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Genetic Health Conditions A-Z

Explore the signs and symptoms, genetic cause, and inheritance pattern of various health conditions.

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DNA carries an organism's genetic instructions – the blueprints for their physical, biochemical and behavioural characteristics. These are all inherited, but are also subject to environmental influences. It was discovered by James Watson and Francis Crick using data that Rosalind ??? provided. DNA is a double-stranded macromolecule and its backbone contains alternating phosphate and sugar (deoxyribose) residues linked to one of four bases – adenine (A), thymine (T), cytosine (C) and guanine (G). The structure is in a double helix – a twisted ladder that have base-pairs as the rungs. The two strand are antiparallel, running in opposite directions with 5' (phosphate) and 3' (sugar) ends. These two strands are held together through complementary base-pairing by H-bonding. The base-pairing rule is A-T and C-G.

From the human genome project, it was determined that the human genome contained 3×109 base-pairs of DNA. This DNA is divided up into discrete packages called chromosomes. About 30,000 genes are scattered along these chromosomes, separated by DNA of unknown function (intergenic DNA). Genes only represent about 2% of all DNA.


A chromosome contains a single molecule of DNA, consisting of chromatin (DNA and protein [histones] packaged to form a coiled structure. Each somatic cell contains 23 pairs of chromosomes in the nucleus, 22 autosomal pairs and 1 pair of sex chromosomes (XY for males and XX for females). Chromosomes are elongated during interphase and are of varying lengths.

Chromosomes replicated prior to mitosis, containing two chromatid (although still a single chromosome). Chromosomes are condensed during metaphase and can be ordered according to length and position of centromere as a karyotype.

Some chromosomes are 'gene-rich' such as chromosomes 1 and 2 while others are 'gene-poor' such as 13 and 21. Mitochondria also contain a circular chromosome coding for a limited number of genes. Mitochondrial DNA is maternally inherited.

Before DNA can be replicated, it needs to unwind (denature). This allows the base sequences on each strand to be copied. It is the complementarity between the two strands that allows a faithful copy to be made of the entire chromosome.


Genes are the DNA sequences that contain all the information required to form specific peptides or RNA molecules. It is basically the information required for body cells to form. This information can include structural as well as regulatory elements. The can code for peptides (proteins) via messenger RNAs (mRNA), directly for ribosomal RNAs (rRNA) or directly for transfer RNAs (tRNA). Usually, there are many copies of genes that code for rRNAs and tRNAs, and both are involved in protein synthesis (translation). As cells grow, divide and differentiate only a small, select number of genes are expressed to form protein at any one time. Altogether, about 20,000 to 30,000 genes work at different times.

Different cells make different proteins according to the cell structure, function, development and growth. Gene expression is under tight control. Each gene is localised at a specific point (locus) on the chromosome.


Within DNA, DNA replication, DNA repair and genetic recombination occurs. This leads to RNA synthesis (transcription) which then leads to protein synthesis (translation). Codons, which are base triplets, are read to determine the type of amino acid that is used to form the protein. There are also stages in between post-transcriptional processing and post-translational processing. This translation happens at the cytoplasm.

Simplified Diagram of a Gene

The structural part of a gene includes both exons and introns. Exons (EXpressing regiONS) are the regions which contain sequences coding for specific polypeptide while introns (INtervening regiONS) are regions found between exons and may be involved in regulation of most eukaryotic genes. Regulatory sequences control when, where and how much gene is expressened (i.e. Peptide made). It includes promoter regions, 5' or upstream of the first exon, and enhancer or silencer regions that further modify expression, which can be upstream, downstream, in introns or even quite far away from the coding regions.


In a sequence of DNA, 5'-3' is called the coding (sense) strand while 3'-5' is called the noncoding (anti-sense) strand. RNA polymerase synthesises an RNA copy of the sense strand, using the anti-sense strand as a template. Thus the mRNA is a copy of the coding strand and is complementary to the non-coding strand.

Transcription starts when transcription factors (proteins) and RNA polymerase (enzyme) bind to promoter. Both exons and introns are transcribed. Many RNA molecules can be transcribed from the same gene during that period of gene expression.

During post-transcriptional processing, the precursor RNA is modified at both ends and introns are removed to prduce the final mRNA. The mRNA then leaves the nucleus for translation in the cytoplasm. (Alternative splicing?)


The sequence of bases along the mRNA is read in groups of three called codons. Each codon specifies a particular amino acid and ultimately the sequence of the amino acids along a peptide. There are 64 (43) possible codon combinations with 61 specifying amino acids and 3 specifying stop signals. There are only 20 amino acids so some amino acids are specified by more than one codon.

