic diseases

Genetic diseases generally fall into one of the following 4 categories:

  • Mendelian disorders
  • Chromosomal disorders
  • Multifactorial disorders
  • Single gene diseases with nonclassic patterns of inheritance.

Mendelian disorders (Genetic Disorders)

  • – Each medelian disorder is caused by a single mutant gene.
    • affects transcription, mRNA processing, or translation
    • abnormal protein or decreased protein
    • may affect any type of protein →Disease.
  • show the classic mendelian patterns of inheritance.
  • are also called monogenic mendelian disorders.
  • are uncommon.
  • can be classified into the following based on their patterns of inheritance:
    • Autosomal dominant inheritance
    • Autosomal recessive inheritance
    • X-linked recessive inheritance

In Genetic Disorders, The mode of inheritance for a given phenotypic trait/disease is determined by pedigree analysis in which all affected & unaffected individuals in the family are recorded in a pedigree using standard symbols & indicating the sex, the generation, & biologic relationship among the family members. In all mendelian disorders, the distribution of the parental alleles to their offspring depends on the combination of the alleles present in the parents.

1. Autosomal dominant disorders (Genetic Disorders)

Will be discussed under the following 4 headings:-

  • The criteria for autosomal inheritance
  • Additional features of autosomal dominant disorders
  • Pathogenesis
  • Clinical examples

Dominant implies that the disease allele needs to be present only in a single copy (as in the heterozygote) to result in the phenotype.

a. The criteria of autosomal inheritance include

  • The transmission of the trait is from generation to generation without skipping. In a typical dominant pedigree, there can be many affected family members in each generation.
  • Except for new mutation, every affected child will have an affected parent Some patients do not have affected parents because the disease in such cases is due to new mutations in the sperm/ovum from which the patients were derived. New germ line mutations occur more frequently in fathers of advanced age.
  • In the mating of an affected heterozygote to a normal homozygote (the usual situation), each child has a 50% chance to inherit the abnormal allele & be affected & a 50 % chance inherit the normal allele.
  • The 2 sexes are affected in equal numbers (because the defective gene resides on one of the 22 autosomes (i.e. nonsex chromosomes). The exceptions to this rule are the sex-limited disorders such as breast & ovarian cancers in females & familial male precocious puberty in boys.

b. Additional features of autosomal dominant disorders

Each of the following may alter the idealized dominant pedigree (& they should be considered to provide the most accurate counselling):-

  • Autosomal dominant disorders can sometimes be caused by new mutations. New mutations may give rise to an isolated case of a dominant disorder. New mutations are more often seen with diseases that are so severe that people who are affected by them are less likely to reproduce than normal. For example, the majority of cases of achondroplasia are the results of new mutations.
  • Autosomal dominant disorders can show reduced penetrance (i.e. some individuals inherit the mutant gene but are phenotypically normal). Penetrance is the probability of expressing the phenotype given a defined genotype. Penetrance is expressed as the percentage of individuals who have the mutant allele & are actually phenotypically affected. For example, 25% penetrance indicates that 25% of those who have the gene express the trait. Penetrance can be complete or incomplete. Reduced (incomplete) penetrance is when the frequency of expression of a genotype is < 100%. Nonpenetrance is the situation in which the mutant allele is inherited but not expressed.
  • Autosomal dominant disorders commonly show variable expressivity.Variable expressivity is the ability of the same genetic mutation to cause a phenotypic spectrum. It is when the trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals. For example, some patients with neurofibromatosis type 1 (which is an autosomal dominant disorder) have only brownish spots (café au lait spots) on their skin whereas other patients with the same disease have multiple skin tumors & skeletal deformities. Therefore, neurofibromatosis is said to show variable expressivity. Variable expressivity most likely results from the effects of other genes or environmental factors that modify the phenotypic expression of the mutant allele. For example, individuals with familial hypercholesterolemia who take cholesterol-rich diet have a higher risk of manifesting with atherosclerosis than those individuals with hypercholesterolemia & who take low cholesterol diet. Hence, the variable expressivity in this case is brought about by the influence of an environmental factor (i.e. the diet).In general, variable expressivity & reduced penetrance can modify the clinical picture of autosomal dominant disorders.

c. Pathogenesis of autosomal dominant disorders

In Genetic Disorders, Autosomal dominant disorders are caused by 2 types of mutations:

  • Loss of function mutations
  • Gain of function mutations

i. Loss of function mutations

Cause autosomal dominant disorders when they result in inactive or decreased amount of regulatory proteins (e.g. cell membrane receptors such as LDL receptor), or structural proteins (e.g. collagen, fibrillin, spectrin, dystrophin). A 50% reduction in the levels of such nonenzyme proteins results in an abnormal phenotype (i.e. the heterozygote, who produces this much amount, will manifest the disorder). This can sometimes be explained by the dominant negative effect of the mutant allele (i.e. product of the mutant allele impairs the function of the product of the normal allele).

ii. Gain of function mutations

In Genetic Disorders, are much less common than loss of function mutations. In such cases, the mutant gene produces a toxic protein (i.e. the protein will have a new toxic function). This is exemplified by Huntington disease. Gain of function mutations almost always have autosomal dominant pattern.

d. Clinical examples of autosomal dominant disorders (Genetic Disorders)

