correspondence
not. This suggests that differences with previous studies may be explained by residual confounding in those studies. Our study addresses only one piece of the complex risk–benefit equation of antidepressant use in pregnancy, during which other risks associated with antidepressant use have been well documented. Our findings certainly do not justify incautious use of such drugs in these patients. Krista F. Huybrechts, Ph.D. Harvard Medical School Boston, MA
[email protected]
Sonia Hernández-Díaz, M.D., Dr.P.H. Harvard School of Public Health Boston, MA
Jerry Avorn, M.D.
Since publication of their article, the authors report no further potential conflict of interest. 1. Palmsten K, Huybrechts KF, Kowal MK, Mogun H, Hernán-
dez-Díaz S. Validity of maternal and infant outcomes within nationwide Medicaid data. Pharmacoepidemiol Drug Saf 2014; 23:646-55. 2. Toh S, Mitchell AA, Werler MM, Hernández-Díaz S. Sensitivity and specificity of computerized algorithms to classify gestational periods in the absence of information on date of conception. Am J Epidemiol 2008;167:633-40. 3. Cooper WO, Willy ME, Pont SJ, Ray WA. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007; 196(6):544.e1-545.e1. 4. Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernandez-Diaz S. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol 2011;205(1):51.e1-58.e1. 5. Huybrechts KF, Palmsten K, Mogun H, et al. National trends in antidepressant medication treatment among publicly insured pregnant women. Gen Hosp Psychiatry 2013;35:265-71. DOI: 10.1056/NEJMc1409203
Harvard Medical School Boston, MA
Diagnostic Clinical Genome and Exome Sequencing To the Editor: Biesecker and Green (June 19 issue)1 mention the recommendations by the American College of Medical Genetics and Genomics (ACMG) for laboratories to report incidental findings in clinical genome and exome sequencing (CGES) in a total of 56 genes (which, when mutated, cause an aggregate total of 24 disorders). Most of these conditions are associated with cancer or death from cardiovascular causes.2 Instead of focusing on relatively rare but treatable high-impact diseases, we suggest a greater focus on genetic causes of perhaps less threatening but treatable disorders that require specific treatments. Examples include diabetes caused by mutated HNF1A, with its strong response to sulfonylurea derivatives; sitosterolemia, with its strong response to ezetimibe and a specific diet; and Liddle’s syndrome, a genetic form of pseudo-aldosteronism, which can be treated with triamterene. The knowledge that a genetic mutation is the cause of treatable disease has direct consequences. Early case finding and screening might provide early and probably better, more specific treatment. We therefore suggest that the list of reported genetic conditions be expanded to genetic causes of diseases requiring specific treatments.
Jan Westerink, M.D., Ph.D. Frank L.J. Visseren, M.D., Ph.D. Wilko Spiering, M.D., Ph.D. University Medical Center Utrecht Utrecht, the Netherlands [email protected] No potential conflict of interest relevant to this letter was reported. 1. Biesecker LG, Green RC. Diagnostic clinical genome and
exome sequencing. N Engl J Med 2014;370:2418-25.
2. Green RC, Berg JS, Grody WW, et al. ACMG recommenda-
tions for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013;15:565-74. DOI: 10.1056/NEJMc1408914
To the Editor: Biesecker and Green inform clinicians about indications for and limitations of CGES, and they offer concise, practical guidance on its effective and appropriate implementation. They do not discuss genetic counseling,1 a crucial element in implementing CGES. Genetic counselors are specialists with expertise in obtaining thorough, targeted family histories; identifying and addressing ethical issues (e.g., informed consent and communicating with at-risk family members) and psychosocial issues (e.g., guilt and fatalism) that are commonly attendant
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org on January 30, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1169
The
n e w e ng l a n d j o u r na l
to genetic testing; interpreting complex results, including incidental findings; and communicating about risk.2,3 Genetic counselors also assist in obtaining third-party reimbursement for tests and provide an ongoing resource for reanalysis of negative results or interpretation of unknown variants. Implementation of CGES provides important opportunities for fruitful partnerships between physicians and genetic counselors. Such partnerships, which warrant explicit attention, support physicians and enhance patient satisfaction with care.4 Alice Virani, Ph.D. Jehannine Austin, Ph.D. University of British Columbia Vancouver, BC, Canada [email protected] No potential conflict of interest relevant to this letter was reported. 1. Resta R, Biesecker BB, Bennett RL, et al. A new definition of
genetic counseling: National Society of Genetic Counselors’ Task Force report. J Genet Couns 2006;15:77-83. 2. Davey A, Rostant K, Harrop K, Goldblatt J, O’Leary P. Evaluating genetic counseling: client expectations, psychological adjustment and satisfaction with service. J Genet Couns 2005; 14:197-206. 3. McAllister M, Payne K, Macleod R, Nicholls S, Donnai D, Davies L. Patient empowerment in clinical genetics services. J Health Psychol 2008;13:895-905. 4. Waxler JL, Cherniske EM, Dieter K, Herd P, Pober BR. Hearing from parents: the impact of receiving the diagnosis of Williams syndrome in their child. Am J Med Genet A 2013;161A: 534-41. DOI: 10.1056/NEJMc1408914
of
m e dic i n e
