Clin Genet 2015 Printed in Singapore. All rights reserved
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12566
Short Report
Ethical considerations of population screening for late-onset genetic disease Golden-Grant K., Merritt II J.L., Scott C.R. Ethical considerations of population screening for late-onset genetic disease. Clin Genet 2015. © John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2015 Population-based genetic screening has been a mainstay of public health in the United States for many years. The goal of genetic screening is to identify individuals at increased risk for treatable diseases. The evolution of genetic testing to include multi-disease panels allows for new screening applications which challenge the traditional model of clinical genetics care by the identification of late-onset disorders in an asymptomatic fetus, child, or adult. We present two unique examples of individuals referred to a biochemical genetics clinic due to the detection of late-onset Pompe disease by population-based screening modalities. We review early experiences in counseling and management of pre-symptomatic individuals and highlight some of the primary ethical factors warranting consideration as we enter the era of genomic medicine. Conflict of interest
The authors report no other acknowledgements or conflicts of interests.
Population-based screening is intended to identify individuals at increased risk for disease with the goal of providing an improved health outcome for affected individuals by early initiation of available therapies (1). The two most prevalent population-based screening programs – prenatal carrier screening and newborn screening (NBS) – have rapidly expanded in the past decade. Prenatal carrier screening transitioned from ethnicity-based to universal carrier screening utilizing untargeted screening panels (2, 3). Some universal panels provide carrier information for over 100 recessive disorders including some considered to be mild or to have adult-onset presentations (4). State programs have similarly experienced significant growth through the use of tandem mass spectrometry to detect fatty acid oxidation disorders, amino acidopathies, and organic acidemias and now continue their expansion to include the lysosomal storage disorders (5, 6). Prenatal and newborn screening platforms will continue to expand because of the rapid progression in genomic sequencing technologies and applications (7). These advances in screening technologies now permit the identification of individuals with late-onset disease,
K. Golden-Granta , J.L. Merritt IIb and C.R. Scottb a Seattle
Children’s Hospital and of Pediatrics, University of Washington, Seattle, WA, USA
b Department
Key words: autonomy – beneficence – ethics – genetic screening – justice – newborn screening – non-maleficence – next-generation sequencing – Pompe disease Corresponding author: Kathryn Golden-Grant, Department of Pediatrics, Seattle Children’s Hospital, M/S O.C.9.850, PO Box 5371, Seattle, WA 98105, USA. Tel.: +1 206 987 1389; fax: +1 206 987 2495; e-mail: [email protected] Received 19 December 2014, revised and accepted for publication 3 February 2015
creating so-called ‘patients in waiting’ – those with a genetic diagnosis but without clinical symptoms and without indication for treatment initiation (8). The aim of this paper is to encourage discussion of the ethical considerations related to population screening for mild and late-onset disorders. We highlight this topic by sharing two unique patients diagnosed with late-onset Pompe disease by prenatal carrier screening. Pompe disease provides an excellent example for this discussion because of its significant variability in age of onset and symptom severity, as well as our incomplete knowledge of genotype–phenotype correlations. Pompe disease background
Pompe disease is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid alpha-glucosidase (GAA) which results from mutations in the gene GAA (9). Enzyme activity is generally lower in individuals with infantile-onset Pompe disease compared to those with adult-onset disease; however, there is overlap and the two forms are sometimes indistinguishable by enzyme measurement. As of 2012, there
1
Golden-Grant et al. were 248 known pathogenic mutations in the GAA (10). Although genotype may help predict disease course, there are other unknown factors which influence age of onset and disease progression (11, 12). The GAA IVS1-13T > G mutation has a residual enzyme activity of 20–40% and is present in around 71% of people with late-onset Pompe disease worldwide. This mutation has not been identified in patients with infantile-onset Pompe (13, 14). There is significant phenotypic variability among individuals with the IVS1-3T > G mutation which appears to be dependent upon the nature of the paired mutation (13, 15). Homozygosity for IVS1-13T > G has been hypothesized to result in an asymptomatic presentation and has been described in a single report of a