  • Marfan syndrome*
  • Some variants of Ehlers – Danlos syndrome
  • Osteogenesis imperfecta
  • Achondroplasia
  • Huntington disease
  • Neurofibromatosis*
  • Tuberous sclerosis
  • Myotonic dystrophy
  • Familial hypercholesterolemia*
  • Hereditary spherocytosis
  • Familial polyposis coli
  • Polycystic kidney disease

i. Marfan syndrome

  • is a defect of connective tissue characterized by faulty scaffolding.
  • is caused by mutations of FBN1 gene → Abnormal fibrillin (which is a structural protein) No normal microfibrils in the extracellular matrix→ No scaffolding on which tropoelastin is deposited to form elastic fibers → Marfan’s syndrome.Microfibrils are normally abundant in the aorta, ligaments, & ciliary zonules of the lens where they support the lens. Hence, Marfan syndrome (in which there is deficiency of normal fibrillin & microfibrils) mainly involves these tissues.
  • is characterized by defects in skeletal, visual, & cardiovascular structures:-
    • Patients are tall & thin with abnormally long legs & arms, spider like fingers (arachnodactyly), hyperextensible joints.
    • Dislocation of the ocular lens (Ectopia lentis) is frequent.
    • Cardiovascular changes include: a. Mitral valve prolapse due to loss of connective tissue support in the mitral valve leaflets. b. Dilatation of the ascending aorta due to cystic medionecrosis (→lack of medial support). Dilatation of the aortic valve ring & the root of the aorta → Aortic regurgitation. c. Dissecting aneurysm of the aorta due to medial necrosis & intimal tear.

ii. Familial hypercholesterolemia

  • is possibly the most frequent mendelian disorder
  • is caused by mutation of the gene for LDL (low density lipoprotein) receptor → Decreased functional LDL receptor → Increased plasma cholesterol → Premature atherosclerosis → Increased risk of myocardial infarction & other complications of atherosclerosis/ The occurrence of xanthomas (which are raised yellow lesions filled with lipid-laden macrophages in the skin & tendons).
  • is best understood by knowing the normal process of cholesterol metabolism & transport which is briefly described below.7% of the body’s cholesterol circulates in the plasma, predominantly in the form of LDL. The level of plasma cholesterol is influenced by its synthesis & catabolism. The liver plays an important role in both these processes. The following flow chart illustrates the normal cholesterol metabolism. Abbreviations used in this flow chart
  • TG = Triglyceride VLDL = Very Low Density Lipoprotein = has a lot of triglyceride (TG), very little cholesterol, & 3 apoproteins. IDL = Intermediate Density Lipoprotein= has less TG & more cholesterol than VLDL & also has 2 apoproteins.LDL = Low Density Lipoprotein = has much more cholesterol than IDL. Liver cell Secrets ↓ VLDL ↓
  • VLDL is transported to the capillaries of adipose tissue or muscle which contain lipoprotein lipase. The lipoprotein lipase degrades the VLDL into TG & IDL.
  • The TG is stored in fat cells or is used for energy in skeletal muscle.
  • The IDL follows 2 pathways:-
    • 50% of plasma IDL is cleared by the liver. The liver uses LDL receptors to remove plasma IDL.
    • The rest of IDL is converted to plasma LDL (which is cholesterol-rich).↓Plasma LDL is removed by the following 2 pathways:-
  1. The scavenger receptor pathway:- In which oxidized LDL or acetylated LDL is removed by a scavenger receptor on the cells of the mononuclear phagocyte system, &
  2. Hepatic clearance:- 70% of plasma LDL is removed by the liver (because LDL binds with LDL receptors which are concentrated in certain regions ( called the coated pits) of the cell membrane of the hepatocyte). Then, the coated vesicles containing the bound LDL fuse with the lysosomes.↓ in the lysosomes, LDL is degraded into free cholesterol which enters the cytoplasm. There, cholesterol does the following things:-
    • It is used for the synthesis of cell membrane & bile acids.
    • It stimulates storage of excess cholesterol
    • It inhibits the synthesis of LDLreceptors thus protects the cell from excessive accumulation of cholesterol.

Familial hypercholesterolemia Is caused by different types of mutations in the gene for LDL receptor → No functional LDL receptor → Leads to:-

  • Impaired plasma LDL clearance. This leads to the accumulation of LDL in plasma (i.e. hypercholesterolemia).
  • Impaired IDL uptake by the liver ( because IDL uses hepatic LDL receptors for this uptake).→ Diversion of a greater proportion of plasma IDL into the precursor pool for plasma LDL. → Hypercholesterolemia.
  • Increased scavenger receptor – mediated clearance of LDL into the cells of the mononuclear phagocyte system & possibly the vascular walls. This leads to xanthomas & contributes to premature atherosclerosis.

In Genetic Disorders, The hypercholesterolemia & the accumulation of LDL inside macrophages produced by the above mechanisms lead to premature atherosclerosis & xanthomas. This knowledge of the pathogenesis of familial hypercholesterolemia has led to a logical discovery of its treatment. We have said that the basic problem in this disease is absence of LDL receptors. Hence, the logical treatment is to increase the number of LDL receptors. (i.e. to remove the basic problem). This can be done by:-

  1. Statins: are drugs which inhibit hepatic HMG CoA reductase→ Inhibits intracellular cholesterol synthesis→ leads to greater synthesis of LDL receptors (See the normal cholesterol metabolism above)
  2. Gene therapy (under investigation): by giving normal LDL receptor genes via a viral vector.

This illustrates that knowing the pathogenesis of diseases greatly helps not only in understanding their morphologic & clinical features but also in the logical discovery of their treatment.

iii. Neurofibromatosis

In Genetic Disorders,  it Is a familial neoplasm. Familial neoplasms have neoplasm-causing mutations ransmitted through the germ line. Familial neoplasms account for about 5% of all cancers & they are mendelian disorders. They are often inherited in autosomal dominant pattern with few exceptions. They are caused by mutations that affect proteins which regulate cell growth. And they are exemplified by neurofibromatosis types 1 & 2. It should be noted that most cancers are not familial & these non-familial cancers are caused by mutations of tumor-suppressor genes, proto-oncogenes, & apoptosis- regulating genes in somatic cells. Hence, these mutations are not passed in the germ line. Therefore, most cancers are not mendelian disorders i.e. they are sporadic or nonfamilial disorders. Here, neurofibromatosis which is a mendelian neoplasm is discussed.

a. Neurofibromatosis type 1 (Genetic Disorders)

  • was previously called von Recklinghausen disease.
  • has autosomal dominant transmission in 50% of cases. (The rest 50% are due to new mutations.
  • has extremely variable expressivity but the penetrance is 100%.
  • is due to a mutation in the NF1 gene (which is a tumor-suppressor gene).
  • mainly shows neurofibromas in the skin & other locations, café au lait spots (i.e. light brown skin pigmentations), & pigmented iris hamartomas (Lisch nodules). The benign neurofibromas can sometimes become malignant.
  • may also show skeletal disorders such as scoliosis & bone cysts & increased incidence of other tumors especially pheochromocytoma & malignancies such as Wilm’s tumor, rhabdomyosarcoma, & leukaemia.

b. Neurofibromatosis type 2 (Genetic Disorders)

  • was in the past called acoustic neurofibromatosis.
  • is much less common than neurofibromatosis type 1.
  • is an autosomal dominant disorder.
  • is due to a mutation of the NF-2 gene ( which is a tumor suppressor gene)
  • shows bilateral acoustic schwannomas, multiple meningiomas, & gliomas (typically ependymomas of the spinal cord).