In translation, the mRNAs are used as a template on ribosomes. The amino acids are carried to the ribosomes and put into place by specific tRNAs, which match the amino acids with the right codon. There are different reading frames and thus depending on where the tRNA starts reading from, the protein sequence may be very different from the original. However, each mRNA has the same starting codon, which is AUG for methionine. This establishes the reading frame of the mRNA so that the codons are read correctly.

Many peptide chains are synthesised from a single mRNA molecule. Peptides usually undergoes further processing, including removal of initial methionine.

In the regulation of gene transcription, the chromatin is more open because the actively transcribed genes need to be accessed by transcription factors while the tightly packed for inactive genes. Methylation (addition of methyl group) of cytosine residues in promoter contributes to the silencing of genes. Different gene promoters bind to different transcription factors present in a cell which may be cell-specific. So, gene expression is influenced by the conformation of chromatin, the methylation of DNA and the availability of transcription factors.


Alterations of DNA sequences are called mutations. Mutations contribute to natural variation between individuals. There are about 5×106 differences between individuals (about 1-2%). Mutations are responsible for changes during evolution.

Mutations, however, can be detrimental depending upon their nature and their position. Mutations can be at the gross level of the chromosome resulting in chromosomal abnormality or at the DNA level, within genes and between genes.

Chromosomal Abnormalities

Aneuploidies are abnormal chromosome numbers caused by misassortment such as trisomy 21 which leads to Down Syndrome. A trisomy is when there is an extra chromosome. Deletion of a chromosome results in monosomy and multiple complements of chromosomes are called polyploidy. An example of polyploidy is in 3n as triploid, 2n as diploid and 1n as haploid. Structural abnormalities are rearrangements or deletions of chromosomes, cause by chromosome breakage during the cross over. A karyotype is a picture of chromosomes [see pic].

There are methods to detect chromosomal abnormalities such as looking at karyotypes or FISHing for chromosomes. FISH stands for Fluorescent In Situe Hybridisation which is the technique of determining chromosomal location or expression pattern of genomic DNA or cDNA fragments by examining chromosomes or tissue sections under a fluorescent microscope.

There are two types of translocation of chromosomes. In balanced translocations, no genes are lost or gained in the process, while unbalanced translocations may result in a net loss or gain of part or all of a chromatid. In such cases, disorders are named as the following: translocation down syndrome.

Single-cell Mutations

These can affect a single base, a small number of bases or a very large number of bases. There are three classes of mutations, namely base-substitution, Deletions and Insertions. In base-substitution, there is a replacement of a single base, and are either silent mutations, nonsense mutations or missense mutations.

Silent mutations has no effect on the final sequence of amino acids within a peptide, and hence on its function. E.g. UCA becomes UCU, however, both codons translate to a Serine amino acid, and thus has no overall effect.

A Nonsense mutation produces a stop codon and thus results in a truncated protein. E.g. UCA becomes UGA, and effectively the Serine amino acid is replaced with a stop signal.

Missense mutations can either be conservative or radical. When conservative, the alteration produces an amino acid that is not too different in function, hence the peptide's function may not change much. E.g. An Aspargine amino acid may be replaced with a Glutamine amino acid, both of which are in the acidic group. When radical, the alteration produces an amino acid that is quite different in function, hence the peptide's function will change to a varying degree. E.g. An Aspargine amino acid may be replaced with a Glycine amino acid, which are in very different groupings.

In deletion mutations and insertion mutations, these can often alter the reading fram which would result in a completely different sequence of amino acid, and thereby completely alter the protein. These are also called frameshift mutations. When the deletion or insertion is a single-base, the result is dramatic and the rest of the the code is altered. A codon deletion or insertion may have a range of effects depending on where they take place and whether they occur as a group of three at once or in separate places. Large deletions and insertions clearly will be detrimental.

Causes of mutations

Mutations can be spontaneous or induced. Spontaneous mutations occurs when there are errors in chromosome segregation at meiosis, during DNA replication and repair or during spontaneous chemical attacks. Induced mutations are caused by exposure to environmental agents (mutagens) such as radiation (e.g. cosmic, UV, X-rays, atomic) or chemicals (dietary, occupational or environmental). Mutation rates.


DNA Replication

Replication occurs at many points along the chromosome, thus speeding up replication. Both strands are copied during replication. Replication occurs prior to cell division. After unwinding, the new strands are synthesised using free nucleotides, to form two new strands.

Enzymes control the many steps in DNA replication. Enzymes build strands only in one direction, resulting in one complementary strand being made in fragments that are later joined together.

