Cellular and Molecular Genetics

Humans have 46 chromosomes arranged in 23 pairs. Twenty-two pairs are autosomes (the same in males and females) and are homologous because their deoxyribonucleic acid (DNA) is very similar. The remaining pair is the sex chromosomes, with two X chromosomes for females and one X and one Y chromosome for males. They are not homologous. Each chromosome has a long arm (q) and a short arm (p) and is numbered according to its distinct appearance from the largest to the smallest. The gametes (egg and sperm) have half the chromosome complement from the parents (23). During meiosis (formation of the haploid with 23 chromosomes from the egg or sperm), the original paired chromosomes from paternal and maternal sides cross over and exchange genetic material, resulting in genetic diversity. Fusion at fertilization restores the 46-chromosome (23-pair) complement, with one of each chromosome pair from each gamete. As a result of genetic variation, a gene may differ from one individual to another in its DNA sequence. These differences in sequencing are called alleles. If the two alleles at any given location of a pair of homologous chromosomes are identical, the locus is homozygous. If the two alleles are different, the locus is heterozygous.

Genes, which carry the information about inherited characteristics from parent to child, are arranged linearly on the chromosomes, each with a specific locus. Thousands of genes are located on each chromosome. Not all genes are active at once; certain mechanisms activate them at various developmental points. In homozygous loci, the genes from a pair of chromosomes carry similar instructions regarding the trait of interest; in heterozygous loci, the instructions are different for each gene. In the latter case, one gene may be dominant, with its instructions manifested in the phenotype, as in Huntington disease, or the genes can be co-dominant, as in the case of individuals with blood type AB.

The human genome contains approximately 25,000 to 30,000 genes. Genes are composed of DNA. Each DNA molecule includes pairs of nitrogenous bases—adenine, cytosine, guanine, and thymine (labeled A, C, G, T)—wound around a histone protein core in a double helix. There are more than 3 billion base pairs in the human genome for an individual. From the four nitrogenous bases, 64 triple-base combination sequences (codons) of A, C, G, and U (uracil is substituted for thymine in the messenger ribonucleic acid [mRNA] at this point) such as GUA, UUG, and CGG are possible (Jorde et al, 2006). Three codons signal the end of a gene (stop codons) and 61 define the 20 amino acids. Thus each amino acid may be specified by more than one codon. The sequence of the amino acids directs the synthesis of proteins in the cell cytoplasm (Fig. 40-1). Telomeres at the tips of each chromosome protect the chromosome from breaking down. These deteriorate with age.

FIGURE 40-1 Genetic diagram.

(From the U.S. Department of Energy, Washington, DC.)

Now that the genome has been defined, geneticists are working to understand the functions of individual genes. In the case of conditions such as Down syndrome, which has been identified as a chromosomal disorder, understanding of the functions of the many genes on chromosome 21 may help clarify how some of the various phenotypes of the condition are controlled and, ultimately, might be able to provide therapies for some of the problems such as leukemia or cataracts, which emerge later in life (Patterson, 2009). Similar progress may offer new perspectives and options for other genetic conditions.

Epigenetics

Epigenetics is defined as the study of heritable changes in genome function that occur without a change in DNA sequence. This includes the study of how patterns of gene expression are passed from one cell to its descendants, how gene expression changes during the differentiation of one cell type into another, and how environmental factors can change the way genes are expressed (Bagot and Meaney, 2010; Epigenome Network of Excellence, 2009).

In the nucleus of nondividing cells, genomic DNA is highly folded and compacted with histone and nonhistone proteins into a polymer called chromatin (DNA does not normally look like the nice double helix strands seen in many diagrams). The epigenome is the group of proteins around the genome that tells genes when to turn on and off. An analogy could be made to computers: the genome is the computer’s hardware; the epigenome is the software that tells it what to do.

