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Multifactorial inheritance disorders


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Related Terms
  • Anencephaly, asthma, atherosclerosis, cancer, CCM, chemical cleavage of mismatch, cleft lip and palate, congenital heart disease, coronary artery disease, diabetes, DNA microarray, DNA sequencing, environmental factors, first degree relatives, HBV, hepatitis B virus, hereditary nonpolyposis colon cancer, HNPCC, Lynch syndrome, myocardial infarction, neural tube defects, oligogenic, pancreas, polygenic, protein translation, protein truncation test, psoriasis, PTT, pyloric stenosis, ribosome, SDS-PAGE, second degree relatives, single nucleotide polymorphism, single strand conformation polymorphism, SNP, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, spina bifida, SSCP, third degree relatives, transcription.

  • Multifactorial inheritance disorders are malformations and diseases which are caused by a combination of genetic and environmental factors. Such disorders are complex in their origin due to the convergence of a number of influences at times including multiple genes and external variables (nongenetic e.g., diet, lifestyle, exposure to chemicals, etc). Multifactorial inheritance disorders represent the single largest class of genetic disorders affecting the human population and include some of the most common health problems such as cancer, heart disease, and diabetes, as well as other more rare diseases.
  • Genetic factors: Multifactorial inheritance of diseases may involve the presence of mutations in a small number of genes (oligogenic) or many genes (polygenic). The pattern of inheritance of these faulty genes (mutations) is complex and may be predicted only to a certain extent. Some of the mutations may be present since birth (inherited) while others may arise from the influence of various environmental factors (e.g., exposure to chemicals, radiation, etc.) during an individual's life time.
  • Multifactorial inheritance disorders tend to run in families. Thus, a person's family health history may be an indication that a faulty gene (or set of genes) is running in the family. For multifactorial disorders, there is an increased risk of developing the condition among first, second, and third degree relatives of the affected individual. First degree relatives are parents, children, brothers, and sisters. Second degree relatives are grandparents, aunts and uncles, nieces and nephews, and grandchildren. Third degree relatives are first cousins. For most of the multifactorial inheritance disorders, there is a baseline risk of approximately 2-5% for first degree relatives, about half of that percentage for second degree, and about a quarter for third degree relatives. Other factors such as severity, relative age at which afflicted, and sexual preference of the disorder may alter these probabilities in a given individual.
  • Environmental factors: Other factors involved in the development of multifactorial inheritance disorders may be internal such as aging or external such as diet, lifestyle, exposure to chemical, toxins, radiation, drugs, and viruses.
  • Interplay of genetic and environmental factors: While an individual's genetic make-up may make him or her more likely to develop a condition, it is possible that such conditions will never manifest if the appropriate environmental factors are not present.

