New technologies have given us the ability to detect genomic variation at resolutions 50-100 times greater than earlier tests. The good news is that we can now detect variations that help explain developmental delays, autism, or multiple congenital anomalies in up to 20% of children. The bad news is that we can also detect small missing or extra pieces of chromosomes that remain unexplained: that is, we don’t know whether they have any clinical significance at all. The rapid pace of technological change may have outpaced the lab’s ability to interpret, providers’ abilities to explain, and patients’ abilities to understand the test results. This Issue Brief summarizes a series of studies examining the uncertainties revolving around chromosomal microarray testing, which has become the new standard of practice in genetic testing of children with unexplained anomalies

Bernhardt, Barbara A

Mulchandani, Surabhi

Reiff, Marian

English

ScholarlyCommons@Penn

University of PennsylvaniaScholarlyCommonsIssue Briefs Leonard Davis Institute of Health Economics3-19-2013Genomic Variation: What Does It Mean?Marian ReiffBarbara A. BernhardtSurabhi MulchandaniFollow this and additional works at: http://repository.upenn.edu/ldi_issuebriefsPart of the Health Services Research Commons, and the Medical Genetics CommonsThis paper is posted at ScholarlyCommons. http://repository.upenn.edu/ldi_issuebriefs/107For more information, please contact repository@pobox.upenn.edu.Reiff, Marian; Bernhardt, Barbara A.; and Mulchandani, Surabhi. Genomic Variation: What Does It Mean?. LDI Issue Briefs. 2013; 18(4). http://ldi.upenn.edu/policy/issue-briefs/2013/03/19/genomic-variation-what-does-it-meanGenomic Variation: What Does It Mean?AbstractNew technologies have given us the ability to detect genomic variation at resolutions 50-100 times greaterthan earlier tests. The good news is that we can now detect variations that help explain developmental delays,autism, or multiple congenital anomalies in up to 20% of children. The bad news is that we can also detectsmall missing or extra pieces of chromosomes that remain unexplained: that is, we don’t know whether theyhave any clinical significance at all. The rapid pace of technological change may have outpaced the lab’s abilityto interpret, providers’ abilities to explain, and patients’ abilities to understand the test results. This Issue Briefsummarizes a series of studies examining the uncertainties revolving around chromosomal microarray testing,which has become the new standard of practice in genetic testing of children with unexplained anomalies.Keywordsmedical technology, personalized medicine and genomicsDisciplinesHealth Services Research | Medical GeneticsLicenseThis work is licensed under a Creative Commons Attribution-No Derivative Works 4.0 License.This brief is available at ScholarlyCommons: http://repository.upenn.edu/ldi_issuebriefs/107Leonard Davis Institute of Health Economics Volume 18, Issue 4 • February/March 2013Marian Reiff, PhD, MScResearch AssociateBarbara A. Bernhardt, MS, CGCClinical Professor of MedicineSurabhi Mulchandani, MSc, MS, CGCGenetic CounselorCenter for the Integration of Genetic Healthcare Technologies University of PennsylvaniaGenomic Variation: What Does It Mean?Editor’s note: New technologies have given us the ability to detect genomic variation at resolutions 50-100 times greater than earlier tests. The good news is that we can now detect variations that help explain developmental delays, autism, or multiple congenital anomalies in up to 20% of children. The bad news is that we can also detect small missing or extra pieces of chromosomes that remain unexplained: that is, we don’t know whether they have any clinical significance at all. The rapid pace of technological change may have outpaced the lab’s ability to interpret, providers’ abilities to explain, and patients’ abilities to understand the test results. This Issue Brief summarizes a series of studies examining the uncertainties revolving around chromosomal microarray testing, which has become the new standard of practice in genetic testing of children with unexplained anomalies.Increasingly, geneticists, pediatricians and subspecialists are ordering CMA to diagnose children with unexplained neurodevelopmental delays. CMA can detect thousands of “copy number variants” throughout the genome, and yields a diagnosis three to five times more often than older methods of chromosome analysis. Finding a genetic diagnosis can often provide relief to families, target future medical care, facilitate access to educational interventions, and help parents understand the risk of recurrence in future offspring.  •	 In	2008,	the	American	College	of	Medical	Genetics	recommended	that	CMA	replace karyotyping as a first-line genetic test in infants and children, because of the test’s enhanced diagnostic abilities. CMA practice guidelines emphasize the importance of pre-test counseling and informed consent to ensure that families are prepared for the information, and can choose how much information to receive.•	 Microarray	testing	results	fall	into	three	main	categories:	negative	(no	clinically	significant	variation),	pathogenic	(a	variation	known	to	result	in	a	genetic	condition),	and	“variant	of	unknown	significance	(VUS)”.	