Guidelines and Policies on Genetic Testing in Children and Families

Abstract

Rapid advances in genomic-based sciences are facilitating the collection of a burgeoning amount of knowledge about the role that genomic factors play in human disease. The resulting body of knowledge provides hope for more effective treatments and eventually the prevention of diseases and disorders affecting children, adults, and families (Feero, Guttmacher, & Collins, 2008; Guttmacher & Collins, 2005). However, this knowledge and technology could be used inappropriately, resulting in harm to the medical, psychological, and social well-being of those pursuing testing (Hudson, Javitt, Burke, & Byers, 2007; Robertson, 2003). The rapidly increasing breadth and availability of genomic tests are leading to heightened concerns about their application in clinical settings, public health, and outside of the health-care setting, through direct-to-consumer (DTC) marketing (Hudson et al., 2007; Javitt, Stanley, & Hudson, 2004).

The views expressed in this chapter are those of the authors and do not necessarily reflect the official policy or position of the National Institutes of Health, the Department Health and Human Services, or the US Government.

APPENDIX

Case Scenario 1

Pediatric Genetic Testing for Diagnostic and Medical Management Purposes

A comprehensive examination of the child depicted in Figure 1 (Individual III-5) included a genetics physical examination, collection and review of family medical history, a neurological examination, electromyography (to evaluate and record muscle signals), and nerve conduction velocity studies (to evaluate the function, especially the electrical conduction, of the motor and sensory nerves). This led to a preliminary diagnosis of spinal muscular atrophy (SMA). SMA is an autosomal recessive condition, which results in progressive muscle weakness due to the loss of lower motor neurons in the spinal cord and brain stem. Individuals affected with SMA have mutations in both copies of either the SMN1 or the SMN2 gene. After comprehensive education and counseling, the child’s parents elected to pursue genetic testing, with the hope of finding a specific cause for their child’s progressive muscle weakness. Testing of the child’s blood sample demonstrated the classic SMA mutation in both copies of SMN1, suggesting that both parents are unaffected carriers of a mutation in one copy of SMN1. Based on this information, the parents have a 25% chance of having another child affected with SMA each time a pregnancy is conceived. Given the incidence of non-paternity within the USA, if private conversations with the mother indicate that non-paternity should be considered, carrier status should be confirmed through molecular testing. Approximately 1 of every 50 people in the USA is an unaffected carrier of an SMA mutation, making it relatively common. The identification of such mutations within the immediate family (parents and child) simultaneously identifies risks for more distant family members, i.e., siblings of the child, uncles/aunts, and grandparents.

SMA has different levels of severity. Given the age at which this child developed symptoms, she would be classified as having SMA II and would be expected to have normal cognitive development; however, her gross motor development will be hampered, and she may only be able to sit independently. Unfortunately, this skill is often lost by the mid-teens, and wheelchair dependence is inevitable. The literature suggests that about 70% of persons with SMA II are still alive by the age of 25 years. Based on the diagnosis, questions about the future will need to be addressed, including appropriate medical, educational, socio-legal preparations; however, this is often very challenging to address with the family.

Case Scenario 2

Carrier Testing

Reconsidering the pedigree presented in Figure 1, carrier testing might be of interest to several family members to determine if they carry a single copy of the mutation for SMA. This would provide information about their reproductive risks (e.g., risks to future offspring). For example, the partner of the index case’s maternal uncle (II-5) is currently pregnant (12th gestational week). They have close contact with the affected child and observed her developmental difficulties. Having lost a previous pregnancy, they have expressed interest in knowing if the father (II-5) carries the SMA mutation, increasing the chances that the child of the current pregnancy could be affected. With ample time remaining for testing during this pregnancy, carrier testing would first be conducted on the father; if he is a carrier, then carrier testing would be conducted on his partner. If both prospective parents carry a SMA mutation, prenatal genetic testing for SMA could be considered for the current pregnancy. Although professional guidelines suggest that carrier testing is most appropriate when considered by an adult following education and counseling, and conducted outside of pregnancy or other stressful life events, this is not always possible, as this scenario presents.

Other family members might also express interest in carrier testing for themselves or their children to clarify reproductive risks. As seen in Figure 1, the mother of the affected child has a 12-year-old son (III-6) with a previous partner and would like her son to have carrier testing. Limited research exists to guide such requests, with conflicting results and conclusions. Some parents maintain that they are in the best position to make decisions about obtaining information about their child’s genetic status for the disease in their family and educating their child about their status. However, parents deciding to have their child undergo carrier testing precludes the right of that child not to know their carrier status. Certainly, parents may involve a child in the education and counseling leading to a decision regarding carrier testing. However, in the absence of emotional maturity, a child’s assent leaves the parent in a position of power.

