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Genetic testing: when to test and when to refer
Occasional review
Genetic testing: when to test and when to refer
What is ‘thinking genetically’? Hayflick and Eiff1 describe ‘thinking genetically’ as considering genetics at every patient encounter. The authors will apply and adapt the concept of thinking genetically to the issue of when and why to use genetic testing in pediatric practice. They think that a pediatrician who can answer the following set of questions is thinking genetically.
Roberta A Pagon Tracy L Trotter
What are genetic tests? Genetic tests include: • biochemical tests, such as measurements of analytes and assays of enzyme activity • cytogenetic tests, such as routine karytoyping, fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (CGH) • molecular genetic tests, such as sequence analysis, targeted mutation analysis, deletion testing and other methods of DNA analysis. Note that this approach to genetic thinking focuses on testing related to germline mutations (i.e. mutations present in every cell of the body that have implications for the health of that individual, his or her reproductive risks, or both). This approach does not consider genetic testing for somatic mutations (those that occur after conception and may be associated with specific disease states of a subset of cells, such as cancer). Biochemical genetic testing and routine karyotyping have been available for decades. Molecular genetic testing, which was first clinically available In routine patient care for around 100 disorders about 15 years ago, is now available for more than 1000 disorders (see www.genetests.org).
Abstract Paediatricians care for children with known or suspected genetic condi tions and children at risk of genetic disorders based on family history. Paediatricians are expected to help establish the diagnosis of a ge netic disorder, coordinate long-term care and serve as a resource for the family. The ever-changing landscape of genetic tests, test methods, and test sensitivity can be daunting to even the most experienced geneticist. Paediatricians need to ask questions addressing the timely use of genetic testing and thereby make decisions about when to test and when to refer.
Keywords biochemical genetic testing; cytogenetic testing; genetic counselling; genetic testing; molecular genetic testing
Introduction Pediatricians care for children with developmental delay/learning difficulties, birth defects, growth failure, sensory deficits, and other disabilities, many of which have a genetic cause. They also care for children who are at risk of genetic disorders based on their family history. In the care of patients with a genetic disorder, it is expected that the pediatrician will help in establishing the diagnosis, coordinating long-term care and serving as resource for the family, schools and other health-care providers. In the care of patients at risk of a genetic disorder, pediatricians are expected to implement appropriate surveillance to reduce morbidity or mortality through early diagnosis. In patients with known or suspected genetic disorders or who are at risk of a genetic disorder, the paediatrician must be able to weigh the issues concerning which patient to test and when, what test to use, and when to refer for a medical genetics consultation. Efficiently managing this triage requires the pediatrician to ‘think genetically’, using his or her skills in diagnosis and management to provide a cost-effective route to the most appropriate genetics professional at the most appropriate time in the child’s care.
How is genetic testing used in patient care? Genetic testing can be used in a medical paradigm and in a personal decision-making paradigm. Medical paradigm includes: • establishing the diagnosis of disorders that can be diagnosed only by genetic testing (e.g. fragile X syndrome) • confirming a diagnosis that can be first established by clinical findings based on accepted clinical diagnostic criteria (e.g. Prader–Willi syndrome) • predictive testing for asymptomatic, at-risk family members to initiate early treatment that alters the course of the disease (e.g. enzyme replacement therapy for a lysosomal storage disease) or surveillance to enable early identification and prompt treatment of potential complications (e.g. colon polyps in familial adenomatous polyposis). Although another possible use of genetic testing in the medical paradigm is for prognostication (e.g. distinguishing between patients with von Hippel–Lindau disease who have mutations that confer a high risk of phaeochromocytoma vs mutations that confer a low risk of these tumours). However, most genotype– phenotype correlations are not yet sufficiently sensitive or specific to use in prognostication.
Roberta A Pagon MD is Professor of Paediatrics, University of Washington, Gene Tests, Suite 602, 9725 Third Avenue NE, Seattle, WA 98115, USA.
Personal decision-making paradigm refers to genetic testing performed to provide an individual with information that does not influence medical care, but rather clarifies his or her genetic
Tracy L Trotter MD San Ramon Valley Primary Care, 200 Porter Drive, 3rd Floor, San Ramon, CA 94583, USA.