2. Autosomal recessive disorders (Genetic Disorders)

In Genetic Disorders,  it will be discussed under the following headings:-

  • Criteria
  • Additional features
  • Pathogenesis
  • Clinical examples

In autosomal recessive genetic disorders, the phenotype is usually observed only in the homozygote. The typical pedigree shows affected male & female siblings with normal parents & offspring. Recessive inheritance is suspected when parents are consanguineous; it is considered proven when the corresponding enzyme levels are low or absent in affected individuals & are at half normal values in both parents.

a. Criteria (Genetic Disorders)

  • If the trait is rare, parents & relatives other than siblings are usually normal
  • In the mating of 2 phenotypically normal heterozygotes, the segregation frequency with each pregnancy is 25% homozygous normal, 50% heterozygous normal, & 25% homozygous affected. See Fig. 2 below.
  • All children of two affected parents are affected.
  • Both sexes are affected in equal numbers
  • If the trait is rare in the population, the probability of parenta consanguinity is increased.

b. Additional features (Genetic Disorders)

  • Autosomal recessive disorders show more uniform expression of the trait than autosomal dominant disorders. (i.e. they don’t show variable expressivity).
  • They commonly show complete penetrance.
  • They frequently show signs & symptoms early in life, whereas many autosomal dominant disorders have delayed onset e.g. Huntington disease clinically manifests for the first time during adulthood.

c. Pathogenesis (Genetic Disorders)

In Genetic Disorders, Many autosomal recessive disorders are caused by loss of function mutations which result in decreased enzyme proteins. Homozygotes → No normal enzyme → Disease. Heterozygotes →Equal amounts of normal & defective enzymes→Cells with half the normal amount of the enzyme function normally →No disease.

d. Clinical examples include (Genetic Disorders):-

  • Sickle cell anemia
  • Thalassemia’s
  • Congenital adrenal hyperplasia
  • Cystic fibrosis Wilson disease
  • Hemo-chromatosis-Mendelian disorders associated with enzyme defects:*
    • Phenylketonuria
    • Galactosemia
    • Homo-cystinuria
    • Lysosomal storage diseases
    • Alpha 1 antitrypsin deficiency
    • Glycogen storage disease
  • These will be discussed further.

Mendelian disorders associated with enzyme defects –

  • have mutations → decreased amount of a normal enzyme or abnormal enzyme with decreased activity→ Metabolic block → Consequences → Disease.
  • show autosomal recessive pattern of inheritance because half the normal amount of enzyme is enough for normal function. Hence, heterozygotes (who produce this amount) do not manifest the disease. I.e. the inheritance is autosomal recessive.
  • is illustrated by the following model of a metabolic pathway:- Substrate ↓ Enzyme 1↓ Intermediate 1↓ Enzyme 2↓Intermediate 2 →→ M1 →→ M2 ↓ (Minor pathway products) Enzyme 3 ↓ Final product If an enzyme of the above pathway is defective, then the consequences may be:
  1. Accumulation of the substrate, &/or one or both of the intermediates, & the products of the minor pathway depending on the level of the block. These substances may be toxic in high concentrations & result in tissue damage. This mechanism occurs in the following diseases:
    • Lysosomal storage diseases
    • Galactosemia
    • Phenylketonuria
  1. Decreased amount of the final end product. This is exemplified by albinism.
  2. Failure to inactivate a toxic substrate. E.g. Hereditary alpha -1 antitrypsin deficiency.

Mendelian disorders associated with enzyme defects include most inborn errors of metabolism such as:

  • Lysosomal storage diseases (E.g. Gaucher disease)
  • Phenylketonuria
  • Severe combined immunodeficiency disease
  • Alpha 1 antitrypsin deficiency
  • Albinism
  • Lesch – Nyhan syndrome

In order to illustrate the basic principles of this category, only the first two disorders from the above list are discussed below in moderate depth.

i. Lysosomal storage diseases (Genetic Disorders)

In Genetic Disorders, Result from lack of any protein essential for the normal function of lysosomes. Lysosomes are intracellular organelles used for degrading a variety of complex substrates. They do so by means of a variety of enzymes. The following figure compares the normal lysosomal degradation pathway with that of lysosomal storage disease.Complex substrate

  • Normal lysosomal degradation pathway : enzyme A → intermediate 1 → enzyme B → intermediate 2 → enzyme C → small soluble end product
  • Lysosomal enzyme deficiency pathway: enzyme A →  intermediate 1 → enzyme B → intermdeiate 2 → enzyme C absent → no soluble end product

Lysosomal storage diseases can be divided into the following subgroups based on the nature of the accumulated substance:

  • Sphingolipidoses e.g. Tay-Sachs disease in which there is deficiency of the alpha subunit of the enzyme – hexosaminidase leading to the accumulation of GM2 gangliosides.
  • Sulfatidoses e.g. 1. Gaucher disease e.g. 2. Niemann-Pick disease types A & B (have deficiency of sphingomyelinase resulting in the accumulation of sphingomyelin).
  • Muopolysacharidoses (MPS)
  • Mucolipidoses (ML)
  • Type 2 glycogenosis ( Pompe disease) etc..

