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Clinical genetics

What is clinical genetics?

Clinical Genetics is a specialized field concerned with diagnosing and managing the wide variety of genetic conditions and abnormalities. These abnormalities include: sporadic birth defects, chromosomal abnormalities, mendelian conditions, mitochondrial conditions, and multifactorial conditions. Patients afflicted by a genetic disorder may be recommended for genetic counseling, which aims to educate families and individuals about the specific disease with which they are afflicted and help them cope with the psychological aspect of disease.

Why is clinical genetics necessary?

Approximately 3-4% of babies born each year are born with a genetic abnormality or severe birth defect. Around 1% of babies will also have a chromosomal abnormality, which can lead to problems including mental and physical retardation. Not only this, but genetic defects account for ~20% of postnatal mortalities, as well as nearly a tenth of hospitalizations in adults and a third of childhood hospitalizations. Genetic disorders can put a strain on healthcare services and can have serious implications for not only the afflicted individual but, because of the nature of genetic diseases, the individual's extended family. By identifying affected individuals through genetic screening, it is possible to help counsel them through the psychological aspect of the diagnosis as well as establish a long-term care plan.

How is genetic Analysis conducted?

Once an individual with a genetic disease, or an at-risk individual, has been identified, samples are sent to a lab for a variety of different types of testing depending on the nature of the genetic disorder. These tests include:

  • Cytogenetics: for chromosomal abnormalities. In cytogenetics, sample cells are arrested in metaphase and DNA is partially digested with trypsin and then stained with Giemsa to produce an effect known as "G-banding." This type of staining is the most common and each chromosome has its own particular banding pattern. This technique is useful in identifying gross chromosomal abnormalities, such as aneuploidy or large-scale deletions, insertions, or inversions, though smaller mutations cannot be identified via this technique. Terminology to describe these chromosomal mutations is given by the International System for Human Cytogenetic Nomenclature (ISCN).
  • Molecular genetics: DNA analysis Molecular genetic analysis is necessary for cases in which a mutation or gene disruption is too small to be identified by cytogenetic analysis. Individuals are screened for mutations such as SNPs in genes that are known to be involved in disease. These genes are usually identified by researchers by analysing pedigrees of affected families and determining what regions of the genome correlate with the disease phenotype. Once a linkage has been established candidate genes in that region can be identified and sequenced in an attempt to pinpoint any mutations, and markers are created for patient screening.
  • Biochemical genetics: for metabolic disorders Biochemical genetics aims to identify the single gene disorders associated with inborn metabolic conditions through the study of gene products (usually enzymes). These diseases are quite rare individually, but account for a substantial proportion of genetic diseases as a whole. Furthermore, if identified early many of these metabolic conditions are treatable and their long-term effects can be avoided.


A type of chromosomal disorder where the patient has either more or less than the average number of chromosomes (46+/-n). This condition can be either autosomal or sex linked. Most cases of aneuploidy result in spontaneous abortion, making these types of chromosomal abnormalities fairly rare. The condition is usually due to nondisjunction previous to fertilisation (see figure 1).

Aneuploidy causes defects mostly due to imbalances in gene expression and the exposure of recessive diseases. The over expression of genes in polyploidy conditions is associated with the toxic build up of gene products. For this reason most cases of live birth polyploidy occur with smaller chromosomes, which contain fewer genes.  Polyploidy in larger chromosomes with more genes is usually lethal. Monoploidy, on the other hand, can result in the exposure of recessive alleles, as a dominant allele is no longer available to cover the effects of the deleterious one. 

Nondisjunction after fertilization can cause chromosomal mosaicism in which certain cells derived from the abnormal cell will have less than the normal number of chromosomes and the rest will have more than the normal number of chromosomes. Events such as these can cause similar phenotypic effects as nondisjunction prior to fertilization; however they tend to be less severe and may be localized to specific areas of the body.


Figure 1: Aneuploidy

Figure depicting nondisjunction resulting in abnormal chromosome segregation and aneuploidy.