forms routine evaluation of the ACMG 56 genes, with an optional extended panel of additional “disease” genes. The ACMG has appointed a standing committee to evaluate suggestions that additional genes and conditions be added or subtracted from the original list, and we support the suggestion that HNF1A-related late-onset diabetes be evaluated. Virani and Austin rightly underscore the importance of the role of the genetic counselor in CGES. We strongly support genetic counselors, some of whom are indispensable members of our clinical and research teams. Our omission of the role of genetic counselors was deliberate, and we also did not emphasize the role of the clinical geneticist. We took a different approach, which was to delineate the specific tasks and objectives for the appropriate care of patients who undergo sequencing, without specifying which health professional should perform those tasks. Indeed, we believe that it would be appropriate for any clinician with the necessary training and skills in genomics to perform these tasks. At present, very few clinicians outside the fields of medical genetics and genetic counseling have these skills, and so it will often be necessary and appropriate to involve such professionals in the care of patients. In the future, genomic analysis will be a common component of health care that will be ordered, interpreted, and managed by many health professionals. Leslie G. Biesecker, M.D. National Human Genome Research Institute
The Authors Reply: Westerink et al. thought- Bethesda, MD fully question the genes selected by the ACMG [email protected] for evaluation as secondary findings.1 Both of us Robert C. Green, M.D., M.P.H. participated in the selection of the genes for that Harvard Medical School recommendation. That list of genes was short be- Boston, MA Since publication of their article, the authors report no furcause the initial recommendation was for routine ther potential conflict of interest. evaluation and return of such variants. If analysis 1. Green RC, Berg JS, Grody WW, et al. ACMG recommendaof secondary findings is routine, it is appropriate tions for reporting of incidental findings in clinical exome and to return only the most medically compelling genome sequencing. Genet Med 2013;15:565-74. variants. At least one clinical exome service per- DOI: 10.1056/NEJMc1408914
Resistance to Therapy in Acute Promyelocytic Leukemia to the editor: Acute promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) (APL) is driven by an oncogenic chromosomal genes. APL responds to two targeted therapies: translocation fusing the promyelocytic leukemia all-trans retinoic acid (ATRA) and arsenic trioxide.
1170
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org on January 30, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
not. This suggests that differences with previous studies may be explained by residual confounding in those studies. Our study addresses only one piece of the complex risk–benefit equation of antidepressant use in pregnancy, during which other risks associated with antidepressant use have been well documented. Our findings certainly do not justify incautious use of such drugs in these patients. Krista F. Huybrechts, Ph.D. Harvard Medical School Boston, MA
[email protected]
Sonia Hernández-Díaz, M.D., Dr.P.H. Harvard School of Public Health Boston, MA
Jerry Avorn, M.D.
Since publication of their article, the authors report no further potential conflict of interest. 1. Palmsten K, Huybrechts KF, Kowal MK, Mogun H, Hernán-
dez-Díaz S. Validity of maternal and infant outcomes within nationwide Medicaid data. Pharmacoepidemiol Drug Saf 2014; 23:646-55. 2. Toh S, Mitchell AA, Werler MM, Hernández-Díaz S. Sensitivity and specificity of computerized algorithms to classify gestational periods in the absence of information on date of conception. Am J Epidemiol 2008;167:633-40. 3. Cooper WO, Willy ME, Pont SJ, Ray WA. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007; 196(6):544.e1-545.e1. 4. Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernandez-Diaz S. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol 2011;205(1):51.e1-58.e1. 5. Huybrechts KF, Palmsten K, Mogun H, et al. National trends in antidepressant medication treatment among publicly insured pregnant women. Gen Hosp Psychiatry 2013;35:265-71. DOI: 10.1056/NEJMc1409203
Harvard Medical School Boston, MA
Diagnostic Clinical Genome and Exome Sequencing To the Editor: Biesecker and Green (June 19 issue)1 mention the recommendations by the American College of Medical Genetics and Genomics (ACMG) for laboratories to report incidental findings in clinical genome and exome sequencing (CGES) in a total of 56 genes (which, when mutated, cause an aggregate total of 24 disorders). Most of these conditions are associated with cancer or death from cardiovascular causes.2 Instead of focusing on relatively rare but treatable high-impact diseases, we suggest a greater focus on genetic causes of perhaps less threatening but treatable disorders that require specific treatments. Examples include diabetes caused by mutated HNF1A, with its strong response to sulfonylurea derivatives; sitosterolemia, with its strong response to ezetimibe and a specific diet; and Liddle’s syndrome, a genetic form of pseudo-aldosteronism, which can be treated with triamterene. The knowledge that a genetic mutation is the cause of treatable disease has direct consequences. Early case finding and screening might provide early and probably better, more specific treatment. We therefore suggest that the list of reported genetic conditions be expanded to genetic causes of diseases requiring specific treatments.
