Impressions & Impressions & Questions Questions This - - PDF document

3/18/2011 1

Dick Sobsey Dick Sobsey ‐ ‐ University of Alberta University of Alberta

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Impressions & Impressions & Questions Questions

This presentation is based on my impressions as a This presentation is based on my impressions as a parent and a professional and not on formal parent and a professional and not on formal research. research. Parent… Genetic Counseling across the decades Parent… Genetic Counseling across the decades As a professional, working with children and adults As a professional, working with children and adults with severe disabilities and their families since the with severe disabilities and their families since the

• 1960. International
• 1960. International Rett

Rett Syndrome Foundation Syndrome Foundation Professional Resource, MECP2 parents groups. Professional Resource, MECP2 parents groups.

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Testing & CMA Testing & CMA

This presentation is partly about CMA (Chromosomal This presentation is partly about CMA (Chromosomal ( Microarray Analysis) BUT it is not intended to be just Microarray Analysis) BUT it is not intended to be just about this specific procedure… about this specific procedure… New tests… New tests…

…based on genomic information …based on genomic information …can find much (about 100 times) smaller deletions …can find much (about 100 times) smaller deletions d d li ti d d li ti and duplications and duplications …test concurrently for large number of possible …test concurrently for large number of possible conditions conditions

currently about 1700 possible deletions or duplications currently about 1700 possible deletions or duplications can be assessed in a single test can be assessed in a single test

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About Testing & CMA About Testing & CMA

CMA is currently expensive and used sparingly CMA is currently expensive and used sparingly Cost per procedure is coming down and CMA use is Cost per procedure is coming down and CMA use is expanding expanding Newer versions of the test are increasing the number of Newer versions of the test are increasing the number of genes that can be probed genes that can be probed “During his progress report on the evolution of testing for “During his progress report on the evolution of testing for During his progress report on the evolution of testing for During his progress report on the evolution of testing for genetic abnormalities, Arthur genetic abnormalities, Arthur Beaudet Beaudet, M.D., chair of , M.D., chair of molecular and human genetics at BCM, pointed out that molecular and human genetics at BCM, pointed out that these tests represent a these tests represent a double double‐edged sword edged sword. While they . While they reveal a wealth of information about individuals, they also reveal a wealth of information about individuals, they also introduce complex ethical quandaries.” Tomin, 2006 introduce complex ethical quandaries.” Tomin, 2006

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2010 Consensus 2010 Consensus Statement Statement

Consensus Statement: Chromosomal Microarray Is a Consensus Statement: Chromosomal Microarray Is a First First‐Tier Clinical Diagnostic Test for Individuals with Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies Developmental Disabilities or Congenital Anomalies –

Miller et al. Miller et al. Am J Hum Genet. Am J Hum Genet. 2010 May 14; 86(5): 749 2010 May 14; 86(5): 749– – 764. 764.

August, 2009 August, 2009 ‐ ‐The case for offering all women

The case for offering all women i t i d h l i i t i d h l i amniocentesis and chromosomal microarray amniocentesis and chromosomal microarray analysis analysis – Beaudet Beaudet, 2009. , 2009.

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Concerns Concerns

“… molecular genetic testing represents more than a “… molecular genetic testing represents more than a single discrete research or clinical intervention since the single discrete research or clinical intervention since the single discrete research or clinical intervention, since the single discrete research or clinical intervention, since the information obtained may predict future events or affect information obtained may predict future events or affect the lives of others besides the person consenting to be the lives of others besides the person consenting to be tested.” tested.” – Grody Grody, 2003 , 2003 “As this sort of testing continues to proliferate, referral of “As this sort of testing continues to proliferate, referral of all such cases to a medical genetics clinic for proper all such cases to a medical genetics clinic for proper interpretation becomes less of a practical option, as there interpretation becomes less of a practical option, as there are not enough genetic counselors in the entire country to are not enough genetic counselors in the entire country to g g y g g y handle the anticipated case load of even a single large handle the anticipated case load of even a single large program, such as nationwide carrier screening for cystic program, such as nationwide carrier screening for cystic fibrosis mutations” fibrosis mutations” – Grody Grody, 2003 , 2003