PAEDIATRICS AND CHILD HEALTH 17:9
367
© 2007 Elsevier Ltd. All rights reserved.
Occasional review
status to inform personal choices. The personal decision-making paradigm includes: • carrier testing for an autosomal recessive disorder or an X-linked disorder for the purpose of reproductive decision-making • prenatal testing • preimplantation genetic diagnosis (PGD) • predictive testing in an individual at risk of a disorder for which no medical intervention is available (e.g. Huntington disease). Personal decisions that might be influenced by pre-symptomatic testing include educational planning, career options, social relationships and financial planning. Predictive testing for an adult-onset disorder for which no treatment exists is usually not appropriate in an asymptomatic patient under 18 years of age. For paediatric patients, the medical paradigm for genetic testing predominates. However, for the parents of a child with a genetic disorder, personal decision-making involving reproductive risks and options may be one of the key motivators for them seeking a diagnosis for their child.
Why do I want to test this patient at this time? Critical questions that underlie the paediatrician’s decision to test are as follows. Before the test, the paediatrician needs to ask: • What is the test? • What do I need to know to order the test? • What do I need to know to interpret the test result? • What resources are available to help me clarify these issues to save time, avoid injury and improve accuracy? After the test, the questions are: • How is the medical management of my patient influenced by the test result? • How does the test result help the family? • Who else in the family could get this disorder? • What social issues about this disorder need to be addressed for the family? Patients (or their parents) may misunderstand the use of genetic tests and may be overly optimistic that identification a genetic cause such as a mutation will lead to hitherto unavailable interventions. The publicity surrounding gene therapy a decade ago gave hope that cellular manipulation of genetic information might alter abnormal gene expression and hence modify the phenotype, but the enormous difficulties of gene therapy have eliminated it as a real option for almost all disorders at present. The focus has now shifted to other means of modifying gene expression, based to date on investigational studies with no (or at best, limited) clinical applications. However, these strategies may ultimately be important to patients and their families. Studies sponsored by the US National Institutes of Health can usually be identified through www.clinicaltrials.gov. A corollary is, if a patient has undergone genetic testing in the past, was that test sufficient to answer the questions that the patient/paediatrician has now or does new knowledge or the availability of new/improved tests require additional testing? This is one of the most difficult questions to answer. Regarding molecular genetic testing: • the number of inherited diseases for which molecular genetic testing is available is increasing each year (from about 100 diseases in 1993 to more than 1000 in 2007) • new molecular genetic tests are ‘brought online’ at an unpredictable rate • the introduction of new molecular genetic testing methods increases the ability to identify mutations in a specific gene. Regarding cytogenetic testing: • general improvements in routine karyotyping have increased the ability to detect small chromosome aberrations (many geneticists advocate repeating even routine karyotyping every 5–10 years because of the increased yield as even the best laboratories become more skilled over time) • new methods of chromosome analysis (e.g. FISH, subtelomeric chromosome analysis) allow detection of submicroscopic deletions and duplications not seen on routine karyotyping • new methods (e.g. array CGH) can detect smaller deletions and duplications than FISH and can test for many (>100) aberrations at one time.
Who needs to be tested? When considering genetic testing to clarify the genetic status of family members for predictive testing or for carrier testing/prenatal testing/PGD, it is essential that the paediatrician understands the correct way to use testing. When molecular genetic testing is highly sensitive and specific, it is necessary to first confirm the diagnosis in an affected family member before testing at-risk relatives. For example, molecular genetic testing for fragile X syndrome involves assessing the size of the CGG repeat in the FMR1 gene, a test that can accurately determine whether a disease-causing mutation is present or absent in any individual. However, learning difficulties have numerous genetic and non-genetic causes; therefore, the diagnosis of fragile X syndrome must be confirmed in at least one affected family member before genetic testing can be used to clarify the genetic status of other family members (i.e. whether they are carriers of fragile X syndrome or have fragile X syndrome). If the diagnosis of fragile X syndrome is not first established by molecular genetic testing in an affected family member, testing relatives for an expansion in the FMR1 gene is meaningless and provides false reassurance when the test is negative. When multiple mutations in a given gene can give rise to a disorder, the family-specific disease-causing mutation or mutations must be identified in an affected family member first. If the family-specific mutation is unknown, failure to identify a mutation in another family member is ‘uninformative’; that is, one does not know whether a negative test result is a true negative (the family member does not have the family-specific mutation) or a false negative (e.g. the wrong portion of the gene was tested to identify the mutation or the wrong gene was tested). For example, the offspring of a parent with familial adenomatous polyposis (FAP) have a 50% risk of having the disorder. It is reasonable to use molecular genetic testing to establish the genetic status of a child at risk of FAP at a young age (<10 years) so that only children with the family-specific mutation have to undergo routine colonscopy. However, the exact (family-specific) mutation must first be identified in an affected individual. Only when the exact mutation is known can predictive testing be informative.
