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Genes and Disease
Birth Defects: Causes and Statistics
By: Ingrid Lobo, Ph.D. (Write Science Right) & Kira Zhaurova, M.S. (Nature Education) © 2008 Nature Education Citation: Lobo, I. & Zhaurova, K. (2008) Birth defects: causes and statistics. Nature Education 1(1) Every year, about 7.9 million infants (6% of worldwide births) are born with serious birth defects. With the causes of over 50% of birth defects unknown, how do we diagnose and prevent them?
1Introduction2Chromosomal Abnormalities 3Single-Gene Defects 4Multifactorial Influences 5Prenatal Environment 6Limiting the Frequency of Birth Defects 7References and Recommended Reading
Every year, an estimated 7.9 million infants (6% of worldwide births) are born with serious birth defects. Although some congenital defects can be controlled and treated, an estimated 3.2 million of these children are disabled for life. Moreover, birth defects are the leading cause of infant mortality in the United States. But where do these defects come from? Although some birth defects are inherited, others are a product of harmful environmental factors known as teratogens, and still others are multifactorial, resulting from a complex interaction of genetic and environmental influences. However, in approximately half of all birth defect cases, the causes are unknown (Christianson et al., 2006).
Genetic causes of birth defects fall into three general categories: chromosomal abnormalities, single-gene defects, and multifactorial influences. Prenatal environment can play a major role in the development of defects in all three categories, especially those linked to multifactorial causes.
Chromosomal Abnormalities
Figure 1
A person’s genetic makeup is determined at conception. It is then, during the nuclear events of fertilization, that the genetic causes of many birth defects are determined. For example, chromosomal abnormalities, or large-scale duplications or deletions of chromosomal segments or entire chromosomes, can become apparent during this period. Many zygotes that carry such abnormalities do not develop into embryos, but among those that are carried to term, trisomy 21 (Down syndrome), trisomy 13 (Patau syndrome), and trisomy 18 (Edwards syndrome) are the most frequent birth defects. Embryos with these three conditions will develop severe disabilities regardless of the environmental factors associated with the pregnancy.
Unlike Down syndrome patients, who usually have a relatively long life span, children with Patau and Edwards syndromes often die soon after birth (March of Dimes, 2006). Individuals diagnosed with Patau syndrome suffer from neurological problems, mental and motor deficiencies, and polydactyly (Figure 1), as well as eye, heart, and spine defects (Patau et al., 1960). Those born with Edwards syndrome suffer mental retardation, breathing and feeding difficulties, delayed growth, and malformations of the kidneys, intestines, and heart (Edwards et al., 1960; Van Dyke & Allen, 1990). Thankfully, both of these devastating syndromes are rare.
Figure 2: Primary Down syndrome is caused by the presence of three copies of chromosome 21.
(a) A child who has Down syndrome. (b) Idiogram of a person who has primary Down syndrome.
Copyright National Institutes of Health.Down syndrome, on the other hand, is by far the most common chromosomal abnormality, affecting 1 in 800 babies. The risk of having a child with this condition increases with maternal age, rising exponentially after a woman reaches age 35. For instance, in young mothers, the frequency of trisomy 21 is about 1 in 2,000, but this frequency rises to 1 in 100 when a woman is 40 and to 1 in 12 when she is 50 years old (Figure 2). People who have Down syndrome suffer from moderate to severe mental retardation and a wide variety of health problems, including heart defects, leukemia, and Alzheimer’s disease. The severity of these defects varies widely, however, and the majority of people with Down syndrome live semi-independent lives, with an average life expectancy of 56 in the United States (Eyman et al., 1991). Aneuploidies such as Down syndrome can generally be detected by the presence of additional chromosomes or chromosome translocations in a karyotype or FISH profile.
Single-Gene Defects
As opposed to chromosomal abnormalities, single-gene defects are usually inherited. For example, phenylketonuria (PKU) is a heritable condition caused by the malfunction of the PAH enzyme that breaks down the amino acid phenylalanine. Because this enzyme is coded for by the PAH gene on chromosome 12, PKU falls under the category of single-gene defects.
Interestingly, many single-gene defects are variably prevalent among different racial and ethnic groups. For instance, sickle-cell anemia (a disorder of the hemoglobin) is most common among people of African, Indian, and Mediterranean descent, whereas Tay-Sachs and Sandhoff diseases (both of which affect the nervous system) occur most frequently among Ashkenazi Jews. Tay-Sachs and Sandhoff diseases are both caused by a lack of the protein hexosaminidase, which controls the levels of fatty buildup in the brain. Specifically, autosomal recessive mutations in the HEXA gene on chromosome 15 cause various forms of Tay-Sachs, while the presence of a mutated HEXB gene on chromosome 5 causes Sandhoff. These disorders mainly affect young children, who typically die during the first few years of life from progressive neural degeneration.
