The Genetic Approach in Pediatric Medicine

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Chapter 73 The Genetic Approach in Pediatric Medicine

With the completion of the human genome sequence and the haplotype map, investigative and diagnostic tools are available to determine the genetic contributions to uncommon and common disorders. Information about the genetic aspects of all pediatric diseases is readily available on numerous websites and in other locations (Table 73-1).


WEB ADDRESS DATABASE General reference maintained by National Library of Medicine Online Mendelian Inheritance in Man, an extremely useful for clinicians ~20,000 entries of genetic traits indexed by gene name, symptoms, etc General reference to current efforts to map the human genome Searchable repository of all DNA sequence data Cancer Genome Anatomy Project (National Cancer Institute) National Human Genome Research Institute; useful information about human genetics and ethics issues Human Gene Mutation Database, a searchable index of all described mutations in human genes with phenotypes and references A database of chromosomal alterations seen in normal controls Health, clinical, legal, social, and ethics issues American Society of Human Genetics American College of Medical Genetics Committee on Genetics of the American Academy of Pediatrics: health supervision guidelines for common genetic disorders

The Burden of Genetic Disorders in Childhood

Genetic disorders can appear at any age, but some of the most obvious and severe diseases begin 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, owing to changes in health care delivery and a greater understanding of the genetic basis of many disorders, that percentage rose to 71% in one large pediatric hospital in the USA, and 96% of chronic disorders leading to admission had an obvious genetic component or were influenced by genetic susceptibility. Major categories of genetic disorders include single-gene, genomic, chromosomal, and multifactorial conditions.

Individually, single-gene disorders are 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/or stochastic factors. This feature of genetic disease is termed variable expressivity. Common single-gene disorders include sickle cell anemia and cystic fibrosis.

Single-gene disorders tend to occur when changes in a gene have a profound effect on the function of the gene product. Such effects can include insufficient product (structural protein, enzyme, metabolites), loss of function, or a harmful gain of function. Testing for single-gene disorders typically involves searching for mutations most often by directly sequencing the gene and, in some cases, looking for small deletions and/or duplications that might affect the causative gene. Single-gene disorders can occur sporadically, owing to occurrence of de novo mutations (mainly true for dominant disorders), but they can also be caused by inherited changes.

The risk of having a child with a single gene disorder can vary from one population to another. In some cases this is due to the founder effect, in which a specific change affecting the causative gene achieves relatively high frequency in a population derived from a small number of founders. This frequency is maintained because of restricted interbreeding with persons outside of that population. 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, such as hemoglobin mutations that confer relative resistance to malaria.

Genomic disorders are a group of diseases caused by rearrangements of the genome including deletions (loss of a copy of DNA), duplications (addition of a new copy of DNA), and inversions (altered organization of DNA). When these disorders are caused by rearrangements that affect several adjacent genes that contribute to a specific phenotype they are sometimes referred to as contiguous gene disorders. 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 that can be recognized clinically, and others produce nondescript phenotypes of developmental impairment with variable effects on intellect as well as growth and physical appearance. Genomic disorders are often identified by fluorescent in situ hybridization (FISH) or by array comparative genome hybridization (aCGH) technologies. Larger changes may be seen on a chromosome (cytogenetic) analysis.

Deletions, duplications, and inversions that affect whole chromosomes, or large portions of a chromosome, are commonly referred to as chromosomal disorders. One of the most common chromosomal disorders is Down syndrome, which is most commonly 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

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