PAEDIATRICS AND CHILD HEALTH 17:9
What is a genetics consultation? A genetics consultation includes a genetic evaluation and genetic counselling. Genetic evaluation is the process of gathering 368
© 2007 Elsevier Ltd. All rights reserved.
Occasional review
Puberty: for those without a diagnosis, the social and/or medical upheaval accompanying puberty can re-energize the search for a diagnosis, particularly if the patient becomes distanced from his or her peers due to health issues and/or ability.
information on a patient or family with a known or suspected genetic disorder and includes a three-generation family history, establishing a diagnosis through physical examination and genetic testing, and risk assessment. Genetic counselling is the process of educating patients and parents about the nature and cause of the inherited disorder, conveying genetic risks, providing information for informed medical and personal decisionmaking, offering psychosocial support and referral, and referring geographically dispersed at-risk family members to local genetic services.2 Most paediatricians do not have the time or the personnel to undertake extensive information gathering (e.g. obtaining medical records of relatives who are not in their practice, interpreting/clarifying the results of previous genetic studies) and/or genetic counselling.
Age 18 years and above: the focus shifts to the recurrence risk in the child with the disorder and/or sibs of reproductive age, thereby renewing the search for a diagnosis, if one has not been established, and/or raising questions about the use of genetic testing to clarify the genetic status (and recurrence risk) in family members. Where can I go to get help and information about the condition? GeneTests (www.genetests.org) is a resource widely used by health-care professionals and comprises: • GeneReviews (more than 380 expert-authored, peer-reviewed disease descriptions emphasizing the use of currently available tests in patient care) • a laboratory directory of over 600 laboratories offering molecular genetic, biochemical and specialized cytogenetic testing for more than 1000 inherited disorders • a searchable directory of over 1000 US genetics clinics by city • consumer-oriented resources.
Who provides genetic services? Genetic professionals comprise three groups. When the concern is diagnosis, paediatricians are likely to consult a medical geneticist with training in paediatrics. For children with a known or suspected metabolic disorder based on newborn screening, expanded newborn screening or clinical presentation, the pediatrician is likely to consult a biochemical geneticist. When personal decision-making is the key issue, referral to a genetic counsellor may be the most appropriate. When should I refer my patient for a genetics consultation? ‘When to test’ can become overwhelmingly complicated for paediatricians who are ‘trying to do everything’. However, the process becomes feasible if they reframe the approach and consider themselves to be part of a triage system in which their role is to make a ‘first cut’ based on ‘what I can do myself’ and ‘what I need to refer to the experts’. Pediatricians who take this approach can determine the boundaries of their expertise and practice para meters when asking themselves the questions discussed above. When to refer a patient with a known or suspected genetic disorder to a genetics professional is not a fixed point. It depends on: • the knowledge base and experience of the physician regarding the disorder • the stage of the disease, the current availability of treatment, and the possibility of new treatment in the future • the family’s need for an expert or second opinion • the family’s stage of dealing with the disorder • the mode of inheritance and reproductive issues for the parents, the sibs of the affected child and the extended family (autosomal dominant disorders and X-linked disorders can have recurrence risk implications for the extended family, while autosomal recessive disorders typically have recurrence risk implications for sibs of the proband only). In the authors’ experience, the issues for families tend to vary with the age of the child.