Common Examples of Anueploidy:

  • Down Syndrome (Trisomy 21). Down syndrome is probably one of the most well-known examples of aneuploidy with an overall occurrence of about 1 in 700 live births. This condition is the result of triploidy of the autosomal chromosome 21. Although the survival rate of children born with Down syndrome is quite high, most eventually succumb to congenital heart defects, although respiratory illnesses, leukemia and other congenital defects can also lead to death.
  • Klinefelter syndrome (XXY). Klinefelter syndrome is caused by the inheritance of an excess X chromosome in males and thus is a sex-linked form of aneuploidy. This is among the most common disorders among patients with aneuploidy with an incidence of approximately 1 in 1000 males. Patients may exhibit hypogonadism and reduced fertility and will need testosterone replacement therapy, though many others will show no symptoms and their abnormal karyotype will go undiagnosed.
  • Other conditions include Trisomy 18 (Edwards Syndrome), Trisomy 13 (Patau Syndrome), Trisomy 8 (Warkany syndrome 2), XXX (Triple X syndrome), XXY syndrome, and Turner syndrome (X)

Chromosomal Translocations

This is a type of genetic disorder occurs when a fragment of chromosome becomes ligated to another chromosome. Chromosomal translocations are mainly spontaneous and tend to occur during or shortly after conception. There are two varieties of translocations:

  • Reciprocal: Characterized by the exchange of segments between two different chromosomes. Balanced Translocations are harmless and generally go undiagnosed; however unbalanced translocations tend to result in spontaneous abortion or partial trisomy of the segment of chromosome, which has been inherited twice. Also, although balanced translocations may be harmless to the parent then can cause unbalanced inheritance of specific chromosome regions in their offspring. 

      Figure 2: Reciprocal Translocation

      Robertsonian Translocation

      • Robertsonian: Two acrocentric chromosomes (13, 14, 15, 21, 22) become joined together. Robertsonian Translocation may result in trisomy, due to the extra inheritance of the long arm of an acrocentric chromosome. For example, Robertsonian translocations account for a small percentage of Down syndrome cases, though the majority of cases are caused by nondisjuntion of chromosome 21.

      Figure 3: Robertsonian Translocation

      Chromosomal Deletions

      Caused when a segment or whole chromosome is lost resulting in the loss of genetic material.  These deletions may be phenotypically harmless depending on their size and location, especially if the other chromosome in the pair compensates for the loss of genes. However in some cases such compensation is not possible and the condition may result in the complete loss of certain important genes or regulatory regions, causing much more severe changes in phenotype. An example of a condition associated with a chromosomal deletion is 1p36 deletion syndrome. This is caused by the loss of a fragment of DNA on the short arm of chromosome one toward the outermost band. This genetic disorder is characterized by delayed development both mentally and physically, as well as hypotonia, vision and hearing impairments, and seizures.

      Chromosomal Inversions

      Chromosomal inversions are caused when a fragment of chromosome is inverted end-on-end and re-ligated to the whole chromosome. This is not generally associated with disease phenotypes, but can result in disruptions of genes at the break points, as well as cancer-causing fusion genes.

      Figure 4: Chromosomal Inversion

      Single Gene Disorders

      There are a huge variety of single gene disorders, numbering somewhere in the thousands and as our understanding of genetics improves and our technology improves this number will undoubtedly grow as well. All known inherited genetic disorders are well-characterized in an online data base called, Online Mendelian Inheritance in Man (OMIM). As there are so many distinct genetic diseases, the following section will focus on the underlying mutations and outline a paradigm to exemplify how these single gene defects may cause disease.

      Missense Mutations

      A single base pair substitution resulting in an alternative amino acid in the final protein sequence. Just one example of a disease-causing missense mutation can be seen in the dystrophin gene. The dystrophin gene is an X-linked gene and is the longest known DNA gene in humans, though it does not code for the longest protein. The length of this gene, however, makes it susceptible to mutations. Missense mutations in one particular region of the gene, the Actin-Binding Domain 1 ABD1 region, can result in Becker Muscular Dystrophy or X-linked Cardiomyopathies, due to impairment of the interaction between dystrophin and actin

      Figure 5: Missense Mutation

      Nonsense Mutations

      A single base pair substitution resulting in a premature stop codon within the mRNA sequence, ultimately resulting in a truncated isoform of a particular protein. Such mutations account for nearly one third of human genetic disorders.