Firstly, the enzyme Helicase splits and unwinds the DNA. Then the RNA Polymerase makes a short RNA primer which is later removed. The DNA Polymerase extends RNA primer with short lengths of complementary DNA. The DNA Polymerase then digests the RNA primer and replaces it with DNA. DNA Ligase joins neighbouring fragments together into longer strands. A primer is a molecule (which may be a small polymer) that initiates the synthesis of a larger structure. The DNA Polymerase only synthesises from the 5' end to the 3' end. DNA polymerases can 'proof read', i.e. Edit their mistakes. Therefore mistakes are kept to just one error in every 109 base-pair replicated. Faithful repliction is essential but a low number of errors also allows evolution to occur.

Genetic Variation

Sources: Genetic factors and environmental factors. Causes: mutations, sexual reproduction [meiosis (independent assortment, crossing over) and fertilisation (random), leads to mixing and matching of different forms of a gene (recombination)]. Most natural variations are normal and determines the way we look, behave, etc. Some variations can cause disease.

Genotype is the genetic constitution of an organism. Phenotypes are the physical characteristics (morphological, biochemical, molecular) of an organism or cell. Genotype ± environment = phenotype. A locus is the position of a gene on a chromosome. An allele is an alternative variant (DNA sequence) of a particular gene. Polymorphism is where there are at least two or more relatively common alleles of a gene in the population. e.g. alleles responsible for ABO blood groups. Polymorphisms are due to mutations. Homozygous means there are two copies of the same allele while heterozygous means there are two different allels of the same gene. A phenotype is dominant if the trait can be seen in individuals who are heterozygous for an allele and it is recessive if the trait is seen only in individuals homozygous for the allele. a phenotype is codominant when the effects of both alleles are seen in the heterozygote. [ABO Blood Type example]


Inheritance of genes can be followed through families by looking at pedigrees, or family trees. Dominant and recessive phenotypes have characteristic pedigrees. Males are represented by squares and females with circles.

In autosomal dominant disorders, if both the paternal and maternal genotypes are of the type Aa, then the offspring will have about a 3 in 4 chance of developing the disease. These pedigrees are characterised by the vertical transmission of disease phenotype, lack of skipped generations and equal numbers of affected males and females. Examples include Huntington's disease, polydactyly and dentinogenesis imperfecta.

In autosomal recessive disorders, the offsprings have a 1 in 4 chance of developing the disease. These pedigrees are characterized by the horizontal appearance of disease phenotype, especially among siblings. There are equal numbers affecting males and females and consanguinity (mating of related individuals) may be present. Heterozygotes are carriers and are generally healthy, and thus these phenotypes may have skipped generations. Examples include cystic fibrosis, thalassaemia and oligodontia.

X-linked recessive disorders allow offsprings a 1 in 4 chance of developing this disease. There is an absense of father-son transmission and skipped generations when genes pass through female carriers. Affected males are much more common and examples include haemophilia A, Duchenne muscular dystrophy, colour blindness, adrenoleucodystrophy and X-linked hypohidrotic ectodermal dysplasia. X-linked dominant disorders ard clinically less common. It occurs about twice as common in females as males and skipped generations are uncommon, an example being hypophosphataemic rickets. Males are hemizygous, rather than heterozygous.


Although females have two X chromosomes, only one X is active in any one cell. Females have X-chromosome are inactive, i.e. not expressed. This usually occurs randomly, therefore females are mosaic for X chromosome. X-chromosome inactivation can be skewed, such as having 90:10 rather than 50:50. If the more active X has an altered gene for a disorder such as adrenoleucodystrophy, then the female can show symptoms (although milder), called a manifesting heterozygote/carrier. This occurs quite rarely.

There are three types of disorders, although these are not generally separated finely. In classic monogenic (single-gene) disorders, many hundreds are known such as cystic fibrosis, thalassaemia, Duchenne Muscular Disorder and Huntington's disease. Pathology can generally be related to faults in a single gene. Polygenic disorders are controlled by the added effects of genes at multiple loci. Diabetes, Alzheimer's disease, coronary heart disease, psoriasis and asthma are examples of such disorders. Multifactorial disorders are affected by both genes and the environment. Nowadays, even single-gene disorders may be considered polygenic or multifactorial.


Haemoglobinopathies (disorder or disease caused by or associated with the presence of abnormal hemoglobins in the blood) are often good models of molecular disease since they are well studied and thus, well understood. These are genetically inherited diseases with changes to one or more globin chain of haemoglobin. These are common disorders with over tens of millions worldwide. There are over 250,000 new severe cases each year.

The haemoglobin protein in the adult (HbA) is a tetramer (having four parts), in the form α2β2 (heterotetramer), with each globin chain having a central haem molecule. There are two α-globin genes on chromosome 16 (four per diploid genome), and one β-globin gene on chromosome 11 (two per diploid genome). There are a number of other different globin genes which are regulated to produce different forms of haemoglobins at different stages of development. [Hb production graph]

There are many type of haemoglobinopathies including structural variants, α- and β- Thalassaemias and hereditary persistence of fetal haemoglobin (HPFH). Structural variants alter globin polypeptide without altering the rate of synthesis. There over 400 different varients such as sickle cell anaemia. α- and β- Thalassaemias have a very high level of HPFH caused by the decreased synthesis of one or more of globin chains. Hereditary persistence of fetal haemoglobin are clinically benign. Some haemoglobinopathies are caused by mutations resulting in a combination of altered structure and synthesis.