On	average,	about	10%	of CMA results fall into the last category. •	 Many	VUS	results	can	be	resolved	by	genetic	testing	of	parents	to	determine	whether a variant has been inherited or has arisen anew in the child. Although most variants inherited from a “normal” parent are assumed to be benign, it is possible that the parent has a very mild or unexpressed form of the child’s condition. Further, genetic testing of a parent or child may yield “incidental” findings not related to the reason for testing, such as a predisposition to develop Alzheimer disease. Chromosomal microarray analysis (CMA) replaces karyotyping as standard of careReiff and colleagues explored clinicians’ perspectives about ordering CMA and about effectively interpreting results and communicating with families. Forty clinicians who had ordered CMA answered an online survey and responded to a hypothetical case of uncertain and incidental findings in a parent.•	 The	clinicians	had	ordered	CMA	at	least	once	from	the	Children’s	Hospital	of	Philadelphia	between	May	2008	and	March	2011.	Respondents	were	general	pediatricians	(27.5%),	medical	geneticists	(12.5%),	and	pediatric	subspecialists	(60%,	including	seven	neonatologists,	five	neurologists,	four	endocrinologists,	three developmental pediatricians, one hematologist, one gastroenterologist, one oncologist, one ophthalmologist, and one critical care specialist). •	 Not	surprisingly,	comfort	levels	differed	for	explaining	the	three	types	of	results,	with the highest comfort levels for normal results and the lowest comfort levels for VUS	results.	Most	non-geneticists	reported	that	they	would	discuss	a	VUS	finding	with a genetic specialist.From the clinicians’ perspective, a need for more education to explain and interpret resultsFrom the parents’ perspective, a struggle for comprehension, meaning, and supportTo explore how families understand and give meaning to the results of CMA testing, Reiff and colleagues interviewed 25 families, 11 of whom had received pathogenic results	and	14	who	had	received	VUS	results.	The	investigators	interviewed	31	parents	(23	mothers	and	8	fathers),	either	in-person	or	by	telephone,	whose	children	had	undergone	CMA	testing	at	the	Children’s	Hospital	of	Philadelphia.	In	17	families,	the	ordering physician was a geneticist; in the other eight families, a non-geneticist.•	 Parents	receiving	both	uncertain	and	pathogenic	results	said	that	they	had	trouble	understanding	the	result	initially	(5	VUS	and	5	pathogenic).	Four	reported	that	they received the results initially from non-genetics professionals lacking the expertise to provide adequate explanation. These misunderstandings were usually resolved eventually by discussion with genetics experts.•	 Receiving	results	by	telephone,	long	waits	to	see	a	geneticist	to	discuss	the	results,	inconsistent information provided by different health professionals, and Internet searches based on inadequate or inaccurate information all contributed to difficulties in understanding the results.•	 Many	participants,	even	when	they	understood	the	results,	still	struggled	to	understand the meaning and potential implications of the results, and expressed a need for more information and explanation. A typical response was, “I understood what they told me, but I wish I could have found out more about what it meant.”•	 Results	were	perceived	to	be	helpful	in	providing	a	causal	explanation	(8	pathogenic	and	5	VUS),	and	in	anticipating	the	child’s	future	needs	(4	pathogenic	and	4	VUS).	Many	expressed	relief	at	finding	a	causal	explanation.	However,	a	parent	who	found out that he had the same deletion as his child reported feeling shocked and subsequently questioning his sense of self.•	 Most	parents	thought	that	the	benefits	of	the	test	would	become	more	apparent	in	the future, as more people are tested. •	 Several	respondents	wanted	to	connect	with	other	families	with	the	same	genetic	variant as a potential source of emotional support. They expressed frustration that the hospital could not facilitate a connection with other parents because of privacy regulations. •	 Our	understanding	of	genomic	variation	is	a	rapidly	moving	target.	Labs	now	routinely	report	new	(de-identified)	variations	to	public	databases	and	publish	clinical	reports	of	novel	findings.	Thus,	the	interpretation	of	a	VUS	result	may	change over time as the worldwide knowledge base grows. Further, there is some variability in how different labs interpret different results.Continued on back.POLICY IMPLICATIONS These studies highlight key challenges in the practice of genomic medicine for patients, families, and clinicians. The increasing use of genetic sequencing technology will likely magnify these problems, as we will be able to quickly describe and detect all human genetic variation long before we understand what most of it means for the individual patient. •	 Genetics	expertise	makes	a	big	difference	in	how	abnormal	and	uncertain results are delivered and received, and yet the current medical genetics workforce is not sufficient to meet this demand. Non-geneticists need educational resources to improve their ability to understand and communicate sometimes complex genetic findings.Prenatal CMA has not yet supplanted karyotyping as the standard of care, but a newly published study has demonstrated its greater diagnostic yield. Prenatal use of CMA poses even more challenges because any indication of a problem with the fetus can transform the experience of pregnancy. To understand women’s experiences, Bernhardt and	colleagues	interviewed	23	women	who	had	both	karyotyping	and	CMA	as	part	of	a	large	multicenter	study,	and	had	received	either	pathogenic	or	VUS	results.	Telephone interviews were conducted at least six month postpartum or post- pregnancy termination.