Where can the family go to get help and information about the condition? Receiving a genetic diagnosis based on laboratory findings can empower parents, many of whom choose to join, or even found, parent support groups to further education and research in that disorder. Such groups can be an important source of patientcentred information and communication, providing families with information on medical problems and management as well as insights into social, emotional and educational issues. Some families who find satisfying emotional support through a patient group are reluctant to embark on testing or further diagnostic evaluations that might dismiss the original diagnosis and possibly result in a new diagnosis for which support is less well developed. Respected, widely used and freely available resources for families with a genetic disorder include the following: • the Genetic Alliance (www.geneticalliance.org), an international coalition of more than 600 advocacy, research and health-care organizations • the Genetics and Rare Conditions site (www.kumc.edu/gec/ geneinfo.html) hosted by the University of Kansas Medical Center provides links to disease-specific lay-advocacy groups, educational materials, specialty clinics and other relevant resources for about 225 genetic diseases • Family Village (www.familyvillage.wisc.edu/index.html), sponsored by the Waisman Center at the University of Wisconsin, provides general resources for families with a disability, along with information on specific diagnoses • Genetics Home Reference (http://ghr.nlm.nih.gov), developed at the National Library of Medicine, comprises specific information on diseases (Genetic Condition Summaries), genes (Gene Summaries), and chromosomes (Chromosome Summaries) as well as a handbook of genetics concepts (Help Me Understand Genetics), a glossary of genetic and medical terms, and links to resources.
Age 0–6 years: parents seek to establish a diagnosis or, if they have a diagnosis, actively gather information on the natural history, prognosis, potential complications, interventions and recurrence risk. Age 6–12 years: identifying appropriate services regarding education, peer relationships, social issues, recreation and activities of daily living become of primary importance.
PAEDIATRICS AND CHILD HEALTH 17:9
369
© 2007 Elsevier Ltd. All rights reserved.
Occasional review
This, along with new advances in testing chromosomes and for metabolic disorders, can be overwhelming for the paediatrician who would like to ‘do it all’. Understandably, this confusion has alienated primary care practitioners and bewildered families. In an ever-changing landscape of test availability, test sensitivity, family issues and needs, paediatrician must be able to think genetically, asking the questions that need to be addressed concerning the use of genetic testing in individual patients at a particular time. By following this process, paediatrician can determine their role in making the decision when to test and when to refer. ◆
What is a common example of genetic testing in pediatric practice? Although molecular genetic testing has added new dimensions to genetic testing, the use of older genetic tests such as cytogenetic testing requires understanding of the core principles of thinking genetically. When and why to test for Down syndrome and what value, if any, new specialized cytogenetic tests have over routine karyotyping are questions familiar to all paediatricians. In most cases, the diagnosis of Down syndrome has been suspected since before birth due to prenatal screening or shortly after birth by an experienced health-care professional. Regardless of the pediatrician’s experience of diagnosing Down syndrome clinically, routine karyotyping is always indicated in a newborn with suspected Down syndrome to: • confirm the diagnosis (parents want the best possible evidence that their child has Down syndrome) • provide risk assessment for the family (the recurrence risk in the parents and extended family for trisomy 21 is different from that for Down syndrome caused by an inherited robertsonian translocation) • address the parents’ questions about the predictive value of karyotyping (e.g. presence or absence of mosaicism). The pediatrician ordering the chromosome test needs to know: • what information the test performed by the laboratory can and cannot provide about the chromosomes • what the test result can and cannot determine regarding the diagnosis, prognosis and management • what questions the parents will ask about the test result and its implications for their child and for them.
References 1 Hayflick SF, Eiff MP. Will the learners be learned? Genet Med 2002; 4: 43–4. 2 Pagon RA. Molecular genetic testing for inherited disorders. Expert Rev Mol Diagn 2004; 4: 135–40.
Practice points • Genetic tests include biochemical, cytogenetic and molecular genetic tests • Genetic testing can be used to clarify the genetic status of an individual to facilitate medical care or personal decisionmaking • The usefulness of genetic testing for a given patient may depend in part on the sensitivity of the test, the age of the patient, the availability of treatment and current family issues • Paediatrician who can ‘think genetically’ (i.e. ask the questions regarding patient care and family issues that need to be answered by the genetic test) are in the optimal position to decide when to test and when to refer
Conclusion Unprecedented and ongoing media publicity about molecular genetic testing, its ethics, the Human Genome Project and the future of ‘personalized medicine’, and previous hyperbole about genetic engineering, have created unwarranted confusion regarding DNA-based testing and its appropriate use in patient care.