French female with onset of myopathy at age 35 years, 90% forced vital capacity, and 11% residual GAA activity (13, 16). Management for late-onset Pompe disease involves a multi-disciplinary medical team and GAA enzyme replacement therapy (ERT) (17). In the infantile Pompe population, ERT has been well-documented to show significant effectiveness in reversing and preventing hypertrophic cardiomyopathy and extending life expectancy (9). ERT appears to be less efficacious in the late-onset Pompe population, with only modest improvements in muscle strength and respiratory function and limited improvement in quality of life (9, 18). Current management guidelines indicate that ERT should be initiated when a patient first becomes symptomatic (17). Methods and materials
We report the experience of two presymptomatic individuals presenting to the Biochemical Genetics program at the University of Washington and Seattle Children’s Hospital. Using Beauchamp and Childress’ four principles of biomedical ethics, the authors highlight several of these principles relating to population screening for late-onset genetic disorders (19). Results
Patient 1 is a healthy 34-year old woman who underwent universal carrier screening by Counsyl (San Francisco, CA) during her first trimester of pregnancy. Screening revealed homozygosity for the IVS1-13T > G mutation in GAA, which was confirmed with Sanger sequencing. The patient exhibited normal strength and endurance. Her forced vital capacity was 114 percent of predicted and her electrocardiogram was normal. Her GAA enzyme activity was in the indeterminate range with normal creatine kinase, AST, and ALT. Patient 2 is an infant female who was prenatally diagnosed as homozygous for IVS1-13T > G on amniocentesis after both parents were identified as carriers by Counsyl universal carrier screening. Following delivery, the infant’s GAA activity was at the low end of the normal range and her creatine kinase level was normal. Echocardiogram and electrocardiogram showed no evidence of hypertrophy or conduction defects. At 1 year of life the patient has normal muscle tone and strength.
2
Per current Pompe management guidelines, Patients 1 and 2 have not initiated ERT. They will both return to clinic annually for assessment of symptom onset. Discussion
In both of the cases described, population-based screening provided information which may imply a future risk for Pompe disease, but immediate health was not impacted. Screening for late-onset disease has implications for patient autonomy, beneficence, non-maleficence, and justice. We present real-world experience of these ethical principles, generated by conversation and questions raised by the patients and their families, which must be considered as new screening platforms continue to be implemented. Autonomy
Autonomy is limited when a patient or parent does not consent to screening or provides consent without awareness of the potential outcomes. Although consent is generally required for women undergoing prenatal carrier screening, these practices face increasing scrutiny as screening panels expand without adequate pre-test genetic counseling, creating increased risk for unclear or unintended results (2). Contributing to the complexity of pre-test education is the possibility of unintentionally identifying a genetic condition in the woman herself, as with Patient 1. The chance of an unintended diagnosis is increased with the inclusion of mild or late-onset disorders on carrier screening panels. Historically, predictive genetic testing of minors has been discouraged and deferred until the child is deemed mature enough to understand the test’s implications (20, 21). The prenatal diagnosis of Patient 2 has removed this child’s autonomy to decline the information that the test provides. She has not considered how this information will affect her future medical care as an adolescent or adult, including its effect on health and life insurance. In addition, results of prenatal testing and newborn screening are shared with parents, eliminating the proband’s choice to share his or her diagnosis with relatives. A competent adult proband has typically consented to screening or testing and determines who to share this information with. This raises the question of whether clinicians have a responsibility to warn at-risk family members of their risk for mild or late-onset disease. The harms of breaking patient–clinician confidentiality may be greater than the harms of withholding disease risk information from relatives. Extrapolating to newborn screening expansion, the proband experiences a similar loss of decision-making capacity. Additionally, parental autonomy is limited by performing NBS without consent. The potential for diagnosis of mild or late-onset disorders has reinvigorated the ongoing debate of parental involvement in NBS and some have argued that consent be required when screening could identify predictive information about the child’s health (5, 7, 8, 22).