•	 All	women	had	received	genetic	counseling	and	were	undergoing	an	invasive	prenatal	diagnostic	procedure	(either	amniocentesis	or	chorionic	villus	sampling)	for karyotype analysis. During the informed consent session, a genetic counselor explained the risks, benefits, and limitations of CMA testing. All women received their results from the genetic counselor or a study obstetrician, with follow-up counseling available.•	 Initially,	receiving	abnormal	CMA	results	left	most	women	shocked,	anxious,	confused, and overwhelmed. Many of those who had received abnormal CMA results after first receiving normal karyotyping results felt “blindsided.” Many women discussed the difficulty of emotionally and intellectually managing the uncertainties of results given how far along they were in their pregnancies.•	 The	women	needed	support	to	manage,	understand,	and	act	on	the	CMA	results.	Most women reported receiving help from the study obstetrician or genetic counselor, although many commented that they wanted more support with decision-making about continuing or terminating the pregnancy.•	 Most	women	understood	that	CMA	could	identify	serious	problems	in	the	baby	missed on routine cytogenetic analysis. But only one recalled being told that some results might be uncertain or uninterpretable. When given those results, many women considered this information to be knowledge they wished they did not have (toxic	knowledge).	Even	after	delivering	a	normal-appearing	baby,	8	of	the 16	women	who	continued	their	pregnancies	had	lingering	worries	about	their	child’s development.Prenatal use of CMA poses even more challenges•	 Overall,	non-geneticists	reported	a	strong	need	for	more	education	about	interpreting and explaining CMA results. Most clinicians felt that parents’ understanding of CMA results was somewhat low, although geneticists rated parent understanding higher than non-geneticists. •	 While	clinical	guidelines	recommend	pre-test	counseling	to	prepare	families	for	incidental or uncertain findings, many clinicians did not consider it pertinent in pre-test counseling of parents to discuss the potential for CMA to uncover incidental findings. This varied by specialty: all general pediatricians felt it was pertinent,	compared	to	60%	of	geneticists	and	39%	of	pediatric	subspecialists.Nonprofit OrganizationU.S. PostageP  A  I  DPermit No. 2563Philadelphia, PA 19104Issue BriefPublished by theLeonard Davis Instituteof Health EconomicsUniversity of Pennsylvania3641 Locust WalkPhiladelphia, PA 19104-6218215.898.5611fax 215.898.0229ADDRESS CORRECTION REQUESTEDPOLICY IMPLICATIONSContinuedVisit	us	on	the	web	at http://ldi.upenn.eduThis Issue Brief is based on the following articles: B.A. Bernhardt, D. Soucier, K. Hanson, et al. Women’s experiences receiving abnormal prenatal chromosomal array testing results. Genetics in Medicine, February 2013, vol. 15, pp. 139-145; M. Reiff, K. Ross, S. Mulchandani, et al. Physicians’ perspectives on the uncertainties and implications of chromosomal microarray testing of children and families. Clinical Genetics, January 2013, vol. 83, pp. 23-30; M. Reiff, B.A. Bernhardt, S. Mulchandani, et al. “What does it mean?”: Uncertainties in understanding results of chromosomal microarray testing. Genetics in Medicine, February 2012, vol. 14, pp. 250-258.This Issue Brief was supported by the National Human Genome Research Institute, Center for the Integration of Genetic Healthcare Technologies, University of Pennsylvania Perelman School of Medicine (P50HG004487).Published by the Leonard Davis Institute of Health Economics, University of Pennsylvania, 3641 Locust Walk, Philadelphia, PA 19104. Janet Weiner, MPH, Associate Director for Health Policy, Editor  Dan Polsky, PhD, Executive DirectorIssue Briefs synthesize the results of research by LDI’s Senior Fellows, a consortium of Penn scholars studying medical, economic, and social and ethical issues that influence how health care is organized, financed, managed, and delivered in the United States and internationally. The LDI is a cooperative venture among Penn schools including Medicine, Nursing, Dental Medicine, Communication, Law, and Wharton, and the Children’s Hospital of Philadelphia. For additional information on this or other Issue Briefs, contact Janet Weiner (e-mail: weinerja@mail.med.upenn.edu; 215-573-9374). ©	2013	Leonard	Davis	Institute•	 Similarly,	families	need	educational	resources	and	support	before	and	after	genetic	testing.	Given	the	limited	number	of	genetics	professionals,	new	strategies	are	needed to overcome long waits for genetic counseling and misinformed Internet searches. Parents who have been through the experience of receiving uncertain results may be the most available and underutilized resource for new families. Programs to train parents and facilitate referrals should be fostered. •	 Both	providers	and	patients	need	regularly	updated	resources	that	summarize	what	is currently known about the specific “copy number variants” reported to them.•	 In	addition	to	provider-	and	patient-level	training	and	support,	we	should	consider	system-level interventions that improve the infrastructure for integrating genomic medicine into clinic care. Institutional policies should encourage compliance with best practice guidelines around ordering and explaining genetic test results. Electronic ordering systems and the electronic medical record provide opportunities to develop and test new, interactive ways of delivering genetics education and information in appropriate and timely formats to both clinicians and families.

Genomic Variation: What Does It Mean?

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Genomic Variation: What Does It Mean?

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