Michael F. Murray, MD

I am not an information technology guy, but by now even I have heard the term "big data" applied to all sorts of topics in our public discourse, from government and accounting to the environment and biology.

Well, consider this big-data issue: There are more than 3 billion (3,000,000,000) nucleotide letters in an individual’s genetic code – and the diagnostic use of "whole genome sequencing" aims to spell out the entire code of an individual to find the one or two variant letters that are causing that individual’s rare disease presentation. Oh, and by the way: There will be about 3 million (3,000,000) variant letters in each genome – you just need to figure out which of these matter and which do not.

There are some relatively simple concepts that can be applied to allow for filtering of the data, such as comparing variants found in an individual against those found in large groups, then eliminating the "common variants" as candidates for the cause of a rare disease. Or generating the complete data set from the relatives of the patient, then comparing the patient’s data to family members’ data.

Among the uses of family data: Positively select for shared variants of patients and their family members with the same medical diagnosis, or reveal both parents to be carriers of single mutations in cases where their children have rare autosomal recessive diseases (caused by two mutations).

The simple concepts aside, this is a massive data analysis task requiring many kinds of clinical and scientific expertise – and the strategies for this interpretation are not fully worked out yet.

Enter into this complex situation a challenge, and a prize.

The Children’s Hospital of Boston (CHB) designed its recent CLARITY (Children’s Leadership Award for the Reliable Interpretation and Appropriate Transmission of Your Genomic Information) Challenge as a way to "inform the creation of much-needed ‘best practices’ in genome analysis, interpretation, and reporting – providing the most meaningful results to patients and their families."

The initiative attracted 23 research teams from around the world, which agreed to receive an abstracted medical record together with genomic information from three children with genetic disorders of unknown causes and their parents. The teams’ challenge was to interpret the genomic data from the cases to find the diagnostic genetic changes in the genomes of the children, two of whom had severe neuromuscular disease and one of whom had died of congenital heart defects.

As incentives, the initiative offered the winning team a $15,000 prize, while finalists would earn $5,000 prizes.

The 23 groups all approached the diagnostic problem in slightly different ways. None of the teams was perfect, but the judges recognized eight of the teams for excellence in one or more aspects of the process. And a team led by Brigham and Women’s Hospital and including researchers from Massachusetts General Hospital, Partners Laboratory for Molecular Medicine, Brown University, and Utrecht University shared the $15,000 prize.

The three families’ stories are shared on the CHB website.

Medical details aside, we as a medical community and as a society are indebted here to the brave families who agreed to share their difficult stories.

Although the "best practices" remain to be better defined, the CLARITY Challenge process has reassured many of us in the field that we are getting closer to standardizing solutions for the most intimate of "big data" issues – namely, the one carried around by each of us in every cell in our body.

Dr. Murray is the director of clinical genomics at Geisinger Health System in Danville, Pa.

I am not an information technology guy, but by now even I have heard the term "big data" applied to all sorts of topics in our public discourse, from government and accounting to the environment and biology.

Well, consider this big-data issue: There are more than 3 billion (3,000,000,000) nucleotide letters in an individual’s genetic code – and the diagnostic use of "whole genome sequencing" aims to spell out the entire code of an individual to find the one or two variant letters that are causing that individual’s rare disease presentation. Oh, and by the way: There will be about 3 million (3,000,000) variant letters in each genome – you just need to figure out which of these matter and which do not.

There are some relatively simple concepts that can be applied to allow for filtering of the data, such as comparing variants found in an individual against those found in large groups, then eliminating the "common variants" as candidates for the cause of a rare disease. Or generating the complete data set from the relatives of the patient, then comparing the patient’s data to family members’ data.

Among the uses of family data: Positively select for shared variants of patients and their family members with the same medical diagnosis, or reveal both parents to be carriers of single mutations in cases where their children have rare autosomal recessive diseases (caused by two mutations).

The simple concepts aside, this is a massive data analysis task requiring many kinds of clinical and scientific expertise – and the strategies for this interpretation are not fully worked out yet.

Enter into this complex situation a challenge, and a prize.