Ethical considerations of population screening Nonmaleficence
Justice
The loss of the proband’s autonomy is compounded by the potential harm to the proband and/or parents. An inactive diagnosis may impart stresses upon the child–parent unit because of anxiety, stigmatization, discrimination, overprotection, and parental guilt (5, 21, 22). Although parents and providers may feel screening is in the child’s best interest, many argue that the child’s loss of self-determination is contrary to his or her own best interest (21). Both Patients 1 and 2 may experience these psychological harms in addition to increased practical and financial burden of health evaluations that may span decades. The benefit of these evaluations is unknown in these cases. If either patient becomes symptomatic, she will be offered ERT, per current guidelines; however, the cost, both monetary and otherwise, of ERT may not outweigh the potential benefits in individuals with late-onset Pompe disease (9, 17, 18). Prenatal carrier screening can lead to prenatal diagnosis of a fetus, as with Patient 2. This family was given the option of pregnancy termination following diagnosis. Termination in this situation would result in the loss of a potentially healthy life, and may result in psychological harm to the parents. Extensive education and counseling is critical for parents considering termination after prenatal genetic diagnosis of a late-onset condition.
The two cases presented describe individuals who had access to healthcare, providers who informed them of prenatal carrier screening, and referrals to the appropriate specialists for follow-up. Not all people have access to these services for various reasons including location and cost of healthcare. The successful implementation of expanded population screening will depend on the involvement of clinical geneticists and genetic counselors to educate other providers, discuss results with patients, and provide medical management for those with positive results (8). However, the current number of genetics providers may not be adequate to accommodate this increased demand (2). This discrepancy may lead to care inequality, such as some individuals not receiving the appropriate education necessary to make informed decisions about screening. People who lack adequate counseling resources may have their results misinterpreted which may lead to misguided medical management.
Beneficence
The avoidance of the ‘diagnostic odyssey’ is often cited as a primary benefit of early diagnosis of late-onset disorders (5). Whereas knowing the diagnosis prior to symptom onset may reduce the stresses of extensive testing, this knowledge of a late-onset condition in the pre-symptomatic state is most beneficial when preventative therapies are available (21). Early diagnosis may also give an individual the opportunity to plan and pursue a lifestyle (i.e. education, career, family) which will not be significantly impacted by the onset and progression of the disease (21). The benefit of a pre-symptomatic diagnosis is less obvious for conditions without available treatment, and it has been argued that screening for untreatable conditions should not be performed (21, 22). Benefit of the knowledge of a late-onset condition has also been called into question for circumstances in which the phenotype and/or age of onset cannot be reliably predicted from the genotype, as in the cases described (21). The potential for patient and familial stress and anxiety may outweigh the benefits, which are unclear. The impact on relatives of an individual diagnosed with a late-onset disorder as a result of screening cannot be ignored. As with screening for any disorder, relatives gain information about their personal health and reproductive risk upon a familial diagnosis. This may encourage medical evaluation and genetic counseling for at-risk individuals.
Conclusion
Advances in genetic technologies have allowed for an ever-evolving number of conditions identified through population screening. The identification of individuals at risk for late-onset genetic disorders presents significant practical and ethical issues, including the training of the consenting provider, availability of genetics providers, autonomy of the patient and family, and potential psychological harms weighed against potential benefits to the patient. These challenges may be further exacerbated by the continued expansion of population screening practices – including the potential use of whole genome sequencing (2, 7). Ethical and responsible implementation of expanding screening technologies requires ongoing critical consideration and discussion among the genetics community. Acknowledgements K. G.-G. and J. L. M. disclose no conflicts of interest for any affiliation, financial agreement, or other involvement with any company in the submitted manuscript. C. R. S. is the recipient of grant support through his institution, the University of Washington, for clinical trials for Pompe and other lysosomal storage diseases. He also receives grants through the UW for research on newborn screening for Pompe disease and other lysosomal storage diseases and for providing education to other providers about these diseases. These clinical trials and grants have been sponsored by the NIH (HHSN267200603429C and 2 R01 DK067859), Genzyme Corporation and Perkin Elmer. Dr. Scott is also a consultant to Genzyme Corporation for Pompe and other lysosomal storage diseases. Potential conflicts of interests are managed through the University of Washington Office of Research.