The organs affected in lysosomal storage diseases (i.e. the distribution of the stored material) are determined by the following 2 factors:

  1. The site where most of the material to be degraded is found. E.g.1. Brain is rich in gangliosides, hence defective degradation of gangliosides as in Tay-Sachs disease results in the storage of gangliosides within neurons leading to neurologic symptoms. E.g.2. Mucopolysaccharides are widely distributed in the body. Hence, mucopolysacharidoses (i.e. defects in the degradation of polysaccharides) affect virtually any organ.
  2. The location where most of the degradation normally occurs. Organs rich in phagocytic cells such as the spleen & liver are frequently enlarged in several forms of lysosomal storage diseases. This is because cells of the mononuclear phagocytic system are rich in lysosomes & are involved in the degradation of a variety of substrates.

From among the various types of lysosomal storage diseases listed above, only Gaucher disease is discussed here to illustrate the basic principles of lysosomal storage diseases.


Gaucher disease (Genetic Disorders)

  • is the most common lysosomal storage disorder.
  • is a disorder of lipid metabolism caused by mutations in the gene encoding glucocerebrosidase.→ Deficiency of glucocerebrosidase→ Accumulation of glucocerebroside mainly in the cells of the mononuclear phagocyte system & sometimes in the central nervous system. Glucocerebrosides are continually formed from the catabolism of glycolipids derived mainly from the cell membranes of old red blood cells & white blood cells.
  • morphologically shows Gaucher cells (distended phagocytic cells with a distinctive wrinkled tissue paper cytoplasmic appearance).
  • has 3 clinical subtypes : Type I (chronic nonneuronopathic), Type II ( acute neuronopathic) , & Type III (Juvenile).


Type I (Chronic non-neuronopathic form) (Adult Gaucher disease) – (Genetic Disorders):

  • accounts for 99% of the cases.
  • is found mainly in European Jews.
  • does not involve the brain.
  • shows accumulation of gluccocerebrosides only in the cells of the mononuclear phagocytic system throughout the body.
  • Hence, it shows Gaucher cells in the spleen, liver, lymph nodes, & bone marrow.
  • clinically manifests by
    • Splenomegaly→Hypersplenism→Pancytopenia.
    • Hepatomegaly
    • Generalized lymphadenopathy
    • Pathologic fractures & bone pain due to erosion of the bone.
    • First appearance of sings & symptoms in adult life.
    • Progressive disease which is compatible with long life.

ii. Phenylketonuria (PKU) – (Genetic Disorders)

  • Is caused by mutation of the phenylalanine hydroxylase gene → Phenylalanine hydroxylase deficiency → Failure of conversion of phenylalanine to tyrosine in the liver →High serum concentration of phenylalanine which is neurotoxic →Progressive cerebralmyelination In addition the minor pathways of phenylalanine metabolism produce phenyl pyruvic acid (“phenylketone”) & phenyl acetic acid which are excreted via the urine.
  • is clinically characterized by:
    • Progressive mental deterioration usually pronounced by age 1.
    • Seizures.
    • Hyperactivity & other neurologic abnormalities.
    • Decreased pigmentation of hair, eyes, & skin. (Children are characteristically blond & blue-eyed).
    • Mousy body odour from phenylacetic acid in urine & sweat.
  • can be successfully treated by a phenylalanine–free diet.
  • Screening tests for serum phenylalanine or urinary catabolites are ordinarily performed on the 3rd or 4th day of life.


3. X-linked recessive inheritance (Genetic Disorders)

In Genetic Disorders, All sex-linked disorders are X-linked. There is no Y-liked inheritance because Y-linked mutations result in infertility. X-linked disorders can be either recessive (almost all) or dominant (rare).

X-linked recessive inheritance (Genetic Disorders)

It is suspected when several male relatives in the female line of the family are affected.

a. Criteria

  • In the mating of a heterozygous carrier female parent & a normal male parent (the most frequent setting), the sons are hemizygous affected 50% of the time (i.e. the sons have 50% chance of being affected) & the daughters are normal heterozygous carriers 50% of the time & normal homozygotes 50% of the time. See Fig.3 below.
  • Affected daughters are produced by matings of heterozygous females with affected males.
  • No male-to-male (i.e. father-to-son) transmission of the trait (in all sex-linked inheritance). This is because a male contributes his Y chromosome to his son & does not contribute an X-chromosome to his son. On the other hand, since a male contributes his sole X-chromosome to each daughter, all daughters of a male with an X-linked disorder will inherit the mutant allele. All female offspring of affected males are carriers if the mother is normal.

b. Pathogenesis of X-linked recessive disorders

In Genetic Disorders, The genes responsible for X-linked disorders are located on the X-chromosome, & the clinical risks are different for the 2 sexes. Since a female has 2 X chromosomes, she may be either homozygous or heterozygous for a mutant gene, & the mutant allele may demonstrate either dominant or recessive expression. The homozygous female (i.e. having the mutation in both the X chromosomes) will express the full phenotypic change of the disease

Clinical expression of X-linked recessive disorders in heterozygous females is often variable & is influenced by the normal random X-chromosome inactivation (i.e. lyonization). Normally, one of the two X-chromosomes in females is randomly inactivated. Therefore, in heterozygous females carrying X-linked recessive mutations, some cells have one active normal X chromosome & other cells have an active abnormal X chromosome containing the mutant allele. I.e. such females have a variable proportion of cells in which the mutant X-chromosome is active. Often the mutant allele is activated in only some of the cells.