There are several recognized mechanisms for epigenetic inheritance, not all of which are discussed here. DNA methylation is the most studied. When DNA material is methylated, the gene is turned off. Methylation is involved with cellular differentiation in utero but the same process occurs throughout life. A second mechanism for epigenetic modifications to DNA functioning involves the way DNA attaches to histones. It is called chromatin modification. DNA is wrapped around a series of proteins called histones. If these proteins are tightly joined to the DNA, the DNA is hidden from exposure and cannot express itself. If the histone wrap is loosened, often through acetylation, enzymes, or certain forms of RNA, then the gene may be expressed (Fig. 40-2). In general, when chromatin is tightly folded, gene expression is restricted while more open chromatin allows gene expression. In other words, gene regulation varies depending on the type of histone linkage. Certain RNA proteins are also transmitted with reproduction and are involved with epigenetic inheritance (Jablonka and Raz, 2009).

FIGURE 40-2 Epigenetic diagram. Chromatin modification: deoxyribonucleic acid (DNA) is wrapped around a series of proteins called histones. If these proteins are tightly joined to the DNA, the DNA is hidden from exposure and cannot express itself. If the histone wrap is loosened, often through acetylation, enzymes, or certain forms of ribonucleic acid (RNA), then the gene may be expressed. Methyl groups attached to the DNA also affect gene expression.

(From The National Institutes of Health Common Fund, Division of Program Coordination, Planning, and Strategic Initiatives, National Institutes of Health.)

Genes are regulated when the histone allows signals to reach the gene. These signals may come from one cell touching another as in neurologic growth, when a cell releases factors that are picked up by neighboring cells as happens at cell synapses, through hormones that are broadcast to the whole body (cells that are tuned in will respond), or by signals coming from environmental factors. Some of these environmental factors reach cells directly and others indirectly (mediated, for example, by stress), and cause responses that are transmitted across body systems. Signals are passed to a gene regulatory protein that attaches to a specific sequence of DNA molecules. Once the protein is attached to the DNA molecule, the gene turns off. The epigenetic tags allow the cell to “remember” what to do over time and over many replications. Some tags are passed on to later generations. Certain enzymes can be recruited to remove epigenetic tags, the histones, or both, and cells are stripped of many of their tags with reproduction of sperm and egg. The tags that remain to be passed along to the next generation are referred to as imprinted. More than 80 genes can be imprinted (Weinhold, 2006). Chemical exposures can cause methylation of DNA and transmission to future generations—altering the function of cells but not the DNA itself (Jablonka and Raz, 2009).

An individual normally has one copy of an imprinted gene (it came along on the sperm or egg chromosome). Improper imprinting can cause an individual to have two copies of active, imprinted genes, or two inactive copies. Prader-Willi and Angelman syndromes come from the same imprinting area on chromosome 15. If the individual is missing gene activity that normally comes from the father or there are two active copies from the mother, Prader-Willi will result; if the imprinting defect results in failed gene activity that normally comes from the mother, Angelman will result.

The study of epigenetics is revolutionizing our understanding of many conditions (e.g., autism spectrum disorders, which are known to have both genetic and environmental etiologic factors; epigenetics may explain how the various factors interrelate to cause these disorders). Rett, fragile X, Prader-Willi, Angelman, and all demonstrate dysregulation of normal epigenetic mechanisms (Grafodatskaya et al, 2010). It is thought that many cancers may result from epigenetic control of gene expression rather than defective genes themselves, or may be caused by a mixture of the two factors. Cancer epigenetics may involve disruption of the stem cells, sometimes when they have replicated many times over years and no longer seem to be able to function properly (Feinberg, 2007; NOVA, 2007). Some of the endocrine disruptor toxins in the environment cause epigenetic trangenerational effects, meaning that the germline is affected and this change is transmitted to future generations (Guerrero-Bosagna and Skinner, 2009).

Epigenetic research has contributed to the development of new epigenetic therapy in which instructions to cells are changed, allowing them to reactivate in a normal way after having been silenced by cancer cells (Issa, 2010).

Ethical Issues

Since 1990, largely due to the work of the Human Genome Project (HGP), the technical capability to diagnose a hereditary condition for those who are presymptomatic or currently symptomatic, to identify those who are carriers of a genetic condition, and to determine susceptibility to a genetic condition has increased dramatically. However, the availability of this technology raises significant ethical issues. The HGP was concerned about these issues from the beginning and has a branch specifically devoted to oversight of these concerns (the Ethical, Legal, and Social Initiative [ELSI]). Issues involve the rights to privacy and confidentiality, rights to know and right not to know, and whether there is a duty to warn third parties (Ross, 2008).