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Concerns Concerns

“Clearly our ability to add more and more mutation “Clearly our ability to add more and more mutation probes to an array will rapidly outstrip our ability to probes to an array will rapidly outstrip our ability to clinically validate each of them.” clinically validate each of them.” ‐ ‐ Grody Grody, 2003 , 2003 “If the DNA alteration detected has not been “If the DNA alteration detected has not been reported before in the context of the disease reported before in the context of the disease phenotype, it may be difficult or impossible to decide phenotype, it may be difficult or impossible to decide whether it represents a pathologic mutation or whether it represents a pathologic mutation or whether it represents a pathologic mutation or whether it represents a pathologic mutation or merely a benign polymorphism.” merely a benign polymorphism.” ‐ ‐ Grody Grody, 2003 , 2003

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A Personal Perspective A Personal Perspective

This presentation is partly from the perspective as the This presentation is partly from the perspective as the parent of a 20 parent of a 20‐ ‐year year‐old son with MECP2 Duplication

• ld son with MECP2 Duplication

p y p syndrome. syndrome. Diagnosed at age 18 through CMA Diagnosed at age 18 through CMA As a family, we were glad to finally get a diagnosis for our As a family, we were glad to finally get a diagnosis for our son… but we were also happy to get it at age 18 and not son… but we were also happy to get it at age 18 and not when he was an infant or even before he was born. when he was an infant or even before he was born. While this syndrome serves as an example, it is just one of While this syndrome serves as an example, it is just one of many that will be identified for the first time or diagnosed many that will be identified for the first time or diagnosed in much larger numbers in the recent past and near future. in much larger numbers in the recent past and near future.

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Our Perspective Our Perspective

Pros Pros

Provided an explanation Provided an explanation Did help with a few Did help with a few

Cons & Cons & Nons Nons

Little value in directing Little value in directing treatment at present treatment at present Did help with a few Did help with a few decisions about treatment decisions about treatment Put us in touch with other Put us in touch with other families for support families for support Presents a bleak outlook Presents a bleak outlook Tended to become an all Tended to become an all encompassing explanation encompassing explanation

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MECP2 Duplication MECP2 Duplication Syndrome Syndrome

First identified syndrome in 2005 First identified syndrome in 2005 b h b d d b h b d d About 300 cases have been diagnosed About 300 cases have been diagnosed worldwide worldwide Progressive Progressive Characterized by severe developmental Characterized by severe developmental disability, autism, disability, autism, hypotonia hypotonia, immune , immune compromise, intractable seizure compromise, intractable seizure disorder, GI symptoms. disorder, GI symptoms. Discovered in mice before humans. Discovered in mice before humans.

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Family Support in the Age Family Support in the Age

• f Social Networking and
• f Social Networking and

the Blogosphere the Blogosphere

The internet has linked families of The internet has linked families of i di id l ith di d i i di id l ith di d i individuals with rare disorders in a individuals with rare disorders in a way never before possible. way never before possible. This has been very positive… but has This has been very positive… but has a possible negative effect of a possible negative effect of fragmenting focus to specific fragmenting focus to specific disorders rather than broader disorders rather than broader categories of common interest. categories of common interest. The upcoming Family Conference The upcoming Family Conference plays a dual role for families and plays a dual role for families and researchers. researchers.

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Family Support in the Age Family Support in the Age

• f Social Networking and
• f Social Networking and

the Blogosphere the Blogosphere

The internet has linked families of The internet has linked families of i di id l ith di d i i di id l ith di d i individuals with rare disorders in a individuals with rare disorders in a way never before possible. way never before possible. This has been very positive… but has This has been very positive… but has a possible negative effect of a possible negative effect of fragmenting focus to specific fragmenting focus to specific disorders rather than broader disorders rather than broader categories of common interest. categories of common interest. The upcoming Family Conference The upcoming Family Conference plays a dual role for families and plays a dual role for families and researchers. researchers.