References 1. Commission on Chronic Illness. Prevention of chronic illness. Chronic illness in the United States. Vol. 1. Cambridge, MA: Harvard University, 1957.
3
Golden-Grant et al. 2. Musci TJ. Screening for single gene genetic disorders. Gynecol Obstet Invest 2005: 60: 19–26. 3. Ram KT, Klugman SD. Best practices: antenatal screening for common genetic conditions other than aneuploidy. Curr Opin Obstet Gynecol 2010: 22: 139–145. 4. Srinivasan BS, Evans EA, Flannick J et al. A universal carrier test for the long tail of Mendelian disease. Reprod Biomed Online 2010: 21: 537–551. 5. Grosse SD, Boyle CA, Kenneson A, Khoury MJ, Wilfond BS. From public health emergency to public health service: the implications of evolving criteria for newborn screening panels. J Pediatr 2006: 117: 923–929. 6. Scott CR, Elliott S, Buroker N et al. Identification of infants at risk for developing Fabry, Pompe, or Mucopolysaccharidosis-I from newborn blood spots by tandem mass spectrometry. J Pediatr 2013: 163: 498–503. 7. Tarini BA, Goldenberg AJ. Ethical issues with newborn screening in the genomics era. Annu Rev Genomics Hum Genet 2012: 13: 381–393. 8. Ross LF, Saal HM, David KL, Anderson RR. ACMG Policy Statement: technical report: ethical and policy issues in genetic testing and screening of children. Genet Med 2013: 15 (3): 234–245. 9. Teener JW. Late-onset Pompe disease. Semin Neurol 2012: 32: 506–511. 10. Kroos MA, Hoogeveen-Westerveld M, Michelakakis H et al. Update of the Pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants. Hum Mutat 2012: 33 (8): 1161. 11. Kroos MA, Pomponio RJ, van Vliet L et al. Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. Hum Mutat 2008: 29 (6): 13–26. 12. Wens SC, van Gelder CM, Kruijshaar ME et al. Phenotypical variation within 22 families with Pompe disease. Orphanet J Rare Dis 2013: 8: 182.
4
13. Hule ML, Chen AS, Tsujino S et al. Aberrant splicing in adult onset glycogen storage disease type II (GSDII): molecular identification of an IVS1 (−13T > G) mutation in a majority of patients and a novel IVS10 (+1GT > CT) mutation. Hum Mol Genet 1994: 3 (12): 2231–2236. 14. Kroos MA, van der Kraan M, van Diggelen OP et al. Glycogen storage disease type II: frequency of three common mutant alleles and their associated clinical phenotypes in 121 patients. J Med Genet 1995: 32: 836–840. 15. Hermans MM, van Leenen D, Kroos MA et al. Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. Hum Mutat 2004: 23 (1): 47–56. 16. Laforet P, Nicolino M, Eymard B et al. Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation. Neurology 2000: 55: 1122–1128. 17. Cupler EJ, Berger KI, Leshner RT et al. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve 2012: 45 (3): 319–333. 18. Toscano A, Schoser B. Enzyme replacement therapy in late-onset Pompe disease: a systematic literature review. J Neurol 2013: 260: 951–959. 19. Beauchamp TL, Childress JF. Principles of biomedical ethics, 6th edn. New York, NY: Oxford University Press, 2013. 20. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet 1995: 57: 1233–1241. 21. Fryer A. Inappropriate genetic testing of children. Arch Dis Child 2000: 83: 283–285. 22. Orzaleski M, Danhive O. Ethical problems with neonatal screening. Ann Ist Super Sanita 2009: 43 (3): 325–330.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12566
Short Report
Ethical considerations of population screening for late-onset genetic disease Golden-Grant K., Merritt II J.L., Scott C.R. Ethical considerations of population screening for late-onset genetic disease. Clin Genet 2015. © John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2015 Population-based genetic screening has been a mainstay of public health in the United States for many years. The goal of genetic screening is to identify individuals at increased risk for treatable diseases. The evolution of genetic testing to include multi-disease panels allows for new screening applications which challenge the traditional model of clinical genetics care by the identification of late-onset disorders in an asymptomatic fetus, child, or adult. We present two unique examples of individuals referred to a biochemical genetics clinic due to the detection of late-onset Pompe disease by population-based screening modalities. We review early experiences in counseling and management of pre-symptomatic individuals and highlight some of the primary ethical factors warranting consideration as we enter the era of genomic medicine. Conflict of interest
The authors report no other acknowledgements or conflicts of interests.
