How is the progress in genetics relevant to children's health care

In my experience, most paediatricians shy away from genetics because they think it is all about esoteric disorders, molecular biology and statistics. The genetics revolution is upon us paediatricians, whether we like it or not. Sarah Dyack's article (pages 241–243) on this issue, begins a column on clinical genetics for the paediatrician which will be a regular feature of Paediatrics & Child Health. Paediatricians, by the very nature of specialty medicine deal with many different disease processes. A recent article reviewed (1) admissions to a typical paediatric hospital and found that 75% have a major genetic component to the disorder that led to their hospitalization. So instead of running in the opposite direction, it is probably time for paediatricians to embrace genetics as a discipline that will help sort out the complex patients with which they deal. Some of the major advances in genetics during the last few decades that are relevant to paediatrics include: the sequencing of the human genome and finding that there are approximately 30,000 genes; the identification of most of the genes responsible for the common single gene (Mendelian) disorders; the recognition of nontraditional genetic mechanisms of disease (such as Fragile X mental retardation [triplet repeats] and genomic imprinting [where only one parental gene copy is expressed]); the development of ways to identify submicroscopic chromosomal deletions; and major improvements in diagnostic tests (such as florescent in situ hybridization, and molecular micro arrays that test for many mutations and diseases simultaneously). In addition, once the molecular basis of a disease is known, creative and inventive therapies are being developed, such as Gleevec (Novartis Pharmaceuticals, Canada), where a molecular therapy completely blocks a cancer producing/growth-promoting pathway. In the dark ages, 10 years ago, we used to think of genetic diseases as falling into three categories: chromosomal, single gene and multifactorial. Today, we recognize two additional important groupings: genetic predispositions (as in familial cancer, drug reactions, diabetes) and nontraditional types of inheritance including mitochondrial inheritance and cytoplasm inheritance, genomic imprinting (reflecting transgenerational effects), allelic expansion (Fragile X), and many more. You do not have to be a molecular geneticist to understand the usefulness of the new diagnostic techniques in sorting out your diagnostic dilemmas, but you will probably need to call your friendly clinical geneticist (almost surely housed in an academic health care centre near you) to learn what can be done and where to send the test. There has been an explosion of diagnostic tests, some more reliable and available than others, but it is hard to keep up, even for clinical geneticists. There has also been an explosion of information and new diagnoses. Your local clinical geneticist should also be able to help you get appropriate literature and find new guidelines for patient care in rare genetic disorders (that is why they are there) (2). It is possible, in this day and age, to develop a molecular method to look for a specific gene mutation or chromosomal deletion. As you probably know, this has been well demonstrated in the 22q deletion syndrome (the common deletion of the long arm of chromosome 22, also known as DiGeorge syndrome or velo-cardio-facial syndrome). This syndrome turns out to be incredibly common and is a frequent cause of congenital heart disease and mental health problems. It is so common that most paediatric cardiac clinics are now screening all children with nonspecific congenital heart disease for the deletion. Fragile X mental retardation, the most common single gene cause of developmental delay, used to be screened for by growing chromosomes under complex culture conditions to look for the loss of the tip of the long arm of the X chromosome (fragile site). It now turns out to be a very easy molecular diagnostic test because the mutation leads to the enlargement of a section of DNA that can be easily spotted on the electrophesis of DNA from an affected individual. Down the road, there will be DNA diagnostic microchips on which arrays of multiple short, single strands of DNA with different mutations will be arranged so that DNA from a patient can be easily tested for many disorders at the same time (up to 30,000 strands on one chip). Refining comparative genomic hybridization and telomeric florescent in situ hybridization probes will allow the identification of the many different very small deletions or duplications responsible for at least 10% of nonspecific behavioural and developmental problems. Kabuki syndrome has just been recognized to occur due to the duplication of the end of the short arm of chromosome 8 (3). What has become clear is that for every chromosomal deletion syndrome (eg, where only one copy of a section of DNA is present) there is likely to be a duplication syndrome (eg, where three copies of the section of DNA are present). These small deletions and duplicates are probably due to the presence, in some regions of the chromosomes, of a series of DNA sequences that are sufficiently similar to