Maintenance of confidentiality is a challenge. The presence of genetic information in the medical record, health insurance diagnostic database, or in DNA databases such as newborn screening specimens mandates policies to maintain the confidentiality and integrity of these records. The Health Insurance Portability and Accountability Act (HIPAA) of 1996 specifies the duty for clinicians not to disclose medical information without the signed consent of the patient or the child’s parents (U.S. Department of Health and Human Services [USDHHS], 2010).

As genetics tests are conducted, it is also possible to discover unanticipated information, for instance, data regarding the parentage of the child being tested. Situations such as misattribution of paternity and children being raised by nonbiologic parents may be discovered. There is disagreement about whether these findings should be routinely disclosed. Prior agreement in the consent process can assist in the decision about whether to disclose this information.

The ability to screen for a large number of genetic disorders via the tandem mass spectrometry newborn screening process has increased the number and types of conditions that can be included. Because these programs are organized by and paid for through state governments, there is some variability in required tests between states. Congenital hypothyroidism, sickle cell disease, sickle-C, sickle-beta thalassemia, classical galactosemia, and phenylketonuria are mandated in newborn screening programs in all U.S. states. An additional sixty-one conditions are included in individual state newborn screening programs (National Newborn Screening & Genetics Resource Center, 2006). Three principals have been suggested by the Institute of Medicine (IOM) to be used in making decisions about the introduction or continuation of tests:

Predictive genetic testing is another area for ethical consideration. The availability of presymptomatic testing for conditions that may not become apparent until adulthood, such as Huntington disease and breast cancer, has raised another set of questions. Should children and adolescents be tested for such conditions? Arguments related to the issue of predictive genetic testing generally fall into four categories: potential provision of good news (i.e., the child is found not to have the genetic markers); unbearability of knowing (if the child has the markers); identity and adjustment (if the child has the markers); and parental anxiety and uncertainty (Borry et al, 2008). Generally it is recommended that genetic testing for late-onset conditions be deferred until adulthood when individuals, rather than their parents, can make the decision, unless there is evidence that early diagnosis can result in treatment strategies that will alter the progression of the disease (American Academy of Pediatrics [AAP] Committee on Bioethics, 2001). If predictive testing is considered, parents should have the right to decide whether to have their child tested and to receive counseling regarding the disease including diagnostic workup, ongoing research, associations, resources available, and clinical trials in progress or registering for trials in the future (Trott and Matalon, 2009).

Biobanks including many thousands of genetic samples from children are being collected to study genetic-environmental influences on disease. Should participants have access to the data? To what extent do those children have a right to privacy?

Families also face issues of disclosure of genetic information within their own families. What information should be disclosed? When? To whom? Disclosure is influenced by the perceived risks and benefits of doing so, the sense of closeness among the family members, concerns about reactions from those receiving the information, their sense of personal risk, and readiness to disclose information (Gallo et al, 2009). Disclosure to children is also an issue many families face. Families worry about psychological harm, the child’s lack of autonomy in deciding whether to be tested, and concerns that the child won’t understand the information given. The child’s developmental age is a key factor. For preschoolers there may only be a dawning awareness of symptoms, treatments, or physical differences. Parents will want to choose whether they disclose information, choose to wait, or want a health care professional to begin the dialogue with the child about the genetic condition of interest. School-age children may question parents about the implications of a particular diagnosis or become aware of reproductive risks. Adolescents are aware of conditions and want information in more depth. They may have very specific questions about reproductive risks. Health care professionals need to assist patients and families to disclose information as is appropriate, Questions such as, “Have you ever talked with your child about his condition?” may start a helpful discussion.

These are only a few of the ethical issues under discussion. Primary care providers must be part of the ongoing debate and be aware of the issues, policies, and laws as they work with families who are trying to make decisions.