After several months of periodic contact between the family, the Pediatrician, and the Genetics team, the index case’s half-brother (III-6) was able to express to his parents his lack of interest in knowing his SMA carrier status at this point in time. He verbalized that he would most likely want to know at a time when he is considering having children. He was also able to express concern about knowing his carrier status. Despite his mother’s initial strong interest in knowing his carrier status, his verbalization of concerns and thoughts about carrier testing curtailed her initial urgency to pursue testing.

Case Scenario 3

Presymptomatic Testing for Disease Potentially Presenting During Childhood

The family depicted in the pedigree presented below (Figure 2) has an autosomal dominant inherited cancer susceptibility syndrome known as multiple endocrine neoplasia, type 2 (MEN 2). MEN 2 poses certain risk for thyroid cancer, along with other health risks. Three MEN 2 subtypes have been identified; MEN 2B causes medullary thyroid cancer (MTC) in early childhood. Thyroid cancer associated with MEN 2 can be prevented by prophylactic thyroidectomy (removal of the thyroid prior to the onset of disease), the timing of which depends on the specific mutation identified within the RET gene. For the family described in Figure 2, surgery is recommended before age 5.

Figure 2.

Pedigree of family with MEN 2B.

Carriers of mutations in the RET gene often demonstrate other physical features suggestive of MEN 2 (e.g., distinctive facial features, tall lanky body, and characteristic findings of the lips and tongue). However, molecular genetic testing provides early identification of at-risk family members, improving diagnostic certainty and reducing the need for costly screening procedures in family members who have not inherited the disease-causing mutation. While prophylactic removal of the thyroid eliminates the risk of thyroid cancer, other health screening is necessary due to increased risk for pheochromocytoma. A pheochromocytoma is a rare tumor that develops in the core of adrenal glands, which sit above each kidney and produce essential hormones. Pheochromocytoma can cause the adrenal glands to produce too much of certain hormones, raising blood pressure and heart rate to potentially life-threatening levels if not treated. Screening for pheochromocytomas include annual biochemical screening, followed by MRI if the biochemical results are abnormal.

In the family illustrated in Figure 2, the 3-year-old boy (III-3) has a 50% risk of inheriting the RET mutation known to be carried by his father (II-3). After careful discussions with both parents, genetic testing for the known RET mutation will be completed to clarify the boy’s mutation status. Should he carry the familial mutation, surgery would be recommended prior to his fifth birthday. While his father demonstrates the classic physical features of MEN 2B, the 3-year-old boy demonstrates facial features reminiscent of both parents. His mother openly shares her belief that her son will not have the mutation carried by his father. While she may be correct in her assessment, the Genetics professionals are careful to recognize her response as an attempt to deny the empiric risks faced by her son. Genetic testing a full year ahead of when surgery might be needed provides adequate time to help the parents anticipate and prepare for the possible outcomes of testing, which, ideally, will assist their adjustment to outcome.

Case Scenario 4

Presymptomatic Genetic Testing for Adult-Onset Disease During Childhood

The family depicted in the pedigree below (Figure 3) has an inherited cancer susceptibility syndrome known as Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC). A person who carries a single copy of a mutation in one of four genes associated with this syndrome has significant risks for multiple cancers, most notably cancer of the colon, endometrium (uterine wall), stomach, and/or ovaries. Colonoscopy can significantly reduce the chances of colon cancer, by removing polyps before they become cancerous, or decrease the severity if cancer does occur, by identifying cancer early, which results in an improved prognosis. Women have significant risks for endometrial and ovarian cancer, for which cancer screening is less effective. Some women may consider having a complete hysterectomy (removal of their uterus and ovaries) after completion of childbearing as one way to reduce their cancer risk. The cancers associated with Lynch syndrome occur during adulthood. Genetic testing for adult-onset disease is typically postponed until after 18 years of age, with hopes that this will facilitate “mature” consideration of the risks and benefits of genetic testing, allow an informed decision about testing, and facilitate coping and adjustment to results.

Figure 3.

Pedigree of family with Lynch syndrome.