each other that they lead to mismatching of the DNA during meiosis and loss or gain of the segment during crossing over. Advances in other areas of medicine have led to the use of molecular genetic techniques to help elucidate the mechanisms of disease. Most recently, many children have been born with the help of assisted reproductive technologies. It is being recognized that there is an increased incidence of intrauterine growth retardation, premature delivery, twinning (both monozygotic and dizygotic), congenital anomalies and imprinting defects among the children conceived by assisted reproductive technologies. However, why such defects occur, how large is the risk and which subtypes of assisted reproductive technologies are at risk is still unclear (4–8). It is very important that children who are the products of assisted reproductive technologies be identified as such, in order that long term follow-up can identify any later complications. Molecular techniques are being used to tease out which and how many of these children are different from spontaneous conceptions. Just as interesting is the recent observation that many things that happen early in human development (eg, during embryonic and fetal development) have long-term implications for adult onset disease. For instance, it turns out that we all carry cells from our mothers that may play a role in autoimmune disease, but undoubtedly play a role in repair (9). Cytokines may have adverse as well as beneficial effects on the growth and maturation of specific organs at various times in early development (10,11). Those children who were given steroids in order to mature their lungs because they were in danger of early delivery, as well as those who experienced excess cytokines because of in utero infectious processes, may have fewer cells in their organs at birth and thus respond differently to adult diseases. Follow-ups of children who are small at birth (including all types of intrauterine growth retardation and prematurity), suggest that they have an increased risk for early onset of diabetes, hypertension, and heart disease as adults. Consequently, the treatment for those disorders in those adults may need to be different from the treatment of those disorders in individuals with a ‘simple’ genetic predisposition, because the in utero fetal programming of their biochemical pathways appears to be different. These fetal effects on adult health may not seem like genetic disorders, but they undoubtedly represent a genetic disposition to the effects of different environments. “What gets inherited is not a deterministic genotype, but rather a genotype that encodes a potential range of phenotypes” (12) that will be developed in response to a variety of different environments during the course of in utero and post birth development. Clearly, the long-term follow-up of problems during pregnancy, infancy, and childhood need to become part of the permanent record of adults so the effects can be screened for and recognized later in life. Traditionally, paediatricians have not sent the pregnancy and birth record or even the family history information on to the internist or family physician caring for their patients as they become adults. Perhaps what we in Canada need to do is to develop a permanent health record that patients are responsible for keeping themselves, much as it is done in the military. Whatever the case, whether you have embraced or resisted it up until now, the time is here for you to inform yourself about what is being learned in genetics. Medicine is undoubtedly going to become individualized and tailored on the basis of individual predispositions (13). Minor DNA differences between individuals almost surely predispose some to environmentally induced problems. Some of the most important drug reactions occur because of alterations in biochemical pathways. Studies in the area of pharmacogenomics suggest that an adverse event or bad drug reaction has its basis in the biochemical pathways which the drug exerts its effect. Drug companies know that for each drug, 1% to 5% of the population will have no useful beneficial effect and 1% to 5% may have an adverse effect. Drug companies may begin to provide preprescription screenings to identify those individuals who would have a bad reaction to a particular drug before they even start taking it. Paediatricians know that children have quite different effects from medications than adults (even several different effects at different ages). For instance, Ritalin (Novartis Pharmaceuticals, Canada) may calm a hyperactive child, while it makes an adult hyperactive and alert. Children may require age specific preprescription screening. Put aside all your struggles with healthcare delivery, physician resource planning, adequacy of resources and educational revamping, and focus on the really exciting new change in medicine – genetics, it is here to stay. Although I have suggested your local friendly clinical geneticist as a great resource, there are several ways you can get at the latest information about a particular genetic disorder. The web sites: Online Mendelian Inheritance in Man and GeneTests give you direct access through the internet. Have fun!

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