Therefore, the heterozygous female expresses the disorder partially & with less severity than hemizygous men. I.e. she usually does not express the full phenotypic change. E.g. G6PD deficiency. Very rarely, the mutant allele may be activated in most cells & this results in full expression of a heterozygous X-linked recessive condition in the female. In males, the Y chromosome is not homologous to the X-chromosome. So mutant genes on the X are not paired with alleles on the Y. The male is, therefore, said to be hemizygous (& not heterozygous) for the X-linked mutant genes. Males have only oner X-chromosome, so they will clinically show the full phenotype of X-linked recessive diseases, regardless of whether the mutation produces a recessive or dominant allele in the female. Thus, the terms X-linked dominant or X-linked recessive refer only to the expression of the mutations in women.

c. Clinical examples of X-linked recessive disorders include

  • Hemophilia A & B
  • Chronic granulomatous disease of childhood
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Agammaglobulinemia
  • Wiskott -Aldrich syndrome
  • Diabetes insipidus
  • Lesch-Nyhan syndrome
  • Fragile X syndrome
  • Duchenne muscular dystrophy

X-linked dominant inheritance

  • is a rare variant of X-linked inheritance.
  • is when heterozygous females & hemizygous males phenotypically manifest the disorder.
  • is caused by dominant disease alleles on the X-chromosome.
  • is transmitted by an affected heterozygous female to half her sons & half her daughters.
  • is transmitted by an affected male parent to all his daughters but none of his sons, if the female parent is unaffected.
  • is exemplified by vitamin D-resistant rickets.

Mitochondrial inheritance

  • is mediated by maternally transmitted mitochondrial genes, which are inherited exclusively by maternal transmission.
  • is a rare form of inheritance mentioned here just for the sake of completeness.


Chromosomal disorders (Cyto-genetic disorders)

In Genetic Disorders, Chromosomal disorders are caused by chromosome & genome mutations ( i.e. abnormal structure & number of chromosomes respectively). Are not uncommon. They are found in 50% of early spontaneous abortuses, in 5% of stillbirths, & in 0.5 -1% of live born infants. may, therefore, be suspected in the following clinical situations:

  • Spontaneous abortion
  • Stillbirth
  • Abnormal live births
  • Infertile couple

The following subtopics will be discussed below:

  • Normal karyotype – Chromosome identification & nomenclature
  • Types of chromosomal abnormalities
  • Abnormalities of autosomal chromosomes E.g. Down syndrome
  • Abnormalities of sex chromosomes. E.g. Klinefelter syndrome, Turner syndrome

A. The normal karyotype

In Genetic Disorders, Chromosome classification & nomenclature: Karyotype is the chromosome constitution of an individual. The term is also used for a photomicrograph of the chromosomes of an individual arranged in the standard classification (i.e. metaphase chromosomes arranged in order of decreasing length). Karyotyping means the process of preparing such a photomicrograph. I.e. it is the study of chromosomes. Karyotyping uses many types of techniques of which G-banding is the most common procedure.

G-banding has the following steps:-

  • Arrest dividing cells in metaphase by using colchicine.
  • Stain the metaphase chromosomes using Giemsa stain, hence thename Gbanding.→ The metaphase chromosomes will show alternating dark staining & lightstaining bands. The dark bands are by convention called G bands, & the light bands are R bands. About 400 -800 dark & light bands can be seen in a haploid set of chromosomes using G banding.
  • Each chromosome can be identified based on its banding pattern & length. The chromosome pairs are arranged in decreasing order of their length. And the first chromosome in such an arrangement is called chromosome 1, the 2nd chromosome is called chromosome 2, etc…. up to chromosome 23. The banding can also identify break points & other chromosomal alterations.

Metaphase chromosomes are divided longitudinally into 2 sister chromatids held together at the centromere, which delineates the chromosome into a short arm (p) & a long arm (q).

The position of the centromere is used in the morphologic description of a chromosome:

  • Metacentric chromosomes have more central centromeres.
  • Acrocentric chromosomes have a centromere that is very close to one end. E.g. chromosomes 13 & 21.

In Genetic Disorders, In a banded karyotype, each arm of the chromosome is divided into 2 or more regions. The regions are numbered e.g. 1, 2, and 3 from the centromere progressing to the telomere. Each region is further subdivided into bands & sub bands which are also similarly numbered. Thus, Xq22.1 refers to a segment located on the long arm of the X chromosome in region 2 band 2, sub band 1.

Karyotypes are usually described using a shorthand system of notations. The following order is used to describe karyotypes:

  • First the total number of chromosomes is given.
  • Second the sex chromosome constitution is given.
  • Finally any abnormality is described.

E.g. 1. A normal female karyotype is 46,XX. E.g. 2. A female with trisomy 21 is described as 47,XX,+21.

B. Types of chromosomal anomalies

Chromosomal anomalies may be numerical or structural.

  1. Numerical anomalies can result in either aneuploidy or polyploidy.
    • i. Aneuploidy: is addition or loss of 1 or rarely 2 chromosomes.
    • ii. Polyploidy – is the addition of complete haploid sets of chromosomes.
  2. Structural anomalies are rearrangements of genetic material within or between chromosomes. These may be either genetically balanced or unbalanced. In balanced structural anomalies, there is no change in the amount of essential genetic material whereas in the unbalanced ones there is a gain or loss of essential chromosome segments.

1. Numerical anomalies

a. Aneuploidy

  • is a chromosome number that is not an exact multiple of 23 (i.e. the normal haploid number). The most common forms of aneuploidy are trisomy & monosomy. Trisomy is the presence of 3 copies of a particular chromosome instead of the normal 2 copies. I.e. it is the presence of an extra chromosome. Monosomy is the presence of only one copy of a particular chromosome instead of the normal pair. I.e. it is the absence of a single chromosome.
  • is caused most often by an addition or loss of 1 or 2 chromosomes. This change may result from anaphase lag or nondisjunction.

i. Anaphase lag

  • During meiosis or mitosis, one chromosome lags behind & is left out of the cell nucleus. This results in one normal cell & one cell with monosomy.

ii. Nondisjunction

  • is the failure of chromosomes to separate during meiosis or mitosis.
  • Nondisjunction can also occur in a mitotic division of somatic cells after the formation of the zygote. Mitotic nondisjunction is the failure of sister chromatids to segregate at anaphase . If mitotic nondisjunction occurs at an early stage of embryonic development, then clinically significant mosaicism may result.

