Daryl A. Scott, Brendan Lee
Since the completion of the Human Genome Project, we have seen an unprecedented expansion in our understanding of how human health is impacted by variations in genomic sequence and epigenetic , non-sequence-based, changes that affect gene expression. This period has also seen the development and implementation of new clinical tests that have made it easier for physicians to detect such changes. In addition, there has been a dramatic increase in the availability of information about the genetic aspects of pediatric diseases, particularly on the internet (Table 95.1 ).
Table 95.1
| RESOURCE | WEB ADDRESS |
|---|---|
| National Center for Biotechnology Information. A general reference maintained by the National Library of Medicine. | www.ncbi.nlm.nih.gov |
| Online Mendelian Inheritance in Man. A useful resource for clinicians containing information on all known mendelian disorders and >12,000 genes. Information focuses on the relationship between phenotype and genotype. | www.ncbi.nlm.nih.gov/omim |
| Genetic Testing Registry. A resource that provides information on individual genes, genetic tests, clinical laboratories, and medical conditions. This resource also provides access to GeneReviews, a collection of expert-authored reviews on a variety of genetic disorders. | www.ncbi.nlm.nih.gov/gtr/ |
| Genetics Home Reference. A resource that provides consumer-friendly information about the effects of genetic variations on human health. | www.ghr.nlm.nih.gov |
| National Human Genome Research Institute. A resource for information about human genetics and ethical issues. | www.genome.gov |
| Human Gene Mutation Database. A searchable index of all described mutations in human genes with phenotypes and references. | www.hgmd.cf.ac.uk |
| DECIPHER. A database designed to aid physicians in determining the potential consequences of chromosomal deletions and duplications. | http://decipher.sanger.ac.uk |
| Database of Genomic Variants. A database of chromosomal alterations seen in normal controls. | http://dgv.tcag.ca/dgv/app/home |
| Gene Letter . An online magazine of genetics. | www.geneletter.com |
| American Society of Human Genetics | www.ashg.org |
| American College of Medical Genetics | www.acmg.net |
Medical problems associated with genetic disorders can appear at any age, with the most obvious and serious problems typically manifesting in childhood. It has been estimated that 53/1,000 children and young adults can be expected to have diseases with an important genetic component. If congenital anomalies are included, the rate increases to 79/1,000. In 1978 it was estimated that just over half of admissions to pediatric hospitals were for a genetically determined condition. By 1996, because of changes in healthcare delivery and a greater understanding of the genetic basis of many disorders, that percentage rose to 71%, in one large pediatric hospital in the United States, with 96% of chronic disorders leading to admission having an obvious genetic component or being influenced by genetic susceptibility.
Major categories of genetic disorders include single-gene, genomic, chromosomal, and multifactorial conditions.
Individually, each single-gene disorder is rare, but collectively they represent an important contribution to childhood disease. The hallmark of a single-gene disorder is that the phenotype is overwhelmingly determined by changes that affect an individual gene. The phenotypes associated with single-gene disorders can vary from one patient to another based on the severity of the change affecting the gene and additional modifications caused by genetic, environmental, and stochastic factors. This feature of genetic disease is termed variable expressivity . Common single-gene disorders include sickle cell anemia and cystic fibrosis. Some identifiable syndromes and diseases can be caused by more than one gene (e.g., Noonan syndrome by RAF1, NF1, NRAS, PTPN11, SOS1, SOS2, KRAS, BRAF, SOC2, LZTR1, and RIT1 ). In addition, mutations affecting a single gene may produce different phenotypes (e.g., SCN5A and Brugada syndrome, long QT syndrome 3, dilated cardiomyopathy, familial atrial fibrillation, and congenital sick sinus syndrome).
Single-gene disorders tend to occur when changes in a gene have a profound effect on the quantity of the gene product produced, either too much or too little, or the function of the gene product, either a loss of function or a harmful gain of function. Single-gene disorders can be caused by de novo sequence changes that are not found in the unaffected parents of the affected individual, or they may be caused by inherited changes. When a single-gene disorder is known to be caused by changes in only 1 gene, or a small number of individual genes, searching for deleterious changes is most often performed by directly sequencing that gene and, in some cases, looking for small deletions and/or duplications. When multiple genes can cause a particular disorder, it is sometimes more efficient and cost-effective to screen large numbers of disease-causing genes using a disease-specific panel that takes advantage of next-generation sequencing technology than to screen genes individually. When such panels are not available, or when the diagnosis is in question, physicians may consider screening the protein-coding regions of all genes by whole exome sequencing (WES) on a clinical basis. In many circumstances, WES is less expensive than sequencing multiple individual genes. In the future, whole genome sequencing , in which an individual's entire genome is sequenced, may become a valid clinical option as the cost of such tests fall and our ability to interpret the clinical consequences of the thousands of changes identified in such tests improves (see Chapter 94 ).
