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.
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.
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:
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.
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:
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 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.
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.
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
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
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
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.
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.
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.
This textbook provides a good overview of the mechanisms behind certain genetic disorders.
This source provides a broad overview of many aspects of clinical genetics including the types of genetic screening and genetic counselling.
This paper provides a good base for the understanding of familial cancer.
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