The Children’s Hospital of Boston (CHB) designed its recent CLARITY (Children’s Leadership Award for the Reliable Interpretation and Appropriate Transmission of Your Genomic Information) Challenge as a way to "inform the creation of much-needed ‘best practices’ in genome analysis, interpretation, and reporting – providing the most meaningful results to patients and their families."

The initiative attracted 23 research teams from around the world, which agreed to receive an abstracted medical record together with genomic information from three children with genetic disorders of unknown causes and their parents. The teams’ challenge was to interpret the genomic data from the cases to find the diagnostic genetic changes in the genomes of the children, two of whom had severe neuromuscular disease and one of whom had died of congenital heart defects.

As incentives, the initiative offered the winning team a $15,000 prize, while finalists would earn $5,000 prizes.

The 23 groups all approached the diagnostic problem in slightly different ways. None of the teams was perfect, but the judges recognized eight of the teams for excellence in one or more aspects of the process. And a team led by Brigham and Women’s Hospital and including researchers from Massachusetts General Hospital, Partners Laboratory for Molecular Medicine, Brown University, and Utrecht University shared the $15,000 prize.

The three families’ stories are shared on the CHB website.

Medical details aside, we as a medical community and as a society are indebted here to the brave families who agreed to share their difficult stories.

Although the "best practices" remain to be better defined, the CLARITY Challenge process has reassured many of us in the field that we are getting closer to standardizing solutions for the most intimate of "big data" issues – namely, the one carried around by each of us in every cell in our body.

Dr. Murray is the director of clinical genomics at Geisinger Health System in Danville, Pa.

I am not an information technology guy, but by now even I have heard the term "big data" applied to all sorts of topics in our public discourse, from government and accounting to the environment and biology.

Well, consider this big-data issue: There are more than 3 billion (3,000,000,000) nucleotide letters in an individual’s genetic code – and the diagnostic use of "whole genome sequencing" aims to spell out the entire code of an individual to find the one or two variant letters that are causing that individual’s rare disease presentation. Oh, and by the way: There will be about 3 million (3,000,000) variant letters in each genome – you just need to figure out which of these matter and which do not.

There are some relatively simple concepts that can be applied to allow for filtering of the data, such as comparing variants found in an individual against those found in large groups, then eliminating the "common variants" as candidates for the cause of a rare disease. Or generating the complete data set from the relatives of the patient, then comparing the patient’s data to family members’ data.

Among the uses of family data: Positively select for shared variants of patients and their family members with the same medical diagnosis, or reveal both parents to be carriers of single mutations in cases where their children have rare autosomal recessive diseases (caused by two mutations).

The simple concepts aside, this is a massive data analysis task requiring many kinds of clinical and scientific expertise – and the strategies for this interpretation are not fully worked out yet.

Enter into this complex situation a challenge, and a prize.

The Children’s Hospital of Boston (CHB) designed its recent CLARITY (Children’s Leadership Award for the Reliable Interpretation and Appropriate Transmission of Your Genomic Information) Challenge as a way to "inform the creation of much-needed ‘best practices’ in genome analysis, interpretation, and reporting – providing the most meaningful results to patients and their families."

The initiative attracted 23 research teams from around the world, which agreed to receive an abstracted medical record together with genomic information from three children with genetic disorders of unknown causes and their parents. The teams’ challenge was to interpret the genomic data from the cases to find the diagnostic genetic changes in the genomes of the children, two of whom had severe neuromuscular disease and one of whom had died of congenital heart defects.

As incentives, the initiative offered the winning team a $15,000 prize, while finalists would earn $5,000 prizes.

The 23 groups all approached the diagnostic problem in slightly different ways. None of the teams was perfect, but the judges recognized eight of the teams for excellence in one or more aspects of the process. And a team led by Brigham and Women’s Hospital and including researchers from Massachusetts General Hospital, Partners Laboratory for Molecular Medicine, Brown University, and Utrecht University shared the $15,000 prize.

The three families’ stories are shared on the CHB website.

Medical details aside, we as a medical community and as a society are indebted here to the brave families who agreed to share their difficult stories.

Although the "best practices" remain to be better defined, the CLARITY Challenge process has reassured many of us in the field that we are getting closer to standardizing solutions for the most intimate of "big data" issues – namely, the one carried around by each of us in every cell in our body.