PAEDIATRICS AND CHILD HEALTH 17:9
370
© 2007 Elsevier Ltd. All rights reserved.
Genetic testing: when to test and when to refer
What is ‘thinking genetically’? Hayflick and Eiff1 describe ‘thinking genetically’ as considering genetics at every patient encounter. The authors will apply and adapt the concept of thinking genetically to the issue of when and why to use genetic testing in pediatric practice. They think that a pediatrician who can answer the following set of questions is thinking genetically.
Roberta A Pagon Tracy L Trotter
What are genetic tests? Genetic tests include: • biochemical tests, such as measurements of analytes and assays of enzyme activity • cytogenetic tests, such as routine karytoyping, fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (CGH) • molecular genetic tests, such as sequence analysis, targeted mutation analysis, deletion testing and other methods of DNA analysis. Note that this approach to genetic thinking focuses on testing related to germline mutations (i.e. mutations present in every cell of the body that have implications for the health of that individual, his or her reproductive risks, or both). This approach does not consider genetic testing for somatic mutations (those that occur after conception and may be associated with specific disease states of a subset of cells, such as cancer). Biochemical genetic testing and routine karyotyping have been available for decades. Molecular genetic testing, which was first clinically available In routine patient care for around 100 disorders about 15 years ago, is now available for more than 1000 disorders (see www.genetests.org).
Abstract Paediatricians care for children with known or suspected genetic condi tions and children at risk of genetic disorders based on family history. Paediatricians are expected to help establish the diagnosis of a ge netic disorder, coordinate long-term care and serve as a resource for the family. The ever-changing landscape of genetic tests, test methods, and test sensitivity can be daunting to even the most experienced geneticist. Paediatricians need to ask questions addressing the timely use of genetic testing and thereby make decisions about when to test and when to refer.
Keywords biochemical genetic testing; cytogenetic testing; genetic counselling; genetic testing; molecular genetic testing
Introduction Pediatricians care for children with developmental delay/learning difficulties, birth defects, growth failure, sensory deficits, and other disabilities, many of which have a genetic cause. They also care for children who are at risk of genetic disorders based on their family history. In the care of patients with a genetic disorder, it is expected that the pediatrician will help in establishing the diagnosis, coordinating long-term care and serving as resource for the family, schools and other health-care providers. In the care of patients at risk of a genetic disorder, pediatricians are expected to implement appropriate surveillance to reduce morbidity or mortality through early diagnosis. In patients with known or suspected genetic disorders or who are at risk of a genetic disorder, the paediatrician must be able to weigh the issues concerning which patient to test and when, what test to use, and when to refer for a medical genetics consultation. Efficiently managing this triage requires the pediatrician to ‘think genetically’, using his or her skills in diagnosis and management to provide a cost-effective route to the most appropriate genetics professional at the most appropriate time in the child’s care.
How is genetic testing used in patient care? Genetic testing can be used in a medical paradigm and in a personal decision-making paradigm. Medical paradigm includes: • establishing the diagnosis of disorders that can be diagnosed only by genetic testing (e.g. fragile X syndrome) • confirming a diagnosis that can be first established by clinical findings based on accepted clinical diagnostic criteria (e.g. Prader–Willi syndrome) • predictive testing for asymptomatic, at-risk family members to initiate early treatment that alters the course of the disease (e.g. enzyme replacement therapy for a lysosomal storage disease) or surveillance to enable early identification and prompt treatment of potential complications (e.g. colon polyps in familial adenomatous polyposis). Although another possible use of genetic testing in the medical paradigm is for prognostication (e.g. distinguishing between patients with von Hippel–Lindau disease who have mutations that confer a high risk of phaeochromocytoma vs mutations that confer a low risk of these tumours). However, most genotype– phenotype correlations are not yet sufficiently sensitive or specific to use in prognostication.
Roberta A Pagon MD is Professor of Paediatrics, University of Washington, Gene Tests, Suite 602, 9725 Third Avenue NE, Seattle, WA 98115, USA.
Personal decision-making paradigm refers to genetic testing performed to provide an individual with information that does not influence medical care, but rather clarifies his or her genetic
Tracy L Trotter MD San Ramon Valley Primary Care, 200 Porter Drive, 3rd Floor, San Ramon, CA 94583, USA.