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Impressions of Family Attitudes Impressions of Family Attitudes

As a result, I have had contact with what is probably the As a result, I have had contact with what is probably the majority of families with diagnosed sons and daughters. majority of families with diagnosed sons and daughters. Many have already lost a previous child or relative… Many have already lost a previous child or relative…

• thers have two affected children
• thers have two affected children

There is a very high level of satisfaction with the diagnosis There is a very high level of satisfaction with the diagnosis among families. among families. There has been significant misinformation given to some There has been significant misinformation given to some families families families. families. There are some very high (unrealistic?) expectations for There are some very high (unrealistic?) expectations for cures and treatment. cures and treatment.

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Positive Aspects of Positive Aspects of Dx Dx and Counseling and Counseling

Families are glad to have an explanation. Families are glad to have an explanation. g Some Some help in getting better treatment (will probably help in getting better treatment (will probably improve over time). improve over time). Provides families, including extended families, with Provides families, including extended families, with useful information for family planning. useful information for family planning. Puts families in touch with each other for practical Puts families in touch with each other for practical and emotional support. and emotional support.

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Problems Encountered Problems Encountered with Counseling with Counseling

Much of the genetic counseling received has come Much of the genetic counseling received has come from health care counselors who were neither from health care counselors who were neither geneticists nor counselors. geneticists nor counselors. In a few cases, even “genuine” genetic counselors In a few cases, even “genuine” genetic counselors did not appear to understand the genetics of the did not appear to understand the genetics of the syndrome. syndrome. In some cases the information available to counselors In some cases the information available to counselors In some cases the information available to counselors In some cases the information available to counselors was incorrect or misinterpreted. For example, was incorrect or misinterpreted. For example, information on life information on life‐expectancy and frequency of expectancy and frequency of seizure disorders. seizure disorders.

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Social and psychological Social and psychological information information

Many families reported that they were told there would be Many families reported that they were told there would be severe negative effects on their marriage and other children severe negative effects on their marriage and other children severe negative effects on their marriage and other children. severe negative effects on their marriage and other children. Research does not actually support the myth of very high rates Research does not actually support the myth of very high rates

• f divorce among parents of children with disabilities.
• f divorce among parents of children with disabilities.

About twice as many parents report that having a child with a About twice as many parents report that having a child with a disability strengthened their marriage as report negative disability strengthened their marriage as report negative effects. effects.

Research suggests that there are positive effects on siblings of Research suggests that there are positive effects on siblings of children with disabilities. children with disabilities. children with disabilities. children with disabilities.

"Results indicated that siblings of children with intellectual "Results indicated that siblings of children with intellectual disabilities evidence higher levels of growth..." including disabilities evidence higher levels of growth..." including personal, social, and spiritual growth.” personal, social, and spiritual growth.” Findler Findler, L., & , L., & Vardi Vardi, , A.2009. A.2009.

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Issues Issues

What constitutes a significant What constitutes a significant atypicality atypicality for which for which g genetic counseling and intervention may be genetic counseling and intervention may be appropriate? appropriate? Testing may be undertaken to look for a specific Testing may be undertaken to look for a specific disorder but other disorder but other atypicalities atypicalities may be found with may be found with known or unknown consequences. Should all known or unknown consequences. Should all findings be recorded and communicated? findings be recorded and communicated? findings be recorded and communicated? findings be recorded and communicated? When is it appropriate to order CMA testing? When is it appropriate to order CMA testing?

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Issues Issues

What happens when we identify deletions or What happens when we identify deletions or duplications for which the clinical implications are duplications for which the clinical implications are unknown or only partially understood? unknown or only partially understood? Are enough appropriate genetic counseling services Are enough appropriate genetic counseling services available to support the potential coming available to support the potential coming widespread use of CMA testing? widespread use of CMA testing? How can informed consent be appropriately How can informed consent be appropriately How can informed consent be appropriately How can informed consent be appropriately

• btained when a single array may involve the
• btained when a single array may involve the

potential for such large numbers of diagnostic and potential for such large numbers of diagnostic and predictive tests. predictive tests.

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Issues Issues

How will the results of diagnostic, carrier, or How will the results of diagnostic, carrier, or g predictive testing affect access to health, life or predictive testing affect access to health, life or disability insurance, employment, etc? disability insurance, employment, etc? Should CMA predictive or carrier testing be Should CMA predictive or carrier testing be undertaken on children? … The general consensus undertaken on children? … The general consensus has been NO, but there seems to be a growing has been NO, but there seems to be a growing second opinion second opinion second opinion. second opinion. How is confidentiality maintained? How is confidentiality maintained?