Jan Westerink, M.D., Ph.D. Frank L.J. Visseren, M.D., Ph.D. Wilko Spiering, M.D., Ph.D. University Medical Center Utrecht Utrecht, the Netherlands [email protected] No potential conflict of interest relevant to this letter was reported. 1. Biesecker LG, Green RC. Diagnostic clinical genome and
exome sequencing. N Engl J Med 2014;370:2418-25.
2. Green RC, Berg JS, Grody WW, et al. ACMG recommenda-
tions for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013;15:565-74. DOI: 10.1056/NEJMc1408914
To the Editor: Biesecker and Green inform clinicians about indications for and limitations of CGES, and they offer concise, practical guidance on its effective and appropriate implementation. They do not discuss genetic counseling,1 a crucial element in implementing CGES. Genetic counselors are specialists with expertise in obtaining thorough, targeted family histories; identifying and addressing ethical issues (e.g., informed consent and communicating with at-risk family members) and psychosocial issues (e.g., guilt and fatalism) that are commonly attendant
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org on January 30, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1169
The
n e w e ng l a n d j o u r na l
to genetic testing; interpreting complex results, including incidental findings; and communicating about risk.2,3 Genetic counselors also assist in obtaining third-party reimbursement for tests and provide an ongoing resource for reanalysis of negative results or interpretation of unknown variants. Implementation of CGES provides important opportunities for fruitful partnerships between physicians and genetic counselors. Such partnerships, which warrant explicit attention, support physicians and enhance patient satisfaction with care.4 Alice Virani, Ph.D. Jehannine Austin, Ph.D. University of British Columbia Vancouver, BC, Canada [email protected] No potential conflict of interest relevant to this letter was reported. 1. Resta R, Biesecker BB, Bennett RL, et al. A new definition of
genetic counseling: National Society of Genetic Counselors’ Task Force report. J Genet Couns 2006;15:77-83. 2. Davey A, Rostant K, Harrop K, Goldblatt J, O’Leary P. Evaluating genetic counseling: client expectations, psychological adjustment and satisfaction with service. J Genet Couns 2005; 14:197-206. 3. McAllister M, Payne K, Macleod R, Nicholls S, Donnai D, Davies L. Patient empowerment in clinical genetics services. J Health Psychol 2008;13:895-905. 4. Waxler JL, Cherniske EM, Dieter K, Herd P, Pober BR. Hearing from parents: the impact of receiving the diagnosis of Williams syndrome in their child. Am J Med Genet A 2013;161A: 534-41. DOI: 10.1056/NEJMc1408914
of
m e dic i n e
forms routine evaluation of the ACMG 56 genes, with an optional extended panel of additional “disease” genes. The ACMG has appointed a standing committee to evaluate suggestions that additional genes and conditions be added or subtracted from the original list, and we support the suggestion that HNF1A-related late-onset diabetes be evaluated. Virani and Austin rightly underscore the importance of the role of the genetic counselor in CGES. We strongly support genetic counselors, some of whom are indispensable members of our clinical and research teams. Our omission of the role of genetic counselors was deliberate, and we also did not emphasize the role of the clinical geneticist. We took a different approach, which was to delineate the specific tasks and objectives for the appropriate care of patients who undergo sequencing, without specifying which health professional should perform those tasks. Indeed, we believe that it would be appropriate for any clinician with the necessary training and skills in genomics to perform these tasks. At present, very few clinicians outside the fields of medical genetics and genetic counseling have these skills, and so it will often be necessary and appropriate to involve such professionals in the care of patients. In the future, genomic analysis will be a common component of health care that will be ordered, interpreted, and managed by many health professionals. Leslie G. Biesecker, M.D. National Human Genome Research Institute
The Authors Reply: Westerink et al. thought- Bethesda, MD fully question the genes selected by the ACMG [email protected] for evaluation as secondary findings.1 Both of us Robert C. Green, M.D., M.P.H. participated in the selection of the genes for that Harvard Medical School recommendation. That list of genes was short be- Boston, MA Since publication of their article, the authors report no furcause the initial recommendation was for routine ther potential conflict of interest. evaluation and return of such variants. If analysis 1. Green RC, Berg JS, Grody WW, et al. ACMG recommendaof secondary findings is routine, it is appropriate tions for reporting of incidental findings in clinical exome and to return only the most medically compelling genome sequencing. Genet Med 2013;15:565-74. variants. At least one clinical exome service per- DOI: 10.1056/NEJMc1408914
Resistance to Therapy in Acute Promyelocytic Leukemia to the editor: Acute promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) (APL) is driven by an oncogenic chromosomal genes. APL responds to two targeted therapies: translocation fusing the promyelocytic leukemia all-trans retinoic acid (ATRA) and arsenic trioxide.
1170
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org on January 30, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