The father (II-3) depicted in Figure 3 is known to carry his family’s mutation for Lynch syndrome and was diagnosed with colon cancer at 35 years of age. His mother (I-2) was diagnosed with colon cancer at 40 and ovarian cancer at 42, which was at an advanced stage and ultimately took her life. The father was 17 at the time of her death and recalls her experiencing tremendous suffering and pain as a result of the ovarian cancer. Her death presented a lasting hardship upon their family, as few relatives were around to help fill the void of his mother’s absence. Understandably, he has palpable fear of recurring cancer for himself and overwhelming concern for cancer affecting his children. He states that his greatest fear is for his daughters. He is adamant that his 13-year-old the daughter (III-5) should undergo genetic testing now so that they can begin to plan her life should she be found to carry the family mutation. He suggests that she could have children at an early age, so that she could undergo a complete hysterectomy and reduce the chances that she experience what his mother went through. In speaking with her pediatrician, the daughter acknowledges her father’s worries about cancer; however, she is not ready to face such big decisions and really just wants to focus on school, soccer, and her friends. She has never told her father how she feels, as she knows how important this is to him.

Case Scenario 5

Genetic Testing for Obesity: A Challenge for the Future

The mother (Individual II-2) in the pedigree in Figure 4 brought her oldest child (individual III-5), age 9, to her primary health-care provider (PCP) for a well-child checkup. While completing the height and weight measurements, the nurse notes that the child is at the 80th percentile for weight and the 50th percentile for height for her age. At her last visit, 2 years earlier, she had been at the 50th percentile for weight and height. The nurse tells the PCP of the new measurements and expresses concern about child III-5’s rapid weight gain.

Figure 4.

Pedigree of family experiencing obesity.

During the visit, the PCP asks the child’s mother if she has noticed any changes in her child’s appearance or eating behaviors. The mother indicates that her daughter has started eating foods high in sugar and salt in between meals, and the mother often feels like her daughter is “eating her out of house and home.” She is particularly concerned because she (the mother) is overweight, as is her husband. The family history reveals that several biological relatives have died of obesity-related causes (see pedigree below). Further questioning reveals that the girl thinks she is bigger than any of the other kids in her class, and that she is teased and mocked at school for her size. While not yet technically obese, the daughter’s weight is high for her height, and she has the potential to become obese during adolescence or early adulthood.

The PCP talks with the child and her mother about healthy food choices and portion control. She refers the family to a registered dietitian for more help making healthy choices at meal and snack times. At the end of the visit, she mentions to the mother that genetic testing for obesity has recently become available. Acknowledging that little is known about the genetic basis of obesity, the PCP asks whether they would be interested in pursuing genetic testing for the most common genetic markers associated with obesity.

Obesity is a complex condition, in which biological (biochemical and genetic) and behavioral (diet, exercise habits, etc.) factors interact to result in the expression of the phenotype of interest (e.g., obesity). Genetic testing is currently available for rare, monogenetic (single-gene) disorders but is not yet available to identify more common genetic factors associated with obesity in the general population. Recent advances in genomic sciences (genome-wide association studies) suggest that genetic testing for complex diseases and characteristics may not be far off. However, interventions specific to the identified genotypic differences (e.g., pharmacogenetic approaches) may never be available or make take many years to develop. This leaves persons considering genomic testing for obesity with the same alternatives for weight loss as others in the general population (diet modification, exercise programs, etc.) leaving the benefit of such testing unclear.

Genetic testing of children for a condition such as obesity is necessarily more complicated than diagnostic or medical testing. Recent studies estimate that obesity in children is likely to have a genetic contribution of about 77% (Wardle et al., 2008); however, this means that the remaining 23% of variation likely has a behavioral component. While genetic testing for obesity might provide valuable information on whether an at-risk child is likely to become obese, there are other issues to consider. One major question is whether providing genetic risk information for a condition such as obesity will lead to behavior changes, resulting in a different phenotype than if those behavioral changes were not implemented. Obesity is also a stigmatized condition; revealing that a genetic predisposition is partly responsible for an obese person’s weight might result in a lower level of stigma. Additional questions include the penetrance of any obesity-related genetic variations (e.g., how likely is it that the child who tests positive for an obesity-related variant will go on to become obese); the possibility that parents of a child with a tendency toward obesity will change their behavior toward that child; and the possibility that stigma and discrimination will not be eliminated even when obesity is found to have a genetic, unchangeable, component.

After consultation with a genetic counselor regarding genetic testing of child III-5 for obesity-related genetic variants, her parents chose not to have her undergo genetic testing. Instead, the family is making changes in food choices and increasing their overall level of physical activity in order to limit their daughter’s weight gain.