  • Multifactorial inheritance disorders refer to the pattern of inheritance of common health problems and rarer conditions caused by a combination of both genetic and environmental factors. The inheritance of the genetic component (mutations) predisposes a person to developing the disease or condition. A mutation is a permanent variation in the nucleic acid sequence of a gene.
  • Most of the multifactorial inheritance disorders are due to point mutations. A point mutation involves a mistake at only a single nucleotide base pair and may consist of the loss of a nucleotide base, a substitution of one nucleotide base for another, or the insertion of an additional nucleotide base. Several laboratory analysis techniques are available to detect these mutations and some of the lab techniques are described here.
  • Polymerase chain reaction (PCR): The amount of DNA extracted from the sample of interest (e.g. blood) may be inadequate for several genetic analysis techniques. This may be overcome by using PCR, an efficient and sensitive laboratory technique which amplifies a specific sequence of DNA (produces additional sample DNA by replication). The amplification process is conducted under controlled conditions in the presence of sequence specific oligonucleotide primers and the DNA polymerase enzyme (a compound which aids certain chemical reactions). An oligonucleotide primer is a sequence of nucleotides, usually of 20-50 bases, that is complementary to a target DNA sequence and serves as a starting point for DNA replication. DNA polymerase is an enzyme that creates new DNA strands using preexisting DNA strands as a template. A fluorescent marker is often also incorporated into the PCR product during the amplification process. This assists in visualizing the PCR products at a later stage.
  • Single strand conformation polymorphism(SSCP): SSCP is a process of electrophoretic separation of single stranded nucleic acids based on the charge difference in a single base pair. Electrophoresis is a technique in which charged particles, such as nucleic acids, are moved under the influence of an applied electric field in a gelatinous medium. In SSCP, a polyacrylamide gel is used for electrophoresis. Polyacrylamide is a large compound that is formed from several small molecules of the chemical acrylamide.
  • The mobility of single stranded DNA is dependent on the length of the fragment and its conformation (structural arrangement). Since the conformation is determined by interactions between nitrogenous bases, any changes in the DNA sequence will alter the conformation. Sequences of different conformation will migrate at different rates and get separated on a gel electrophoresis. SSCP takes advantage of this feature of single stranded DNA to detect sequence variations due to mutations.
  • Following electrophoresis, the separated DNA strands are visualized with the help of autoradiography of the dried gel or silver staining of wet gel. Autoradiography is a technique wherein PCR products are labeled with radioactive molecules, which can then be visualized on film.
  • Chemical cleavage of mismatch (CCM): The cytosine and thymines in single stranded DNA are chemically modified more easily by hydroxylamine and osmium tetroxide (chemical compounds), respectively, than in double stranded DNA. This key observation can be applied to find mutations using heteroduplex DNA (formed by joining complementary or partially complementary single stranded DNA from two different sources). In CCM, the heteroduplex sequence is formed by combining test DNA and radiolabelled normal DNA. The chemically modified bases (cytosine and thymine) at the point of mismatch base pairs are cleaved (cut) by piperidine, a chemical substance. The resulting sequence is analyzed via denaturing polyacrylamide gel electrophoresis and probed with targeted complementary labeled with fluorescent markers for easy detection.
  • CCM analysis has the advantage of detecting nearly 100% of the mismatches (mutations) and can analyze longer DNA fragments than some other methods. CCM also provides positional information of the mutation site.
  • Protein truncation test (PTT): PTT is a laboratory technique that screens for gene mutations that cause premature termination of protein translation leading to the production of incomplete and nonfunctional proteins. Such mutations underlie several diseases. Protein translation is the process by which the genetic code carried by messenger RNA (mRNA) directs the assembly of proteins from amino acids. This process is also known as RNA translation. mRNA is a form of RNA (ribonucleic acid) that carries information from DNA to the ribosome, the site of protein synthesis.
  • PTT involves the amplification of the target gene by PCR followed by in vitro transcription and translation to synthesize the corresponding protein. Transcription is a process by which mRNA is synthesized from a DNA template resulting in the transfer of genetic information from the DNA molecule to mRNA. The mRNA molecule is then translated to a corresponding protein. The translated protein products are analyzed by sodium docecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by autoradiography. SDS-PAGE is a protein electrophoresis method that separates proteins based on their mobility, molecular weight, size, and structure. These proteins are labeled with radioactive molecules, which may be detected by autoradiography. The advantages of PTT include the ability to determine the site of a mutation, and a high sensitivity and specificity.
  • DNA sequencing: DNA sequencing is a process in which the precise sequence of nucleotides in a sample of DNA is determined. This method can be used as a means for detecting single nucleotide polymorphisms (SNP). SNPs are DNA sequence variations that occur when only a single nucleotide in the genome sequence is altered. SNPs are associated with the development of several diseases.
  • DNA microarrays: DNA microarrays or DNA chips consist of miniaturized chemical reaction areas/spots affixed to a surface in a regular pattern for the purpose of rapid, parallel genetic analysis. They are used to test DNA/RNA fragments by fixing a target sequence along with a fluorescent marker on the surface of the chip and binding them with a probed sample. A probe is a complementary sequence to a particular target (e.g., DNA). When the specific target gets hybridized with the probe, the fluorescent marker emits colored light, which is scanned and then analyzed by a computer for identification of the target sequence. The advantage of microarray technology is that multiple markers or thousands of nucleic acid sequences may be detected and identified using a single array.