Population-based screening is intended to identify individuals at increased risk for disease with the goal of providing an improved health outcome for affected individuals by early initiation of available therapies (1). The two most prevalent population-based screening programs – prenatal carrier screening and newborn screening (NBS) – have rapidly expanded in the past decade. Prenatal carrier screening transitioned from ethnicity-based to universal carrier screening utilizing untargeted screening panels (2, 3). Some universal panels provide carrier information for over 100 recessive disorders including some considered to be mild or to have adult-onset presentations (4). State programs have similarly experienced significant growth through the use of tandem mass spectrometry to detect fatty acid oxidation disorders, amino acidopathies, and organic acidemias and now continue their expansion to include the lysosomal storage disorders (5, 6). Prenatal and newborn screening platforms will continue to expand because of the rapid progression in genomic sequencing technologies and applications (7). These advances in screening technologies now permit the identification of individuals with late-onset disease,
K. Golden-Granta , J.L. Merritt IIb and C.R. Scottb a Seattle
Children’s Hospital and of Pediatrics, University of Washington, Seattle, WA, USA
b Department
Key words: autonomy – beneficence – ethics – genetic screening – justice – newborn screening – non-maleficence – next-generation sequencing – Pompe disease Corresponding author: Kathryn Golden-Grant, Department of Pediatrics, Seattle Children’s Hospital, M/S O.C.9.850, PO Box 5371, Seattle, WA 98105, USA. Tel.: +1 206 987 1389; fax: +1 206 987 2495; e-mail: [email protected] Received 19 December 2014, revised and accepted for publication 3 February 2015
creating so-called ‘patients in waiting’ – those with a genetic diagnosis but without clinical symptoms and without indication for treatment initiation (8). The aim of this paper is to encourage discussion of the ethical considerations related to population screening for mild and late-onset disorders. We highlight this topic by sharing two unique patients diagnosed with late-onset Pompe disease by prenatal carrier screening. Pompe disease provides an excellent example for this discussion because of its significant variability in age of onset and symptom severity, as well as our incomplete knowledge of genotype–phenotype correlations. Pompe disease background
Pompe disease is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid alpha-glucosidase (GAA) which results from mutations in the gene GAA (9). Enzyme activity is generally lower in individuals with infantile-onset Pompe disease compared to those with adult-onset disease; however, there is overlap and the two forms are sometimes indistinguishable by enzyme measurement. As of 2012, there
1
Golden-Grant et al. were 248 known pathogenic mutations in the GAA (10). Although genotype may help predict disease course, there are other unknown factors which influence age of onset and disease progression (11, 12). The GAA IVS1-13T > G mutation has a residual enzyme activity of 20–40% and is present in around 71% of people with late-onset Pompe disease worldwide. This mutation has not been identified in patients with infantile-onset Pompe (13, 14). There is significant phenotypic variability among individuals with the IVS1-3T > G mutation which appears to be dependent upon the nature of the paired mutation (13, 15). Homozygosity for IVS1-13T > G has been hypothesized to result in an asymptomatic presentation and has been described in a single report of a French female with onset of myopathy at age 35 years, 90% forced vital capacity, and 11% residual GAA activity (13, 16). Management for late-onset Pompe disease involves a multi-disciplinary medical team and GAA enzyme replacement therapy (ERT) (17). In the infantile Pompe population, ERT has been well-documented to show significant effectiveness in reversing and preventing hypertrophic cardiomyopathy and extending life expectancy (9). ERT appears to be less efficacious in the late-onset Pompe population, with only modest improvements in muscle strength and respiratory function and limited improvement in quality of life (9, 18). Current management guidelines indicate that ERT should be initiated when a patient first becomes symptomatic (17). Methods and materials