In Genetic Disorders, The mitotic nondisjunction occurred in one of cells & resulted in a trisomic cell. All the descendants of this trisomic cell will also be trisomic. Also note that most of the cells undergo normal mitosis resulting in normal cells. Therefore, an individual formed from such an embryo will have 2 populations of cells – a trisomic cell population & a normal cell population. Such an individual is called a mosaic. And the clinical appearance of such an individual depends on the proportion of trisomic cells. Anyway, the clinical feature is less severe than that of an individual in whom all the cells are trisomic.

In general, monosomies & trisomies of the sex chromosomes are compatible with life & usually cause phenotypic abnormalities. But monosomies & trisomies of the autosomal chromosomes are not well tolerated. I.e. monosomies of autosomal chromosomes are lethal to the conceptus. And trisomies of all autosomal chromosomes except chromosomes 13, 18, & 21 cause abortion or early death. However, trisomies of the autosomal chromosomes, 13, 18, & 21 permit survival with phenotypic abnormalities.

b. Polyploidy

  • is a chromosome number that is a multiple greater than 2 of the haploid number. Triploidy is 3x the haploid number (i.e.69 chromosomes).Tetraploidy is 4x.
  • is rarely compatible with life & usually results in spontaneous abortion.


2. Structural anomalies

Result from breakage of chromosomes followed by loss or rearrangement of genetic material, are of the following types:

i. Deletion

Is loss of a portion of a chromosome. Has the following subtypes:

  1. Terminal deletions arise from one break. The acentric fragments that are formed are lost at the next cell division. This is denoted by using the prefix ‘del’ before the notation for the site of the deletion. E.g. 46,XX, del (18)(p14) or it can also be denoted by a minus sign following the number of the chromosome & the sign for the chromosomal arm involved. E.g. 46,XX, 5p- (which indicates deletion of the short arm of chromosome 5)
  2. Interstitial deletions arise from 2 breaks, loss of the interstitial acentric segment & fusion at the break sites.
  3. Ring chromosomes arise from breaks on either side of the centromere & fusion at the breakpoints on the centric segment. Segments distal to the breaks are lost so that individuals with chromosome rings have deletions from both the long arm & short arm of the chromosome involved. May be denoted as for example 46,XX, r(15).

ii. Isochromosome formation

Results when one arm of a chromosome is lost & the remaining arm is duplicated, resulting in a chromosome consisting of 2 short arms only or 2 long arms only. The arm on one side of the centromere is a mirror image of the other. E.g. i(X)(q10) results in monosomy of the genes on the short arm of X & trisomy of the genes on the long arm of X. (See Fig.9)

iii. Inversion

Is reunion of a chromosome broken at 2 points, in which the internal segment is reinserted in an inverted position. are compatible with normal development.

iv. Translocation

Is an exchange of chromosomal segments between 2 non-homologous chromosomes. Is denoted by a “t” followed by the involved chromosomes in numerical order. E.g. the translocation form of Down’s syndrome is designated as t(14q;21q). Has 2 types:

  1. Reciprocal (balanced translocation) – is a break in 2 chromosomes leading to an exchange of chromosomal material between the two chromosomes. Since no genetic material is lost, balanced translocation is often clinically silent. But it can also cause disease as in the t(9,22) which causes chronic myelogenous leukaemia.
  2. Robertsonian translocation – is a variant in which the long arms of 2 acrocentric chromosomes are joined with a common centromere, & the short arms are lost.

Before going into the discussion of some of the chromosomal disorders, it is good to remember what mosaicism is.


  • Is the presence of 2 or more cell lines with different karyotypes in a single individual. In a mosaic individual, a normal diploid cell commonly coexists with an abnormal cell line. The abnormal cell line may have a numerical or structural anomaly. A specific cell line may be represented in all tissues or may be confined to single or multiple tissues. The expression of the phenotype depends on the proportion & distribution of the abnormal cell line.
  • – is caused by mitotic errors in early development (i.e. in the fertilized ovum/embryo).



C. Abnormalities of autosomal chromosomes (Genetic Disorders)

In Genetic Disorders, it Include:

  • Down syndrome
  • Edward syndrome
  • Patau syndrome
  • Chromosome 22q11 deletion syndrome

Down syndrome (Genetic Disorders)

Is the most frequent chromosomal disorder. Is caused by:-

1. Trisomy 21

  • accounts for 95% of cases & its incidence increases with maternal age.
  • – is produced usually (i.e. in 95% of cases of trisomy) by maternal meiotic nondisjunction. When the cause is paternal nondisjunction, there is no relation to paternal age.

2. Translocation

  • accounts for 4% of all cases of Down’s syndrome.
  • has no relation to maternal age.
  • is caused by paternal meiotic robertsonian translocation between chromosome 21 & another chromosome. The fertilized ovum will have 3 chromosomes bearing the chromosome 21 material, the functional equivalent of trisomy 21.
  • leads to a familial form of Down’s syndrome, with a significant risk of the syndrome in subsequent children

3. Mosaicism

  • accounts for 1% of cases.
  • usually shows a mixture of cells with 46 & 47 chromosomes.
  • results from mitotic nondisjunction of chromosome 21 during an early stage of embryogenesis.
  • has milder symptoms depending on the proportion of the abnormal cells.
  • is not influenced by maternal age.

Down syndrome has the following clinical features:

  • Severe mental retardation
  • Broad (flat) nasal bridge & oblique palpebral fissure. Because of these features the old name of this disease is mongolism.
  • Epicanthic folds
  • Wide-spaced eyes
  • Large protruding tongue
  • Small low-set ears
  • Bruschfield’s spots (small white spots in the periphery of the iris).
  • Short broad hands with curvature of the 5th finger, simian crease (a single palmar crease)
  • Unusually wide space between the 1st & the 2nd toes
  • Congenital heart disease (in about 40% of the cases).
  • A 10 – 20 fold increased risk of developing acute leukaemia.
  • Increased susceptibility to infection
  • In patients surviving to middle age, morphologic changes similar to Alzheimer’s disease.