      An example of a disease caused by nonsense mutations is Beta-thalassemia, a blood disorder in which not enough globin is produced. An AAG (lys)-->TAG (STOP) mutation results in the production of a truncated protein, thus causing the condition


      Figure 6: Nonsense Mutation

      Frameshift Mutation

      Either an insertion or a deletion that disrupts the reading frame of the gene sequence. This type of mutation is caused by insertions or deletions that are not a multiple of three and most often results in a premature termination of the coding sequence leading to the production of a truncated protein.

      Cystic Fibrosis is one of the most common genetic disorders within the Caucasian population and can be caused by a variety of mutations. One of the most severe types of the disease is caused by frameshift mutations, such as the insertion of a T at point base 3905 in the CFTR (Cystic fibrosis transmembrane conductance regulator) gene. This ultimately causes a premature termination and truncated protein production


      Figure 7: Frameshift Mutation

      Splicing Abnormalities

      A mutation that results in the aberrant splicing of pre-mRNA resulting in abnormal protein production. Most eukaryotic RNA must go through a process known as splicing in which the introns are removed and the exons are ligated together to form a functional mRNA sequence. Skipping an exon results in an aberrant protein without a section of the amino acid chain; such proteins are usually entirely ineffective.

      Some mutations associated with the Breast Cancer (BRCA) 1 and 2 genes are associated with aberrant splicing. For example the Glu1694Ter point mutation in exon 18 results in the disruption of and Exon Splicing Enhancer resulting in the skipping of exon 18 and the fusion of exon 17 and 19 in the mRNA sequence.


      Figure 8: Splicing Abnormalities

      Familial cancer

      Familial Cancer: Although typically thought of as a disease of old age due to a deleterious accumulation of mutations over time, studies have now begun to see cancer as a heritable disease as well, pointing towards the existence of cancer causing alleles. One well-studied example of familial cancer is breast cancer, a form of the most commonly occurring type of carcinoma in women, which has been linked to mutations in BRCA1 and BRCA2 (Lux et al., 2006). BRCA1 and BRCA2 mutations account for 3-8% of all cases of BC and 30-40% of familial cases and these mutations are found in around 80% of families in which there are more than 6 instances of BC. Unlike non-heritable forms of cancer, BRCA1 and BRCA2 mutations tend to cause cancer at a relatively young age. Although little is known about the BRCA gene functions it is known to have autosomal dominant inheritance. BRCA mutations can be detected directly by sequencing individuals with a history of breast cancer in the family, and women that are at risk are advised to get genetic counseling and may need to take more drastic action, such as surgery.

        Genetic counselling

        Curing genetic disorders is still impossible in most cases because of the nature of a genetic disease. However there are certain measures that at risk individuals can take to help manage these conditions.

        • Some genetic diseases, such as metabolic disorders can be treated using drugs or by changes in diet, which avoid certain metabolic products.
        • The psychological aspect of genetic disorders can be far reaching in terms of the implications for extended family members, thus counseling may be advised.
        • The risk of many genetic diseases, such as Down syndrome or Angelman syndrome, increase with Maternal or Paternal age, thus counseling may be advised for identified at risk parents.
        • The chances of having a child with a genetic defect increase significantly if a sibling has been previously identified to have a genetic condition and again counseling is recommended to discuss alternative options.
        • As technology improves and our understanding of how these diseases work grows new treatments, such as gene therapy using the patients' own cells to create induced pluripotent stem cells with a corrected version of the disease-causing allele, are becoming more viable options.

        Further reading

        • GRIFFITHS, A. J. F., MILLER, J. & SUZUKI, D. 2000. Aneuploidy. In: FREEMAN, W. H. (ed.) An Introduction to Genetic Analysis. 7th ed. New York: WH Freeman and Company.

        This textbook provides a good overview of the mechanisms behind certain genetic disorders. 

        • KINGSTON, H. A. 2002. ABC of Clinical Genetics. 3rd ed. London: BMJ Books.

        This source provides a broad overview of many aspects of clinical genetics including the types of genetic screening and genetic counselling. 

          • LUX, M. P., FASCHING, P. A. & BECKMANN, M. W. 2006. Hereditary breast and ovarian cancer: review and future perspectives. Journal of Molecular Medicine-Jmm, 84, 16-28.

          This paper provides a good base for the understanding of familial cancer.


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