Genetic diseases are present in 8 percent of live births. Based on a population study reported in the "American Journal of Human Genetics" in May 1988, about 0.4 percent of the population have a single gene disorder, 0.2 percent have a chromosomal abnormality and 4.6 percent have a multifactorial condition. Genetic disorders are caused by permanent alterations or mutations of the individual's DNA. Mutations can affect the entire genome, chromosomes, genes or regulatory elements of genes.
Inherited Versus Acquired Causes
Hereditary mutations are passed down from a parent to a child, whereas de novo or new gene mutations occur in germ cells or shortly after fertilization. For example, 75 percent of individuals with Marfan syndrome have inherited the condition from an affected parent. The remaining 25 percent of cases are caused by a de novo mutation, according to Harry C. Dietz, M.D., of Johns Hopkins University School of Medicine. Somatic mutations are acquired during a person's lifetime and may cause cancer. Mosaicism results if a mutation arises in a single cell of an embryo, giving rise to some cells with and some without the mutation.
Mechanisms of Genetic Disease
Single gene disorders are caused by mutations of a single gene and follow specific inheritance patterns. Examples are Marfan syndrome, cystic fibrosis and sickle cell anemia. Multifactorial disorders include some of the most common chronic diseases, such as heart disease, diabetes and cancer, and are caused by a combination of genetic and life-style factors. Chromosomal disorders are caused by changes in the number or structure of chromosomes, as seen in Down or Turner syndrome.
Mutations Cause Protein Dysfunction
Genes contain the instructions on how to make proteins. An altered DNA sequence in a gene causes a change in the protein sequence, potentially resulting in loss of function. Proteins carry out many different functions in the body, and mutations in virtually every functional class of proteins can cause genetic disease. For example, phenylketonuria is caused by a mutated metabolic enzyme, sickle cell disease by mutations in the transport protein beta-globin, and cystic fibrosis by alterations in the cell surface protein CFTR.
Causes of Disease Variability
The manifestations or phenotype of an inherited disease can vary substantially, referred to as variable expressivity. Individuals may carry different mutations at the same gene. Alternatively, the same genetic disease may be caused by different mutated genes. In other cases, modifier genes may affect disease severity even among individuals from the same family. Hereditary breast cancer shows reduced penetrance, which means that not all people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetimes. In most cases, variable expressivity and reduced penetrance probably result from a combination of genetic, environmental and lifestyle factors, most of which have not been identified, according to Nature Education.
Epigenetics and Genomic Imprinting
Epigenetics is the study of how environmental factors can cause heritable changes in gene function without changing the DNA sequence. An example is genomic imprinting, in which the disease phenotype depends on which parent passed on the disease gene. For instance, when a certain part of chromosome 15 is missing in the father, the child has Prader-Willi, but when the same part of chromosome 15 is missing in the mother, the child has Angelman syndrome.
References
- PubMed Central: Genetic Disorders in Children and Young Adults: A Population Study
- GeneReviews: Marfan Syndrome
- Human Genome Project Information: Genetic Disease Information
- Nature Education: Same Genetic Mutation, Different Genetic Disease Phenotype
- "British Medical Journal"; Genomic Imprinting as a Cause of Disease; Clayton-Smith J; 2003