Haemoglobinopathies are inherited as autosomal recessive disorders, such that homozygous affected individuals usually have a severe disease. Heterozygous carriers, while they may show some changes in the blood, are not ill and may have partial protection against malaria. α-Thalassaemia: Global distribution; high in south east Asia. β-Thalassaemia: global distribution; increased frequency in mediterranean countries including north africa, south east asia, india and pakistan.

Sickle Cell Anaemia

Sickle cell anaemia is common in west and central Africa, affecting up to 1 in 50 births. It affects 1 in 400-600 African American births and is also found in Mediterranean and Middle Eastern populations. It is cause by point mutation (different point mutations cause other strucural variants) leading to a single amino acid change that causes insuluble HbS and sickling. Therefore the haemoglobin is sticky and blood clots form.

The clinical features may include anaemia (low haemoglobin count), weakness, failure to thrive, splenomegaly, repeated infections, ischaemia, thrombosis and infarction.


β-Thalassaemia is usually due to a single base-pair substitution rather than deletion. It results in reduced or no synthesis of β-globin mRNA or protein. Patients usually get α homotetramers that are insoluble (α4). It is common in populations from the Mediterranean, Middle East, India, Pakistan and South East Asia.

Nonsense mutations, exon splicing problems or 5' flanking sequences can lead to reduced RNA synthesis. [RBC picture]

Compound Heterozygotes

There are often individuals who have two different mutations who are really compound heterozygotes. An example may be two different types of β-globin mutation, two different β-thalassaemia mutations or a β-thalassaemia mutation and the sickle cell mutation. An example of a double heterozygote may be an individual with a β-globin mutation and an α-globin mutation. These can result in variable phenotypes and sometimes the disease may even be less severe, an example being heterozygous for α-thalassaemia (αα/--) and homozygous for β-thalassaemia (β-/β-).

Coronary Heart Disease

Atherosclerosis, which causes coronary heart disease is clearly multifactorial. Risk factors include obesity, cigarette smoking, hypertension, elevated cholesterol levels, family history of heart disease and diabetes.

There is more than one gene involved, in blood lipids and lipid metabolism, blood pressure and coagulation factors.

Genetic Testing

Genetic testing is done for clinical diagnosis, carrier testing, predictive testing and screening. Diagnostic testing is to confirm presence of disease and/or for clinical prognosis such as karyotyping for Down syndrome, DNA test for Duchenne muscular dystrophy or biochemical tests for Tay Sachs disease (hexosaminidase in lysosomes). Carrier testing is for heterozygous state for autosomal and X-linked recessive disorders. Cascade testing is when test is administered for the rest of the family after one member (proband) is identified. When applying this test, counselling must be given as this test is not for everyone. Predictive testing is for presymptomatic individuals at risk of developing genetic disorder such as DNA testing for mutation in Huntington's disease. It is controversial since if a daughter knows her status, then her father knows his status as well.

Genetic screening identifies a subset of individuals from a population at high risk of having, or of transmitting to children, a specific genetic disorder. It allows early recognition of affected individuals who benefit by medical intervention. Screening is not a definitive test. It offers informed reproductive choices and/or opportunities for early treatment in prenatal, neonatal and populations. These is a possibility of a false positive.

There are about 4 out of 100 births which have a birth defect. Males are generally higher than females. No screening test can ensure a baby free of birth defects. There is no such thing as a “perfect baby”.

Prenatal Testing

Prenatal testing helps families to make informed choices during pregnancies and provides choices. Screening only gives risk values while genetic diagnostic testing is more definitive, however, it requires obtaining a sample of fetal cells or tissue for analysis.

Maternal serum screening by looking at chemical in the blood and ultrasonography/nuchal translucency are examples of prenatal screening and are non-invasive procedures but give risk values only.

Chorionic Villus Sampling and Amniocentesis are invasive testing techniques with about a 1% and 0.5% risk of miscarriage respectively. These are examples of diagnostic testing.Other diagnostic testing procedures include umbilical vein sampling, fetal cells/DNA in maternal blood, pre-fertilisation and pre-implantation (PGD), but are much less common due to the higher risks involved.

The main techniques used to look for mutations are polymerase chain reaction (PCR), Restriction fragment polymorphisms (RFLPs) and DNA sequencing.

Genetic terms glossaries.

Glossary of Genetics | Glossary of genetic testing terms

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