The Genetic Approach in Pediatric Medicine

The Burden of Genetic Disorders in Childhood

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.