We report the experience of two presymptomatic individuals presenting to the Biochemical Genetics program at the University of Washington and Seattle Children’s Hospital. Using Beauchamp and Childress’ four principles of biomedical ethics, the authors highlight several of these principles relating to population screening for late-onset genetic disorders (19). Results
Patient 1 is a healthy 34-year old woman who underwent universal carrier screening by Counsyl (San Francisco, CA) during her first trimester of pregnancy. Screening revealed homozygosity for the IVS1-13T > G mutation in GAA, which was confirmed with Sanger sequencing. The patient exhibited normal strength and endurance. Her forced vital capacity was 114 percent of predicted and her electrocardiogram was normal. Her GAA enzyme activity was in the indeterminate range with normal creatine kinase, AST, and ALT. Patient 2 is an infant female who was prenatally diagnosed as homozygous for IVS1-13T > G on amniocentesis after both parents were identified as carriers by Counsyl universal carrier screening. Following delivery, the infant’s GAA activity was at the low end of the normal range and her creatine kinase level was normal. Echocardiogram and electrocardiogram showed no evidence of hypertrophy or conduction defects. At 1 year of life the patient has normal muscle tone and strength.
2
Per current Pompe management guidelines, Patients 1 and 2 have not initiated ERT. They will both return to clinic annually for assessment of symptom onset. Discussion
In both of the cases described, population-based screening provided information which may imply a future risk for Pompe disease, but immediate health was not impacted. Screening for late-onset disease has implications for patient autonomy, beneficence, non-maleficence, and justice. We present real-world experience of these ethical principles, generated by conversation and questions raised by the patients and their families, which must be considered as new screening platforms continue to be implemented. Autonomy
Autonomy is limited when a patient or parent does not consent to screening or provides consent without awareness of the potential outcomes. Although consent is generally required for women undergoing prenatal carrier screening, these practices face increasing scrutiny as screening panels expand without adequate pre-test genetic counseling, creating increased risk for unclear or unintended results (2). Contributing to the complexity of pre-test education is the possibility of unintentionally identifying a genetic condition in the woman herself, as with Patient 1. The chance of an unintended diagnosis is increased with the inclusion of mild or late-onset disorders on carrier screening panels. Historically, predictive genetic testing of minors has been discouraged and deferred until the child is deemed mature enough to understand the test’s implications (20, 21). The prenatal diagnosis of Patient 2 has removed this child’s autonomy to decline the information that the test provides. She has not considered how this information will affect her future medical care as an adolescent or adult, including its effect on health and life insurance. In addition, results of prenatal testing and newborn screening are shared with parents, eliminating the proband’s choice to share his or her diagnosis with relatives. A competent adult proband has typically consented to screening or testing and determines who to share this information with. This raises the question of whether clinicians have a responsibility to warn at-risk family members of their risk for mild or late-onset disease. The harms of breaking patient–clinician confidentiality may be greater than the harms of withholding disease risk information from relatives. Extrapolating to newborn screening expansion, the proband experiences a similar loss of decision-making capacity. Additionally, parental autonomy is limited by performing NBS without consent. The potential for diagnosis of mild or late-onset disorders has reinvigorated the ongoing debate of parental involvement in NBS and some have argued that consent be required when screening could identify predictive information about the child’s health (5, 7, 8, 22).