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Issues Issues

When should CMA and other such tests be covered as When should CMA and other such tests be covered as a legitimate healthcare costs? a legitimate healthcare costs? Does CMA and similar testing promote a new Does CMA and similar testing promote a new eugenics? eugenics?

"Is this a new eugenics? I think it is.” Margaret "Is this a new eugenics? I think it is.” Margaret Somerville (quoted in Collier, 2009) Somerville (quoted in Collier, 2009)

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Readings Readings

Al Al‐Mulla Mulla, F. (2007). Utilization of microarray , F. (2007). Utilization of microarray platforms in clinical practice: an insight on the platforms in clinical practice: an insight on the preparation and amplification of nucleic acids from preparation and amplification of nucleic acids from frozen and fixed tissues. Methods frozen and fixed tissues. Methods Mol Mol Biol Biol, 382, , 382, 115 115‐ 136. 136. Manamperi Manamperi, A. (2008). Current developments , A. (2008). Current developments in genomics in genomics and personalized health care: and personalized health care: impact on public health impact on public health. Asia Pac J Public . Asia Pac J Public Health, 20 Health, 20(3), 242 (3), 242-

• 250.

250. Sh t E (2007) Mi ti Sh t E (2007) Mi ti Ball, C., Ball, C., Brazma Brazma, A., , A., Causton Causton, H., , H., Chervitz Chervitz, S., Edgar, , S., Edgar, R., R., Hingamp Hingamp, P., et al. (2004). Standards for , P., et al. (2004). Standards for microarray data: an open letter. microarray data: an open letter. Environ Health Environ Health Perspect Perspect, 112 , 112(12), A666 (12), A666‐667. 667. Beaudet Beaudet, A. (2009), "The case for offering all , A. (2009), "The case for offering all women amniocentesis and chromosomal women amniocentesis and chromosomal microarray analysis", in Scherer, S. (ed.), microarray analysis", in Scherer, S. (ed.), Copy Copy Number Variation: , The Biomedical & Life Sciences Number Variation: , The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online Collection, Henry Stewart Talks Ltd, London (online at at http://hstalks.com/bio) http://hstalks.com/bio) Shuster, E. (2007). Microarray genetic Shuster, E. (2007). Microarray genetic screening: a prenatal roadblock for life? screening: a prenatal roadblock for life? Lancet, 369(9560), 526 Lancet, 369(9560), 526-

• 529.

529. Tomlin, R. (2006, November). The ethics of Tomlin, R. (2006, November). The ethics of genetic testing. FINDINGS, 4(10), retrieved genetic testing. FINDINGS, 4(10), retrieved from from http://www.bcm.edu/findings/vol4/is10/06n http://www.bcm.edu/findings/vol4/is10/06n

• v_n1.html on 15 February 2011.
• v_n1.html on 15 February 2011.

Wilcken Wilcken, B. (2003). Ethical issues in newborn , B. (2003). Ethical issues in newborn screening and the impact of new screening and the impact of new technologies technologies Eur Eur J Pediatr Pediatr 162 162 Suppl Suppl 1 Collier, R. (2009, March 31). Collier, R. (2009, March 31). Prenatal DNA test Prenatal DNA test raises both hopes and worries, raises both hopes and worries, CMAJ,180 CMAJ,180 (7), (7), http://www.cmaj.ca/cgi/content/full/180/7/705 http://www.cmaj.ca/cgi/content/full/180/7/705 Grody Grody, W. W. (2003). Ethical issues raised by , W. W. (2003). Ethical issues raised by genetic testing with genetic testing with oligonucleotide

• ligonucleotide microarrays.

microarrays. Molecular Biotechnology, 23 Molecular Biotechnology, 23(2), 127 (2), 127‐138. 138. technologies.

• technologies. Eur

Eur J J Pediatr Pediatr, 162 , 162 Suppl Suppl 1, 1, S62 S62-

• 66.

66.

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