D. Abnormalities of sex chromosomes

The following subtopics will be discussed below:

  1. General features
  2. Klinefelter syndrome
  3. Turner syndrome
  4. Disorders of sexual differentiation

1. General features

Sex chromosomal disorders have the following general features:

  • a. They generally induce subtle, chronic problems relating to sexual development & fertility.
  • b. They are often difficult to diagnose at birth & many are first recognized at the time of puberty.
  • c. The higher the number of the X chromosomes (both males & females), the higher the likelihood of mental retardation.
  • d. They are far more common than those related to autosomal aberrations.
  • e. They are better tolerated than autosomal disorders. I.e. extreme karyotype deviations in the sex chromosomes are compatible with life. This is due to the following 2 factors that are unique to the sex chromosomes:
    • The scant genetic information carried by the Y chromosome &
    • The lyonization of the X chromosomes

i. The scant genetic information carried by the Y chromosome

Most of the Y chromosome appears to be “junk DNA” i.e. repetitive sequences that are without function. But there are some essential genes on the Y chromosome such as the genes which determine the testes, spermatogenesis, etc…. The Y chromosome is both necessary & sufficient for male development. Regardless of the number of the X chromosomes, the presence of a single Y chromosome leads to the male sex.

ii. The lyonization of the X chromosomes (X chromosome inactivation)

In normal female somatic cells, there are 2 X chromosomes, but most of the genes on one of the X chromosomes are inactive. The process by which this occurs is called X chromosome inactivation or lyonization or Lyon’s hypothesis.

  1. The X chromosome with most of the genes turned off is called the inactive X chromosome. The other one is called the active X chromosome.
  2. If a somatic cell contains more than one X chromosome, all but one are inactivated. E.g.1. In a 47, XXY cell, there is one active & one inactive X chromosome (the Y chromosome is irrelevant to the process of X inactivation). E.g. 2 in a 49, XXXXX cell, there is one active X chromosome & 4 inactive chromosomes
  3. X inactivation occurs early in embryogenesis among all cells of the bastocyst at about the 16th day of embryonic life.
  4. The process of X inactivation is random in any single cell. Either the X chromosome inherited from the mother (called Xm) or the X chromosome inherited from the father (called Xp) may be inactivated with equal likelihood. e.
  5. Once X inactivation occurs in an embryonic cell, the same X chromosome remains inactivated in all of the progeny of that cell. Females are mosaics. On average, half of the cells in a female have an inactive Xm & the other half of the cells have an inactive Xp. However, some tissues (& some women ) may have substantially more cells with one or the other X chromosome active by chance.
  6. X inactivation involves most, but not all, genes on the X chromosome. Some essential genes must be expressed in 2 copies from both X chromosomes for normal growth & development. For this reason, some essential genes on the X chromosome escape Xinactivation. So if one of these essential genes is absent (as occurs in Turner syndrome), it results in abnormal growth & development. Likewise, the presence of an extra X chromosome (as occurs in Klinefelter syndrome) leads to abnormal phenotype.
  7. The inactive X-chromosome may be visible in an interphase cell as a condensed mass of chromatin called the Barr body (X chromatin). The maximum number of Barr bodies seen in a cell is equal to the number of inactivated X chromosomes (i.e. one less than the total number of X chromosomes in the cell). E.g. Normal females (46,XX) will have one Barr body, & individuals with 3 chromosomes (XXX) will have 2 Barr bodies, & those with 4 X chromosomes will have 3, & so on. Counting the number of Barr bodies in somatic cells (usually in smears of buccal mucosa) is the basis of the sex chromatin test for sex chromatin aneuplody. This test is no longer used in the Western countries because karyotyping is much more accurate.
  8. h. X-chromosome inactivation produces dosage compensation. Females normally have 2 Xchromosomes & males have only one. And most of the genes on the X chromosome do not have homologues on the Y chromosome. Despite the fact that females have double doses of most X-linked genes in comparison to males, the amount of X–linked products is usually about the same in males & females. This dosage compensation is produced by X inactivation.

X inactivation has the following clinical implications:

  • A female who carries an X-linked recess
  • A female who carries an X-linked recessive mutation on one of her 2 X chromosomes may express the mutant phenotype if most of her cells happen to have inactivated the X chromosome carrying the normal gene.
  • A female carrier of an X-linked recessive disease may not detectable by gene product assays (e.g. by the amount of protein or enzyme activity) if most of her cells happen to inactivate the X chromosome carrying the mutant gene.
  • Although monosomy (i.e. the presence of one instead of the normal 2 copies) for any autosome is lethal early in embryogenesis; monosomy for the X chromosome is relatively common in live born infants & produces a relatively mild phenotype called Turner syndrome.
  • Trisomy (i.e. the presence of 3 rather than the normal 2 copies) of the sex chromosomes produces a much less severe phenotype than trisomy for any of the autosomes. Trisomy of the sex chromosomes produces phenotypic changes because of the triple dosage of the essential genes on the X chromosomes (1 copy of these essential genes on the active X chromosome & 2 copies of the activated ‘escapee’ essential genes on the inactivated X chromosome). Points 3 & 4 above illustrate that aneuploidy of the sex chromosomes is better tolerated than the aneuploidy of the autosomes.

2. Klinefelter syndrome (Genetic Disorders)

  • is a disorder that occurs when there are at least 2 X chromosomes & 1 or more Y chromosomes.
  • is most often characterized by the karyotype 47, XXY. Variants include additional X chromosomes (e.g. XXXY) & rare mosaic forms. In the typical XXY form, a single Barr body is noted in the buccal smear preparations.
  • is caused by parental meiotic nondisjunction & incidence increases with maternal age.
  • is characterized by male hypogonadism & its secondary effects.
  • shows atrophic testes with decreased spermatogenesis which leads to infertility & decreased testosterone production. In addition, it also shows increased plasma estradiol levels (by unknown mechanism). The ratio of estrogens & testosterone determines the degree of feminization.
  • therefore, shows lack of secondary male sexual characteristics (i.e. no deep voice, no beard, no male distribution of pubic hair).
  • also shows tall stature (because fusion of the epiphyses is delayed), & eunuchoid appearance with gynecomastia.
  • is rarely associated with mental retardation, which is usually mild. The extent of retardation increases with increased number of X chromosomes.
  • is usually undiagnosed before puberty.