Ethical considerations of population screening Nonmaleficence
Justice
The loss of the proband’s autonomy is compounded by the potential harm to the proband and/or parents. An inactive diagnosis may impart stresses upon the child–parent unit because of anxiety, stigmatization, discrimination, overprotection, and parental guilt (5, 21, 22). Although parents and providers may feel screening is in the child’s best interest, many argue that the child’s loss of self-determination is contrary to his or her own best interest (21). Both Patients 1 and 2 may experience these psychological harms in addition to increased practical and financial burden of health evaluations that may span decades. The benefit of these evaluations is unknown in these cases. If either patient becomes symptomatic, she will be offered ERT, per current guidelines; however, the cost, both monetary and otherwise, of ERT may not outweigh the potential benefits in individuals with late-onset Pompe disease (9, 17, 18). Prenatal carrier screening can lead to prenatal diagnosis of a fetus, as with Patient 2. This family was given the option of pregnancy termination following diagnosis. Termination in this situation would result in the loss of a potentially healthy life, and may result in psychological harm to the parents. Extensive education and counseling is critical for parents considering termination after prenatal genetic diagnosis of a late-onset condition.
The two cases presented describe individuals who had access to healthcare, providers who informed them of prenatal carrier screening, and referrals to the appropriate specialists for follow-up. Not all people have access to these services for various reasons including location and cost of healthcare. The successful implementation of expanded population screening will depend on the involvement of clinical geneticists and genetic counselors to educate other providers, discuss results with patients, and provide medical management for those with positive results (8). However, the current number of genetics providers may not be adequate to accommodate this increased demand (2). This discrepancy may lead to care inequality, such as some individuals not receiving the appropriate education necessary to make informed decisions about screening. People who lack adequate counseling resources may have their results misinterpreted which may lead to misguided medical management.
Beneficence
The avoidance of the ‘diagnostic odyssey’ is often cited as a primary benefit of early diagnosis of late-onset disorders (5). Whereas knowing the diagnosis prior to symptom onset may reduce the stresses of extensive testing, this knowledge of a late-onset condition in the pre-symptomatic state is most beneficial when preventative therapies are available (21). Early diagnosis may also give an individual the opportunity to plan and pursue a lifestyle (i.e. education, career, family) which will not be significantly impacted by the onset and progression of the disease (21). The benefit of a pre-symptomatic diagnosis is less obvious for conditions without available treatment, and it has been argued that screening for untreatable conditions should not be performed (21, 22). Benefit of the knowledge of a late-onset condition has also been called into question for circumstances in which the phenotype and/or age of onset cannot be reliably predicted from the genotype, as in the cases described (21). The potential for patient and familial stress and anxiety may outweigh the benefits, which are unclear. The impact on relatives of an individual diagnosed with a late-onset disorder as a result of screening cannot be ignored. As with screening for any disorder, relatives gain information about their personal health and reproductive risk upon a familial diagnosis. This may encourage medical evaluation and genetic counseling for at-risk individuals.
Conclusion
Advances in genetic technologies have allowed for an ever-evolving number of conditions identified through population screening. The identification of individuals at risk for late-onset genetic disorders presents significant practical and ethical issues, including the training of the consenting provider, availability of genetics providers, autonomy of the patient and family, and potential psychological harms weighed against potential benefits to the patient. These challenges may be further exacerbated by the continued expansion of population screening practices – including the potential use of whole genome sequencing (2, 7). Ethical and responsible implementation of expanding screening technologies requires ongoing critical consideration and discussion among the genetics community. Acknowledgements K. G.-G. and J. L. M. disclose no conflicts of interest for any affiliation, financial agreement, or other involvement with any company in the submitted manuscript. C. R. S. is the recipient of grant support through his institution, the University of Washington, for clinical trials for Pompe and other lysosomal storage diseases. He also receives grants through the UW for research on newborn screening for Pompe disease and other lysosomal storage diseases and for providing education to other providers about these diseases. These clinical trials and grants have been sponsored by the NIH (HHSN267200603429C and 2 R01 DK067859), Genzyme Corporation and Perkin Elmer. Dr. Scott is also a consultant to Genzyme Corporation for Pompe and other lysosomal storage diseases. Potential conflicts of interests are managed through the University of Washington Office of Research.