Genetics Testing in the Future

Genetics testing will become more complex in the future and primary care providers will need to be knowledgeable in all these areas. First, universal screening can be expected to expand as therapies evolve, making it possible to prevent or modify significant pathology in affected individuals. Second, screening will be expanded for diagnosis of common conditions. For example, more than 50% of sensorineural hearing loss is due to genetic conditions. When infants are identified through newborn hearing screening, they will then undergo genetic testing to ascertain possible causes. Some autism and obesity cases are now connected to certain genetic profiles in children. Hypertension, diabetes, heart disease, and cancer are adult conditions in which greater genetic information will affect identification of and management of those at risk (Lose, 2008). Third, additional screening will be done to identify those at risk for future problems, such as the breast cancer and Parkinson disease tests that are already available. Finally, pharmacogenetics will involve genetic testing to ascertain drug responses in individuals with different genetic profiles (Cheng et al, 2008). Primary care providers will serve as translators for patients needing and receiving genetic information over their lifetime (Lose, 2008).

Causes of Genetic Variation and Genetic Disorders

Mutations occur when genetic material is permanently changed through alteration, deletion, duplication, or misplacement. Sometimes mutations arise spontaneously, but once the change occurs in the germ cells, it is transmitted to future generations. Mutations are defined as characteristics being present in less than 1% of the population. A change in greater than 1% is called a polymorphism. Mutations and polymorphisms may be benign, beneficial, or detrimental.

Genetic disorders are classified as chromosomal disorders, in which the entire chromosome or large segments of it are duplicated or missing; single-gene disorders, in which single genes are altered; and multifactorial problems, in which multiple genetic and environmental factors interact. Although the majority of genetic conditions fit in these categories, other patterns of inheritance, such as mitochondrial inheritance may lead to genetic disorders. Conditions that result from mutation in mitochondrial DNA are inherited through the maternal line. Some epigenetic changes can also be inherited, at least to the next generation and perhaps more. This is an emerging area of research.

Chromosomal Disorders

Chromosomal disorders are present in 0.6% to 0.9% of the general population (Jorde et al, 2006). There is also a high frequency of chromosomal disorders in spontaneous abortions and stillbirths. Such disorders are commonly linked to alterations in cognitive development; linear growth, usually short stature; and congenital anomalies. The chromosomal disorders include problems of chromosome number (increase or decrease in the number of chromosomes), structure, or both.

The prevalence of chromosomal disorders due to nondisjunction (failure of homologous pairs to separate properly during meiosis) increases with advancing maternal age. Testing to diagnose a chromosome disorder is done through cell culture and chromosome analysis. In addition to the more traditional method of karyotype analysis, in which the total number of each chromosome is identified, staining techniques to identify chromosomal banding assist in the identification of deletions and duplications of chromosomal material. Techniques such as fluorescence in situ hybridization (FISH) provide the ability to identify missing, additional, or rearranged chromosomal material for some of the more common abnormalities but must be ordered for the specific location of interest.

Single-Gene Disorders

Mendelian theory describes four patterns of inheritance: autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. Dominant inheritance disorders occur in heterozygotes, where one gene dominates its counterpart from the other parent. Recessive inheritance disorders occur only when a person is homozygous, when the gene with a disease-causing mutation appears on both of the chromosomes of the pair. However, genetic mutations for some conditions have reduced penetrance, in which a person may have the affected gene (genotype) without expressing the observable characteristics (phenotype), and variable expressivity, in which the severity of the disease condition varies greatly. The result is that some children have clinically severe disease, whereas others, with mutations in the same gene, are more mildly affected.

Multifactorial or Multiple-Gene Disorders

Multifactorial problems result from the complex interaction of multiple genes in various sites and/or interaction of genes with the environment. Several terms are used for this group of conditions (e.g., multifactorial, multiple gene, and polygenic). Cleft lip and palate, spina bifida, hypertension, schizophrenia, pyloric stenosis, diabetes, hypercholesterolemia, Hirschsprung disease, and asthma fall into this category.

Multifactorial problems are more likely to cluster in families. The exact recurrence risk is more difficult to predict because the precise genetic and environmental risks are usually not known. However, in general, the risk for the condition increases if more family members are affected, and if the disease has a more severe expression. It is likely that epigenetics will provide explanations for many of the multifactorial disorders, identifying those combinations of genes, gene mutations, or expression or silencing of genes that result in disease.