Multifactorial Influences
In certain cases, a combination of genetic mutations and teratogens leads to the development of multifactorial birth defects. Although the exact causes of most multifactorial disorders are poorly understood, doctors can often identify common trends among similar conditions. Folate deficiency, for example, appears to play a role in various malformations of the neural tube, but the cumulative causes of such malformations and their relative contribution are rather complex. Neural tube defects have also been linked to trisomy 18, numerous mutations in the genes necessary for the development of the nervous system, and exposure to certain epilepsy drugs. Of the different forms of neural tube defects, a condition known as anencephaly is arguably the most severe. Anencephalic babies lack most of their brain and are often stillborn or die soon after birth. Spina bifida is a (relatively) less severe defect of the neural tube characterized by a series of deformities that are associated with incomplete enclosure of the spinal cord by the twenty-eighth day of development. The exposed spinal cord and the surrounding tissues are usually sealed surgically soon after birth, but the neurological effects, including partial paralysis and loss of bladder control, often last a lifetime.
Of course, not all birth defects have such profound consequences. Consider, for example, cleft lip and palate; this is a multifactorial birth defect that, if left uncorrected, can create difficulties with eating and speech. Children born with cleft lip usually undergo corrective surgery at an early age. Although genes definitely play a role in the development of this defect, environmental factors, including smoking and the use of antiseizure drugs, have been associated with a greater risk of bearing a child with cleft lip and/or palate (Ericson et al., 1979; Knight & Rhind, 1975).
Prenatal Environment
It is difficult to overemphasize the importance of prenatal environment to a developing fetus. Indeed, a pregnant mother’s health, diet, and level of exposure to toxins and environmental pollutants all have a direct effect on fetal development. For example, one of the most highly publicized cases of widespread toxin exposure associated with a pronounced increase in birth defects involves the use of Agent Orange, an herbicide that contains the poison dioxin, by the U.S. Army during the Vietnam War. Since the end of that conflict, the frequency of birth defects in those areas exposed to dioxin has risen to almost three times the norm. Dioxin, a product of industrial processes, disrupts the function of nuclear receptors and interferes with cell signaling. Moreover, dioxin is fat soluble and takes a long time to degrade, which means it can build up over time in soil, in water, and in the fatty tissue of animals that humans consume.
Other environmental toxins that might harm a fetus are taken voluntarily, such as drugs, alcohol, and cigarettes. For instance, excessive maternal alcohol consumption often causes fetal alcohol syndrome, which is characterized by defects of major organs, abnormal facial features, and mental retardation. Similarly, smoking during pregnancy has been linked to an increased risk of stillbirths, low birth weights, and cleft lip and/or palate (Ericson et al., 1979; Knight & Rhind, 1975). Although studies have not demonstrated a strong correlative link between a high incidence of birth defects and consumption of moderate amounts of alcohol and tobacco, doctors strongly recommend complete abstinence from smoking and drinking during pregnancy.
Yet another major factor linked to abnormal prenatal development is poor diet during pregnancy. Certain foods, such as seafood with high mercury content, should be consumed in moderation, whereas other high-vitamin foods are encouraged. Dietary supplements, such as folate (vitamin B9) and iodine taken before and during the early stages of pregnancy, can aid in development of the neural tube. It is important to understand, however, that good diet and a healthy lifestyle do not ensure a healthy child, although they do play a protective role in certain individuals.
Limiting the Frequency of Birth Defects
Although some congenital defects cannot be prevented, improvements in health care, nutrition, and education can reduce their frequency and phenotypic severity. The increasing use of prenatal genetic screens and preimplantation genetic diagnosis (PGD) is also helping limit the frequency and the severity of birth defects. These advances are a great tool, but they also have a surprising downside. Specifically, deleterious genetic mutations that have a recessive pattern of inheritance will remain in the population if the parents seeking PGD are allowed to select only healthy embryos to be carried to term. The current use of this technique, however, is limited to the select few who can afford it, so this phenomenon will not have a noticeable impact on the overall population for quite some time.
References and Recommended Reading
Christianson, A., et al. March of Dimes Global Report of Birth Defects: The Hidden Toll of Dying and Disabled Children. (2006) (accessed August 28, 2008).
Edwards, J. H., et al. A new trisomic syndrome. Lancet 1, 787–790 (1960)
Ericson, A., et al. Cigarette smoking as an etiologic factor in cleft lip and palate. American Journal of Obstetrics and Gynecology 135, 348–351 (1979)
Eyman, R. K., et al. Life expectancy of persons with Down syndrome. American Journal of Mental Retardation 95, 603–612 (1991)
Knight, A. H., & Rhind, E. G. Epilepsy and pregnancy: A study of 153 pregnancies in 59 patients. Epilepsia 16, 99–110 (1979)
Korkko, J., et al. Widely distributed mutations in the COL2A1 gene produce achondrogenesis type II/hypochondrogenesis. American Journal of Medical Genetics 92, 95–100 (2000)
March of Dimes. Chromosomal abnormalities. (2006) (accessed Aug. 28, 2008)
Patau, K., et al. Multiple congenital anomaly caused by an extra autosome. Lancet 1, 790–793 (1960)
Van Dyke, D. C., & Allen, M. Clinical management considerations in long-term survivors with trisomy 18. Pediatrics 85, 753–759 (1990).
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