  • Multifactorial inheritance disorders are complex in their origin due to the convergence of a number of influences at times including multiple genes and external variables (nongenetic e.g., diet, lifestyle, exposure to chemicals, etc). Presently, many studies are underway to identify these factors. The identification of the principles involved may allow for the prevention or treatment of these diseases and disorders.
  • Heart diseases: Some common heart conditions, such as heart attacks (myocardial infarction/MI) and diseases of the blood vessels supplying the heart (coronary artery disease), are associated with multiple genetic and environmental factors. Recently, a gene, 9p21, was identified as being associated with MI. Scientists believe that this discovery may aid in the evaluation of the mechanisms responsible for MI and the development of preventative measures.
  • Lynch syndrome: Lynch syndrome, also called hereditary nonpolyposis colon cancer (HNPCC), is a hereditary cancer syndrome that carries a high risk of developing colon cancer as well as an increased susceptibility to other cancers such as those of the uterus, ovary, stomach, brain, and skin. A new mutation (A636P in the MSH2 gene) was found to be associated with HNPCC, especially in Ashkenazi Jewish population groups. Early detection of such mutations that are more common in certain ethnic populations may aid in preventing the development of associated cancers as well as improve survival rate.
  • Cystic fibrosis (CF): Cystic fibrosis is an inherited disorder affecting the body's ability to move salt and water in and out of the cells and results in thick secretions of mucus. CF affects the lungs, digestive system, sweat glands, as well as male fertility. Several genetic as well as environmental factors affect the severity and progress of CF. Recent research studies have identified two genes that may influence the severity of CF, which may lead to newer treatment options to control the progress and severity of the disease.