PAEDIATRICS AND CHILD HEALTH 17:9
367
© 2007 Elsevier Ltd. All rights reserved.
Occasional review
status to inform personal choices. The personal decision-making paradigm includes: • carrier testing for an autosomal recessive disorder or an X-linked disorder for the purpose of reproductive decision-making • prenatal testing • preimplantation genetic diagnosis (PGD) • predictive testing in an individual at risk of a disorder for which no medical intervention is available (e.g. Huntington disease). Personal decisions that might be influenced by pre-symptomatic testing include educational planning, career options, social relationships and financial planning. Predictive testing for an adult-onset disorder for which no treatment exists is usually not appropriate in an asymptomatic patient under 18 years of age. For paediatric patients, the medical paradigm for genetic testing predominates. However, for the parents of a child with a genetic disorder, personal decision-making involving reproductive risks and options may be one of the key motivators for them seeking a diagnosis for their child.
Why do I want to test this patient at this time? Critical questions that underlie the paediatrician’s decision to test are as follows. Before the test, the paediatrician needs to ask: • What is the test? • What do I need to know to order the test? • What do I need to know to interpret the test result? • What resources are available to help me clarify these issues to save time, avoid injury and improve accuracy? After the test, the questions are: • How is the medical management of my patient influenced by the test result? • How does the test result help the family? • Who else in the family could get this disorder? • What social issues about this disorder need to be addressed for the family? Patients (or their parents) may misunderstand the use of genetic tests and may be overly optimistic that identification a genetic cause such as a mutation will lead to hitherto unavailable interventions. The publicity surrounding gene therapy a decade ago gave hope that cellular manipulation of genetic information might alter abnormal gene expression and hence modify the phenotype, but the enormous difficulties of gene therapy have eliminated it as a real option for almost all disorders at present. The focus has now shifted to other means of modifying gene expression, based to date on investigational studies with no (or at best, limited) clinical applications. However, these strategies may ultimately be important to patients and their families. Studies sponsored by the US National Institutes of Health can usually be identified through www.clinicaltrials.gov. A corollary is, if a patient has undergone genetic testing in the past, was that test sufficient to answer the questions that the patient/paediatrician has now or does new knowledge or the availability of new/improved tests require additional testing? This is one of the most difficult questions to answer. Regarding molecular genetic testing: • the number of inherited diseases for which molecular genetic testing is available is increasing each year (from about 100 diseases in 1993 to more than 1000 in 2007) • new molecular genetic tests are ‘brought online’ at an unpredictable rate • the introduction of new molecular genetic testing methods increases the ability to identify mutations in a specific gene. Regarding cytogenetic testing: • general improvements in routine karyotyping have increased the ability to detect small chromosome aberrations (many geneticists advocate repeating even routine karyotyping every 5–10 years because of the increased yield as even the best laboratories become more skilled over time) • new methods of chromosome analysis (e.g. FISH, subtelomeric chromosome analysis) allow detection of submicroscopic deletions and duplications not seen on routine karyotyping • new methods (e.g. array CGH) can detect smaller deletions and duplications than FISH and can test for many (>100) aberrations at one time.
Who needs to be tested? When considering genetic testing to clarify the genetic status of family members for predictive testing or for carrier testing/prenatal testing/PGD, it is essential that the paediatrician understands the correct way to use testing. When molecular genetic testing is highly sensitive and specific, it is necessary to first confirm the diagnosis in an affected family member before testing at-risk relatives. For example, molecular genetic testing for fragile X syndrome involves assessing the size of the CGG repeat in the FMR1 gene, a test that can accurately determine whether a disease-causing mutation is present or absent in any individual. However, learning difficulties have numerous genetic and non-genetic causes; therefore, the diagnosis of fragile X syndrome must be confirmed in at least one affected family member before genetic testing can be used to clarify the genetic status of other family members (i.e. whether they are carriers of fragile X syndrome or have fragile X syndrome). If the diagnosis of fragile X syndrome is not first established by molecular genetic testing in an affected family member, testing relatives for an expansion in the FMR1 gene is meaningless and provides false reassurance when the test is negative. When multiple mutations in a given gene can give rise to a disorder, the family-specific disease-causing mutation or mutations must be identified in an affected family member first. If the family-specific mutation is unknown, failure to identify a mutation in another family member is ‘uninformative’; that is, one does not know whether a negative test result is a true negative (the family member does not have the family-specific mutation) or a false negative (e.g. the wrong portion of the gene was tested to identify the mutation or the wrong gene was tested). For example, the offspring of a parent with familial adenomatous polyposis (FAP) have a 50% risk of having the disorder. It is reasonable to use molecular genetic testing to establish the genetic status of a child at risk of FAP at a young age (<10 years) so that only children with the family-specific mutation have to undergo routine colonscopy. However, the exact (family-specific) mutation must first be identified in an affected individual. Only when the exact mutation is known can predictive testing be informative.