The risk of having a child with a particular single-gene disorder can vary from one population to another. In some cases, this is the result of a founder effect , in which a specific change affecting a disease-causing gene becomes relatively common in a population derived from a small number of founders. This high frequency is maintained when there is relatively little interbreeding with persons outside that population because of social, religious, or physical barriers. This is the case for Tay-Sachs disease in Ashkenazi Jews and French Canadians. Other changes may be subject to positive selection when found in the heterozygous carrier state. In this case, individuals who carry a single copy of a genetic change (heterozygotes ) have a survival advantage over noncarriers. This can occur even when individuals who inherit 2 copies of the change (homozygotes ) have severe medical problems. This type of positive selection is evident among individuals in sub-Saharan Africa who carry a single copy of a hemoglobin mutation that confers relative resistance to malaria but causes sickle cell anemia in homozygotes.
Genomic disorders are a group of diseases caused by alterations in the genome, including deletions (copy number loss), duplications (copy number gain), inversions (altered orientation of a genomic region), and chromosomal rearrangements (altered location of a genomic region). Contiguous gene disorders are caused by changes that affect 2 or more genes that contribute to the clinical phenotype and are located near one other on a chromosome. DiGeorge syndrome, which is caused by deletions of genes located on chromosome 22q11, is a common example. Some genomic disorders are associated with distinctive phenotypes whose pattern can be recognized clinically. Other genomic disorders do not have a distinctive pattern of anomalies but can cause developmental delay, cognitive impairment, structural birth defects, abnormal growth patterns, and changes in physical appearance. Fluorescent in situ hybridization (FISH) can provide information about the copy number and location of a specific genomic region. Array-based copy number detection assays can be used to screen for chromosomal deletions (large and small) and duplications across the genome, but do not provide information about the orientation or location of genomic regions. A chromosome analysis (karyotype ) can detect relatively large chromosomal deletions and duplications and can also be useful in identifying inversions and chromosomal rearrangements even when they are copy number neutral changes that do not result in a deletion or duplication of genomic material.
Deletions, duplications, and chromosomal rearrangements that affect whole chromosomes, or large portions of a chromosome, are typically referred to as chromosomal disorders . One of the most common chromosomal disorders is Down syndrome, most often associated with the presence of an extra copy, or trisomy , of an entire chromosome 21. When all or a part of a chromosome is missing, the disorder is referred to as monosomy . Translocations are a type of chromosomal rearrangement in which a genomic region from one chromosome is transferred to a different location on the same chromosome or on a different (nonhomologous) chromosome. Translocations can be balanced, meaning that no genetic material has been lost or gained, or they can be unbalanced, in which some genetic material has been deleted or duplicated.
In some cases, only a portion of cells that make up a person's body are affected by a single-gene defect, a genomic disorder, or a chromosomal defect. This is referred to as mosaicism and indicates that the individual's body is made up of 2 or more distinct cell populations.
Polygenic disorders are caused by the cumulative effects of changes or variations in more than 1 gene. Multifactorial disorders are caused by the cumulative effects of changes or variations in multiple genes and/or the combined effects of both genetic and environmental factors. Spina bifida and isolated cleft lip or palate are common birth defects that display multifactorial inheritance patterns. Multifactorial inheritance is seen in many common pediatric disorders, such as asthma and diabetes mellitus. These traits can cluster in families but do not have a mendelian pattern of inheritance (see Chapter 97 ). In these cases the genetic changes or variations that are contributing to a particular disorder are often unknown, and genetic counseling is based on empirical data.
Genetic testing is increasingly available for a wide variety of both rare and relatively common genetic disorders. Genetic testing is typically used in pediatric medicine to resolve uncertainty regarding the underlying etiology of a child's medical problems and provides a basis for improved genetic counseling and possibly a specific therapy. Even in cases where a specific treatment is not available, identifying a genetic cause can aid physicians in providing individuals and family with accurate prognostic and recurrence risk information and usually helps to relieve unfounded feelings of guilt and stem the tide of misdirected blame.
Genetic tests will ultimately come to underlie a high proportion of medical decisions and will be seamlessly incorporated into routine medical care. Although most genetic testing is presently aimed at identifying or confirming a diagnosis, in the future, genetic testing may find wider application as a means of determining if an individual is predisposed to develop a particular disease. Another area in which genetic testing could make a significant impact is on individualized drug treatment. It has long been known that genetic variation in the enzymes involved in drug metabolism underlies differences in the therapeutic effect and toxicity of some drugs. As the genetic changes that underlie these variations are identified, new genetic tests are being developed that allow physicians to tailor treatments based on individual variations in drug metabolism, responsiveness, and susceptibility to toxicity (see Chapter 72 ). It is likely that the expansion of such testing will depend, at least in part, on the extent to which such tests can be linked to strategies to prevent disease or improve outcome (see Chapter 94 ). As such links are made, we will enter into a new era of personalized medical treatment.