  • Multifactorial inheritance disorders involve the interaction of genetic and environmental factors resulting in a wide spectrum of outcomes and diseases.
  • Congenital disorders: A congenital disorder is a condition that is present since birth and is a result of genetic abnormalities such as inherited mutations (passed on from one or both parents) or spontaneous mutations (mutations occurring during the development of the unborn baby) and several other environmental factors affecting the fetus during pregnancy (exposure to chemicals, radiation, etc). Examples of several congenital birth disorders are described below.
  • Neural tube defects: Neural tube defects are caused by the abnormal development of the brain and spinal cord during growth in the womb, often leading to death or serious disability, two examples of which include spina bifida and anencephaly. Spina bifida is the abnormal formation of the spinal column where the usual protective bone and tissue coverings are absent or incomplete, thereby resulting in nerve disorders. Anencephaly is a type of neural tube defect characterized by complete or partial absence of the skull and brain, which is most often fatal at birth or soon thereafter. A lack of folate in the mother's diet has been identified as a major risk factor for the development of a neural tube defect. Supplementation of a woman's diet with folate during pre- and early pregnancy can significantly reduce the chance of a baby born with this condition.
  • Cleft lip and palate: A cleft lip or palate is a congenital deformity of the face due to the incomplete fusion of the upper lip or roof of the mouth during development in the womb. This results in frequent nose and ear infections, abnormal development of teeth, and speech impairment. The development of these conditions is associated with a faulty gene as well as environmental factors such as maternal diet, vitamin A intake during pregnancy, exposure to pesticides, drugs used for seizures, alcohol, cigarette use, toxic chemicals, lead, and drug abuse (cocaine, crack cocaine, heroin). Proper precautions and the avoidance of these environmental factors during pregnancy may reduce the chances of the unborn baby developing these conditions.
  • Congenital heart disease: Congenital heart diseases are the result of the defective formation of the heart or of the major vessels of the heart. Along with genetic influences, other factors associated with congenital heart diseases include, diabetes, the use of alcohol or drugs of abuse (cocaine, heroine), exposure to industrial chemicals, toxins, and radiation, and viral infection (e.g., German measles) during pregnancy. Suitable control of diabetes and avoiding exposure to environmental factors may prevent the development of these conditions.
  • Pyloric stenosis: Pyloric stenosis is the narrowing of the passage between the stomach and the small intestine due to the thickening of the intestinal muscle wall leading to frequent vomiting in infants. This condition has been associated with genetic factors and is more common in girls than boys. The detection of relevant mutations may aid in preventing the development of this condition.
  • Other disorders: Other disorders that result from multifactorial inheritance may develop over the course of a lifetime. Some of these include cancer, diabetes, asthma, heart diseases, and psoriasis.
  • Cancer: Generally, the development of cancer is not associated with one particular faulty gene or mutations, but is believed to be caused by several factors. Some of the factors responsible include exposure to ultraviolet light or or other forms of radiation (e.g. X-rays), infection with certain viruses (for example, hepatitis B virus in the development of liver cancer), and changes in the replication of DNA associated with the aging process. Some cancers which have been identified as having multifactorial inheritance include cancers of the breast, intestines, ovaries, prostate, and skin.
  • Diabetes: Diabetes is a chronic condition characterized by abnormally high sugar levels in the blood resulting in several serious complications. This may be the result of insufficient or ineffective production of insulin, a hormone from the pancreas involved in the regulation of blood sugar levels. This multifactorial inheritance disorder involves several triggering factors such as certain infections involving the pancreas, drugs that are toxic to the pancreas (e.g., steroids, dilantin, alloxan, streptozocin, and thiazide diuretics), aging, obesity, and physical inactivity. The pancreas is a gland that produces enzymes which aid in the digestion of food as well as hormones (insulin, glucagons), which are involved in several critical biochemical reactions (such as metabolism) in the body. Individuals with diabetes in their family health history may prevent or delay the development of the disease by exercising regularly, controlling obesity, avoiding certain drugs, and monitoring blood sugar levels.
  • Asthma: Asthma is a chronic disease of the airways and lungs characterized by recurrent attacks of difficulty in breathing, tightness in the chest, and coughing. This condition is usually triggered by infections, stress, and cold air in addition to various types of allergens such as pollens, dust mites, indoor molds, certain chemicals and pollutants.
  • Heart diseases: Heart disease, such as the blockage of blood vessels of the heart by fat plaques (atherosclerosis), has been associated with multiple factors such as high blood pressure, cigarette smoking, high fat levels (cholesterol), physical inactivity, obesity, diabetes, and aging. Lifestyle changes, weight loss, smoking cessation, blood pressure control, and cholesterol reduction along with multiple lines of disease management such as screening (regular blood check ups), monitoring, and drug treatment may prevent or reduce these heart ailments.
  • Psoriasis: Psoriasis is a chronic skin disorder characterized by reddish small patches covered by silvery-white scabs of dead skin. Apart from genetic influences, other factors that increase the risk of developing or worsening psoriasis include stress, skin irritants, exposure to cold temperatures, injury, illness, infection, and certain medications. Psoriasis recurrence can be avoided or minimized by maintaining a healthy lifestyle, balanced diet, reducing stress, avoiding smoking and alcohol and exposure to cold air, sunburn, or skin irritants.

  • Owing to the complexity of the origin of multifactorial disorders and current limitations in human genetic manipulation, prevention, identification of risk factors, and treatment of these diseases are often difficult or infeasible. A great deal of research remains to be done.


Future research
  • Further study is required to identify the genetic and environmental factors involved in multifactorial inheritance disorders. Continued research will assist in the future prevention of these disorders and the discovery of new treatment methods and drugs.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (

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