PAEDIATRICS AND CHILD HEALTH 17:9
What is a genetics consultation? A genetics consultation includes a genetic evaluation and genetic counselling. Genetic evaluation is the process of gathering 368
© 2007 Elsevier Ltd. All rights reserved.
Occasional review
Puberty: for those without a diagnosis, the social and/or medical upheaval accompanying puberty can re-energize the search for a diagnosis, particularly if the patient becomes distanced from his or her peers due to health issues and/or ability.
information on a patient or family with a known or suspected genetic disorder and includes a three-generation family history, establishing a diagnosis through physical examination and genetic testing, and risk assessment. Genetic counselling is the process of educating patients and parents about the nature and cause of the inherited disorder, conveying genetic risks, providing information for informed medical and personal decisionmaking, offering psychosocial support and referral, and referring geographically dispersed at-risk family members to local genetic services.2 Most paediatricians do not have the time or the personnel to undertake extensive information gathering (e.g. obtaining medical records of relatives who are not in their practice, interpreting/clarifying the results of previous genetic studies) and/or genetic counselling.
Age 18 years and above: the focus shifts to the recurrence risk in the child with the disorder and/or sibs of reproductive age, thereby renewing the search for a diagnosis, if one has not been established, and/or raising questions about the use of genetic testing to clarify the genetic status (and recurrence risk) in family members. Where can I go to get help and information about the condition? GeneTests (www.genetests.org) is a resource widely used by health-care professionals and comprises: • GeneReviews (more than 380 expert-authored, peer-reviewed disease descriptions emphasizing the use of currently available tests in patient care) • a laboratory directory of over 600 laboratories offering molecular genetic, biochemical and specialized cytogenetic testing for more than 1000 inherited disorders • a searchable directory of over 1000 US genetics clinics by city • consumer-oriented resources.
Who provides genetic services? Genetic professionals comprise three groups. When the concern is diagnosis, paediatricians are likely to consult a medical geneticist with training in paediatrics. For children with a known or suspected metabolic disorder based on newborn screening, expanded newborn screening or clinical presentation, the pediatrician is likely to consult a biochemical geneticist. When personal decision-making is the key issue, referral to a genetic counsellor may be the most appropriate. When should I refer my patient for a genetics consultation? ‘When to test’ can become overwhelmingly complicated for paediatricians who are ‘trying to do everything’. However, the process becomes feasible if they reframe the approach and consider themselves to be part of a triage system in which their role is to make a ‘first cut’ based on ‘what I can do myself’ and ‘what I need to refer to the experts’. Pediatricians who take this approach can determine the boundaries of their expertise and practice para meters when asking themselves the questions discussed above. When to refer a patient with a known or suspected genetic disorder to a genetics professional is not a fixed point. It depends on: • the knowledge base and experience of the physician regarding the disorder • the stage of the disease, the current availability of treatment, and the possibility of new treatment in the future • the family’s need for an expert or second opinion • the family’s stage of dealing with the disorder • the mode of inheritance and reproductive issues for the parents, the sibs of the affected child and the extended family (autosomal dominant disorders and X-linked disorders can have recurrence risk implications for the extended family, while autosomal recessive disorders typically have recurrence risk implications for sibs of the proband only). In the authors’ experience, the issues for families tend to vary with the age of the child.