Nontraditional Inheritance

Three additional patterns of transmission of genetic material from generation to generation have been identified—germline mosaicism, uniparental disomy, and mitochondrial inheritance.

Teratogens

Although not strictly genetic in origin, teratogens are often discussed with genetic disorders because the differential diagnosis includes factors that affect the embryo after fertilization and those that affect the DNA of the germ cells or their joining with fertilization. Fetal alcohol syndrome is an example of a condition in this category. Viral diseases, such as rubella, certain drugs, and environmental toxins—such as mercury—are also considered teratogens. The Pregnancy Exposure InfoLine (www.thepeil.org) contains current information on potential teratogenic effects of specific environmental substances.

Assessment

Primary care providers identify possible genetic disorders by using the same skills as those for other pediatric health problems: knowledge of risk factors, collection of a good history, and a complete physical examination augmented with appropriate laboratory or other studies. After the assessment, providers determine the operative genetic mechanism and develop and implement a plan of care for the patient and family with consideration of individual, family, and cultural factors. Box 40-1 identifies some common features of children or family members with genetic disorders that should lead providers to explore issues of possible genetic problems.

Risk Factors

Risk factors that may be identified in the child or family members include the following:

TABLE 40-1 Genetic Risks Associated With Ethnic Background

History

The history of genetic diseases usually includes the following main areas (Dolan and Moore, 2007):

Figures 40-3 and 40-4 illustrate the pedigree notation format. Screening questions for genetic disorders that should be asked of all patients are included in Table 40-2. Families can be encouraged to record their own family history information by using programs such as the U.S. Surgeon General’s Family History Initiative (USDHHS, 2005). Parents and children should be encouraged to learn about the health of members of their family, which may, in turn, provide clues as to specific health risks for themselves. When a genetic disorder is suspected, the history must become more specific, as outlined in Table 40-3.

FIGURE 40-3 Pedigree model. Common pedigree symbols, definitions, and abbreviations.

(Adapted from Bennett R, French KS, Resta RG: Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors, J Genet Counsel 17:424-433, 2008.)

FIGURE 40-4 Pedigree line definitions.

(Adapted from Bennett R, French KS, Resta RG: Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors, J Genet Counsel 17:424-433, 2008.)

TABLE 40-2 General Screening for Genetic Conditions: The History

TABLE 40-3 Specific Genetic History Questions

Topic	Specific Items of History
Family history: helps identify family with conditions that may be genetically transmitted	• The pedigree should focus on at least three generations and look for individuals with similar characteristics. • Consanguinity of partners (closer than first cousins) is very important. • Note the past and current health of each person listed on the pedigree. • Note the age of onset for family members’ illnesses. • Note multiple miscarriages, stillbirths, and anomalies within family. • Family members with learning disabilities or mental retardation are important to document.
Environmental and occupational history	Exposure to environmental toxins, alcohol, cigarette smoke, drugs, or radiation that might affect offspring
Reproductive history: helps identify malformations, genetic conditions, or infectious diseases transmitted from mother to child	Maternal medical history • Uterine anomalies • Maternal illnesses and diseases (e.g., phenylketonuria, diabetes) • Immunization status Prenatal history: The reproductive history should list every pregnancy, stillbirth, and abortion. Fetuses with significant chromosomal disorders are often aborted, and 5% to 7% of stillbirths and perinatal deaths are related to genetic problems. Pregnancy and delivery history • Parity • Advanced maternal or paternal age • Complications of pregnancy • Polyhydramnios or oligohydramnios • Fetal movements • Fetal growth assessments • Prenatal screening results • Breech position • Birth measurements • Gestational age • Results of newborn screening tests • Presence of three or more minor anomalies in neonate • Failure of neonate to adapt to extrauterine life • Complications of delivery < div class='tao-gold-member'> Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Related Related posts: Developmental Management in Pediatric Primary Care Coping and Stress Tolerance: Mental Health and Illness Respiratory Disorders Cardiovascular Disorders Stay updated, free articles. Join our Telegram channel Join Tags: Pediatric Primary Care Jul 24, 2016 | Posted by admin in PEDIATRICS | Comments Off on Genetic Disorders Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access