3. Turner syndrome (Genetic Disorders)

  • is a disorder that occurs when there is a complete or partial monosomy of the X chromosome.
  • is associated with one of the following 3 types of karyotypic abnormalities:
    • 45,X karyotype ( in which no Barr bodies are seen in the buccal smear)
    • mosaics (45, X cell plus one or more karyotypically normal or abnormal cell types)
    • structural abnormalities of the X chromosomes which result in partial monosomy of the X chromosome. E.g. deletion of one of the arms of the X chromosome.
  • This karyotypic heterogeneity associated with Turner’s syndrome is responsible for significant variations in phenotype. E.g. 45, XO causes a severe phenotype whereas mosaics may have a normal appearance with only primary amenorrhea.
  • is characterized by female hypogonadism & its secondary effects. shows:
    • Replacement of the ovaries by fibrous streaks .
    • Decreased estrogen production & increased pituitary gonadotropins from loss of feedback inhibition.
    • Infantile genitalia & poor breast development & little pubic hair.
    • Short stature (rarely exceeding 150cm in height), webbed neck, shield-like chest with widely spaced nipples, & wide carrying angles of the arms.
    • Lymphedema of the extremities & neck.
    • Congenital heart disease (especially preductal coarctation of the aorta & bicuspid aortic valve).

4. Disorders of sexual differentiation (Sexual ambiguity)

are said to be present when genetic sex, gonadal sex, or genital sex of an individual are discordant. The sex of an individual can be defined on many levels:-

1. Genetic sex

Is determined by the presence or absence of a Y chromosome. No matter how many X chromosomes are present, the presence of a single Y chromosome leads to testicular development & a genetic male. At least one Y chromosome is necessary & sufficient for male gender to manifest.

2. Gonadal sex

Is determined by the presence of ovaries or testes. The gene responsible for the development of the testes is localized to the Y chromosome.

3. Ductal sex

Depends on the presence of derivatives of the Mullerian or Wolffian ducts.

4. Phenotypic or genital sex

Is based on the appearance of the external genitalia. Sexual ambiguity is present whenever there is discordance among these various criteria for determining sex.

i. True hermaphrodite

  • is very rare.
  • has both ovaries & testicular tissue, with ambiguous external genitalia.
  • may result from the fusion of 2 sperms (one X-carrying sperm & one Y-carrying sperm) with a binucleated ovum.

ii. Pseudohermaphrodite

  • shows discordance between the phenotypic sex & gonadal sex.
  • i.e. has gonads of only one sex, but the appearance of the external genitalia does not correspond to the gonads present. Thus, a male pseudohermaphrodite has testicular tissue but female-type genitalia. A female pseudohermaphrodite has a ovaries but male external genitalia (or the external genitalia are not clearly male).

a. Female pseudohermaphroditism

  •  is caused by exposure of the fetus to increased androgenic hormones during the early part of gestation as occurs in congenital adrenal hyperplasia, androgen-secreting ovarian or adrenal tumor in the mother, or hormones administered to the mother during pregnancy.

b. Male pseudohermaphroditism

  • has a Y chromosome & only testes but the genital ducts or the external genitalia are either ambiguous or completely female.
  • may be caused by tissue resistance to androgens (called testicular feminization), by defects in testosterone synthesis, or by estrogens administered to the mother during pregnancy.


Disorders with multifactorial inheritance (Genetic Disorders)

  • are more common than mendelian disorders.
  • result from the combined actions of environmental factors & 2 or more mutant genes having additive effects (i.e. 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. include such common diseases as:-
    • Diabetes mellitus,
    • Hypertension,
    • Ischemic heart disease,
    • Gout,
    • Schizophrenia,
    • Bipolar disorders,
    • Neural tube defects,
    • Cleft lip/ cleft palate,
    • Pyloric stenosis,
    • Congenital heart disease, etc….

Are characterized by the following features:-

  • The risk of expressing a multifactorial disorder partly depends on the number of inherited mutant genes. Hence, if a patient has more severe expression of the disease, then his relatives have a greater risk of expressing the disease (because they have a higher chance inheriting a greater number of the mutant gene). In addition, the greater the number of affected relatives, the higher the risk for other relatives.
  • The risk of recurrence of the disorder is the same for all first degree relatives of the affected individual & this is in the range of 2-7%. First-degree relatives are parents, siblings, & offspring. Hence, if parents have had one affected child, then risk that the next child will be affected is between 2 & 7%. Similarly, there is the same chance that one of the parents will be affected.
  • The concordance rate for identical twins (i.e. the probability that both identical twins will be affected) is 20 – 40% but this is much greater than the concordance rate for nonidentical twins.
  • The risk of recurrence of the phenotypic abnormality in subsequent pregnancies depends on the outcome in previous pregnancies. When one child is affected, the chance that the next child will be affected is 7%. When 2 children are affected, then the chance that the next child will be affected increases to 9%.

Single gene disorders with non-classic inheritance (Genetic Disorders)

Are rare & are briefly mentioned here. Can be classified into the following categories:

  • Diseases caused by mutations in mitochondrial genes. E.g. Leber hereditary optic neuropathy
  • Diseases associated with genomic imprinting E.g. Prader-Willi syndrome, Angelman syndrome
  • Diseases associated with gonadal mosaicism. Gonadal mosaicism can explain unusual pedigrees seen in some autosomal dominant disorders such as osteogenesis imperfecta in which phenotypically normal parents have more than one affected children. This cannot be explained by new mutations. Instead, it can be explained by gonadal mosaicism
  • Disorders caused by triplet repeat mutations E.g. Fragile X syndrome

It’s the second most frequent cause of hereditary mental retardation next to Down syndrome. It clinically manifest in both males & females. In males, it is characterized by bilateral macro-orchidism (enlarged testes).