References 1. Commission on Chronic Illness. Prevention of chronic illness. Chronic illness in the United States. Vol. 1. Cambridge, MA: Harvard University, 1957.
3
Golden-Grant et al. 2. Musci TJ. Screening for single gene genetic disorders. Gynecol Obstet Invest 2005: 60: 19–26. 3. Ram KT, Klugman SD. Best practices: antenatal screening for common genetic conditions other than aneuploidy. Curr Opin Obstet Gynecol 2010: 22: 139–145. 4. Srinivasan BS, Evans EA, Flannick J et al. A universal carrier test for the long tail of Mendelian disease. Reprod Biomed Online 2010: 21: 537–551. 5. Grosse SD, Boyle CA, Kenneson A, Khoury MJ, Wilfond BS. From public health emergency to public health service: the implications of evolving criteria for newborn screening panels. J Pediatr 2006: 117: 923–929. 6. Scott CR, Elliott S, Buroker N et al. Identification of infants at risk for developing Fabry, Pompe, or Mucopolysaccharidosis-I from newborn blood spots by tandem mass spectrometry. J Pediatr 2013: 163: 498–503. 7. Tarini BA, Goldenberg AJ. Ethical issues with newborn screening in the genomics era. Annu Rev Genomics Hum Genet 2012: 13: 381–393. 8. Ross LF, Saal HM, David KL, Anderson RR. ACMG Policy Statement: technical report: ethical and policy issues in genetic testing and screening of children. Genet Med 2013: 15 (3): 234–245. 9. Teener JW. Late-onset Pompe disease. Semin Neurol 2012: 32: 506–511. 10. Kroos MA, Hoogeveen-Westerveld M, Michelakakis H et al. Update of the Pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants. Hum Mutat 2012: 33 (8): 1161. 11. Kroos MA, Pomponio RJ, van Vliet L et al. Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. Hum Mutat 2008: 29 (6): 13–26. 12. Wens SC, van Gelder CM, Kruijshaar ME et al. Phenotypical variation within 22 families with Pompe disease. Orphanet J Rare Dis 2013: 8: 182.
4
13. Hule ML, Chen AS, Tsujino S et al. Aberrant splicing in adult onset glycogen storage disease type II (GSDII): molecular identification of an IVS1 (−13T > G) mutation in a majority of patients and a novel IVS10 (+1GT > CT) mutation. Hum Mol Genet 1994: 3 (12): 2231–2236. 14. Kroos MA, van der Kraan M, van Diggelen OP et al. Glycogen storage disease type II: frequency of three common mutant alleles and their associated clinical phenotypes in 121 patients. J Med Genet 1995: 32: 836–840. 15. Hermans MM, van Leenen D, Kroos MA et al. Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. Hum Mutat 2004: 23 (1): 47–56. 16. Laforet P, Nicolino M, Eymard B et al. Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation. Neurology 2000: 55: 1122–1128. 17. Cupler EJ, Berger KI, Leshner RT et al. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve 2012: 45 (3): 319–333. 18. Toscano A, Schoser B. Enzyme replacement therapy in late-onset Pompe disease: a systematic literature review. J Neurol 2013: 260: 951–959. 19. Beauchamp TL, Childress JF. Principles of biomedical ethics, 6th edn. New York, NY: Oxford University Press, 2013. 20. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet 1995: 57: 1233–1241. 21. Fryer A. Inappropriate genetic testing of children. Arch Dis Child 2000: 83: 283–285. 22. Orzaleski M, Danhive O. Ethical problems with neonatal screening. Ann Ist Super Sanita 2009: 43 (3): 325–330.