Where can the family go to get help and information about the condition? Receiving a genetic diagnosis based on laboratory findings can empower parents, many of whom choose to join, or even found, parent support groups to further education and research in that disorder. Such groups can be an important source of patientcentred information and communication, providing families with information on medical problems and management as well as insights into social, emotional and educational issues. Some families who find satisfying emotional support through a patient group are reluctant to embark on testing or further diagnostic evaluations that might dismiss the original diagnosis and possibly result in a new diagnosis for which support is less well developed. Respected, widely used and freely available resources for families with a genetic disorder include the following: • the Genetic Alliance (www.geneticalliance.org), an international coalition of more than 600 advocacy, research and health-care organizations • the Genetics and Rare Conditions site (www.kumc.edu/gec/ geneinfo.html) hosted by the University of Kansas Medical Center provides links to disease-specific lay-advocacy groups, educational materials, specialty clinics and other relevant resources for about 225 genetic diseases • Family Village (www.familyvillage.wisc.edu/index.html), sponsored by the Waisman Center at the University of Wisconsin, provides general resources for families with a disability, along with information on specific diagnoses • Genetics Home Reference (http://ghr.nlm.nih.gov), developed at the National Library of Medicine, comprises specific information on diseases (Genetic Condition Summaries), genes (Gene Summaries), and chromosomes (Chromosome Summaries) as well as a handbook of genetics concepts (Help Me Understand Genetics), a glossary of genetic and medical terms, and links to resources.
Age 0–6 years: parents seek to establish a diagnosis or, if they have a diagnosis, actively gather information on the natural history, prognosis, potential complications, interventions and recurrence risk. Age 6–12 years: identifying appropriate services regarding education, peer relationships, social issues, recreation and activities of daily living become of primary importance.
PAEDIATRICS AND CHILD HEALTH 17:9
369
© 2007 Elsevier Ltd. All rights reserved.
Occasional review
This, along with new advances in testing chromosomes and for metabolic disorders, can be overwhelming for the paediatrician who would like to ‘do it all’. Understandably, this confusion has alienated primary care practitioners and bewildered families. In an ever-changing landscape of test availability, test sensitivity, family issues and needs, paediatrician must be able to think genetically, asking the questions that need to be addressed concerning the use of genetic testing in individual patients at a particular time. By following this process, paediatrician can determine their role in making the decision when to test and when to refer. ◆
What is a common example of genetic testing in pediatric practice? Although molecular genetic testing has added new dimensions to genetic testing, the use of older genetic tests such as cytogenetic testing requires understanding of the core principles of thinking genetically. When and why to test for Down syndrome and what value, if any, new specialized cytogenetic tests have over routine karyotyping are questions familiar to all paediatricians. In most cases, the diagnosis of Down syndrome has been suspected since before birth due to prenatal screening or shortly after birth by an experienced health-care professional. Regardless of the pediatrician’s experience of diagnosing Down syndrome clinically, routine karyotyping is always indicated in a newborn with suspected Down syndrome to: • confirm the diagnosis (parents want the best possible evidence that their child has Down syndrome) • provide risk assessment for the family (the recurrence risk in the parents and extended family for trisomy 21 is different from that for Down syndrome caused by an inherited robertsonian translocation) • address the parents’ questions about the predictive value of karyotyping (e.g. presence or absence of mosaicism). The pediatrician ordering the chromosome test needs to know: • what information the test performed by the laboratory can and cannot provide about the chromosomes • what the test result can and cannot determine regarding the diagnosis, prognosis and management • what questions the parents will ask about the test result and its implications for their child and for them.
References 1 Hayflick SF, Eiff MP. Will the learners be learned? Genet Med 2002; 4: 43–4. 2 Pagon RA. Molecular genetic testing for inherited disorders. Expert Rev Mol Diagn 2004; 4: 135–40.
Practice points • Genetic tests include biochemical, cytogenetic and molecular genetic tests • Genetic testing can be used to clarify the genetic status of an individual to facilitate medical care or personal decisionmaking • The usefulness of genetic testing for a given patient may depend in part on the sensitivity of the test, the age of the patient, the availability of treatment and current family issues • Paediatrician who can ‘think genetically’ (i.e. ask the questions regarding patient care and family issues that need to be answered by the genetic test) are in the optimal position to decide when to test and when to refer
Conclusion Unprecedented and ongoing media publicity about molecular genetic testing, its ethics, the Human Genome Project and the future of ‘personalized medicine’, and previous hyperbole about genetic engineering, have created unwarranted confusion regarding DNA-based testing and its appropriate use in patient care.
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© 2007 Elsevier Ltd. All rights reserved.