Long-standing and highly successful carrier screening programs have existed for disorders such as Tay-Sachs disease and many other rare, single-gene disorders that are prevalent in specific populations. Couples are usually offered screening for a variety of conditions, in part based on ancestry (Tay-Sachs disease, hemoglobinopathies, cystic fibrosis). Couples found to be at increased risk for such disorders can be offered preconception or prenatal testing aimed at detecting specific disease-causing mutations.
Prenatal screening is routinely offered for chromosomal disorders such as trisomy 13, trisomy 18, and Down syndrome. An increasing number of pregnancies affected by these and other genetic disorders are being recognized by noninvasive screening tests targeting fetal cell-free DNA in maternal blood and by fetal ultrasound. When genetic disorders are suspected, chorionic villus sampling at 10-12 wk of gestation or amniocentesis at 16-18 wk of gestation can provide material for genetic testing. When a couple are at risk for a specific genetic defect, preimplantation genetic diagnosis can sometimes be used to select unaffected early embryos, which are then implanted as part of an in vitro fertilization procedure.
Although prenatally obtained genetic material can be used to identify single-gene disorders, genomic disorders, and chromosomal anomalies, the information obtained on any pregnancy depends on the tests that are ordered. It is important that physicians select the most appropriate prenatal tests, and that couples understand the limitations of these tests. No amount of genetic testing can guarantee the birth of a healthy child.
Specific treatments are not available for the majority of genetic disorders, although some important exceptions exist (Chapter 94 ). Inborn errors of metabolism were the first genetic disorders to be recognized, and many are amenable to treatment by dietary manipulation (see Chapter 102 ). These conditions result from genetically determined deficiency of specific enzymes, leading to the buildup of toxic substrates and/or deficiency of critical end products.
Individual metabolic disorders tend to be very rare, but their combined impact on the pediatric population is significant. Tandem mass spectrometry has made it relatively inexpensive to screen for a large number of these disorders in the newborn period. Use of this technology not only dramatically increases the number of metabolic disorders identified within a population, but also allows treatment to be initiated at a much earlier stage in development.
Another area showing progress in genetic therapies is the treatment of lysosomal storage disorders (see Chapter 104.4 ). These metabolic diseases are caused by defects in lysosomal function. Lysosomes are cellular organelles that contain specific digestive enzymes. Some of these disorders that were characterized by early lethal or intractable chronic illness can now be treated using specially modified enzymes administered by intravenous infusion. These enzymes are taken up by cells and incorporated into lysosomes. Conditions such as Gaucher disease and Fabry disease are routinely treated using enzyme replacement , and similar therapies are being developed for other lysosomal disorders.
Therapeutic advances are also being made in the treatment of nonmetabolic genetic disorders. Improvements in surgical techniques and intensive care medicine are extending the survival of children with life-threatening birth defects such as congenital diaphragmatic hernia and severe cardiac defects. In many cases the life expectancy of children with debilitating genetic disorders is also increasing. For example, in cystic fibrosis, improvements in nutrition and the management of chronic pulmonary disease allow an increasing percentage of affected patients to survive into adulthood, creating a need to transition care from pediatric to adult providers.
Gene replacement therapies have long been anticipated and are starting to show some benefit (see Chapter 94 ). Stem cell–based therapies have also been touted as a potential treatment for a number of intractable disorders, but clear evidence that such therapies are effective has yet to materialize.
As with all medical care, genetic testing, diagnosis, and treatment should be performed confidentially . Nothing is as personal as one's genetic information, and all efforts should be made to avoid any stigma for the patient. Many people worry that results of genetic testing will put them, or their child, at risk for genetic discrimination. Genetic discrimination occurs when people are treated unfairly because of a difference in their DNA that suggests they have a genetic disorder or they are at an increased risk of developing a certain disease. In the United States the Genetic Information Nondiscrimination Act of 2008 protects individuals from genetic discrimination at the hands of health insurers and employers, but does not extend protection against discrimination from providers of life, disability, or long-term care insurance.
As in all medical decision-making, the decisions about genetic testing should be based on a careful evaluation of the potential benefits and risks. In the pediatric setting, these decisions may be more difficult because physicians and parents are often called on to make decisions for a child who cannot directly participate in discussions about testing. Molecular diagnostic tests are often used to diagnose malformation syndromes, cognitive delay, or other disabilities in which there is a clear benefit to the child. In other cases, such as genetic testing for susceptibility to adult-onset diseases, it is appropriate to wait until the child or adolescent is mature enough to weigh the potential risks and benefits and make his or her own decisions about genetic testing.
Policies regarding genetic testing of children have been developed collaboratively by the American Academy of Pediatrics (AAP) and the American College of Medical Genetics and Genomics (ACMG; Pediatrics 131[3]:620–622, 2013). These recommendations are outlined next.