Dr. Murray is the director of clinical genomics at Geisinger Health System in Danville, Pa.

A recently published paper on universal preconception screening should be on internists’ radar as it heralds a potential broad new application for genetics in adult care.

The back story behind the publication of “Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing,” has been told in the lay press and it is both tragic and compelling.

Craig Benson got interested in carrier screening for recessive genetic conditions after he and his wife found out that their young daughter had Batten disease, a rare neurodegenerative disease affecting about 1 in 100,000 people. Like most people, the Benson family had never even heard of this disease and yet, after their daughter’s diagnosis, both father and mother discovered that they were carriers for a mutation in one of the genes that cause the disease.

Two years ago, Mr.Benson and others formed the Beyond Batten Disease Foundation (BBDF) and found themselves confronting the question of how a carrier screening concept, inspired by the example of Tay-Sachs, could be applied broadly to all recessive genetic diseases.

The January publication by Callum J. Bell, Ph.D., and colleagues, is the outcome of a collaboration between BBDF and the National Center for Genome Resources (NCGR) in Santa Fe, N.M. (Sci. Transl. Med. 2011;3:65ra4).

The concept appears relatively straightforward. With the cost of DNA sequencing now inexpensive enough to consider offering trait carrier screening to prospective parents for the many rare conditions that in aggregate drive significant childhood morbidity and mortality, and since screening could potentially lead to fewer couples having children with devastating autosomal recessive conditions, then perhaps it is time to make this testing widely available to any adult considering future childbearing. The data in Dr. Bell’s paper suggest that DNA-sequence–based testing on approximately 450 genes linked to genetic conditions can be performed accurately and in a cost-effective manner. According to a statement issued by BBDF and NCGR, “The carrier-screening test is expected to become commercially available in the third quarter of 2011.”

If this preconceptual screening strategy overcomes hurdles and becomes clinically available this year, this screening will be the first of its kind.

Although the authors cite Tay-Sachs screening and many practitioners are familiar with other preconceptual genetic screening such as for cystic fibrosis, this is different. Two new features of this proposed screening are that its use would not be limited to a defined at-risk group (i.e., an ethnic or racial group with a “high” carrier rate) nor would it use a “common mutation” approach. This approach will seek to find any and all mutations in the genes of interest and will seek to offer it to an unselected population.

The analysis from Dr. Bell and his colleagues suggests that everyone who undergoes the testing will have “positive results” that require review. Such positive results that will require counseling fall into two categories: well-defined “mutations” and variants of unknown significance (VUS). Among the 104 volunteers studied, each individual silently harbored between zero and seven mutations conferring recessive traits (average 2.4) and approximately 11 VUS.

If an individual with a mutation mates with another individual with a mutation conferring one of the same recessive traits, then that couple has a 25% chance with each pregnancy of having a child with the recessive condition in question. Any provider who has ever ordered a single genetic screening test and then dealt with the counseling and other needs of the patient when there is a positive result, can appreciate the mountain of patient care that this kind of testing will generate, with the more than 10 results per patient available to review.

If such testing becomes clinically available later this year, there will still be many unanswered questions related to its use. Among them: What is the rate of false positives and false negatives? Who will provide the counseling for each patient who undergoes the testing? Who will pay for the time spent by the provider discussing the complicated results? What kind of changes in reproductive choices will this testing result in? Will this testing generate significant “downstream” costs related to diagnostic evaluations in healthy adults? Will there be a net cost savings for the health care system when the up-front and downstream costs are balanced against whatever savings are realized with less overall childhood morbidity and mortality?

While the prediction that such tests will be available by the third quarter of 2011 might be overly optimistic, it seems certain that it is coming soon to a medical practice near you, perhaps yours. 

A recently published paper on universal preconception screening should be on internists’ radar as it heralds a potential broad new application for genetics in adult care.

The back story behind the publication of “Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing,” has been told in the lay press and it is both tragic and compelling.

Craig Benson got interested in carrier screening for recessive genetic conditions after he and his wife found out that their young daughter had Batten disease, a rare neurodegenerative disease affecting about 1 in 100,000 people. Like most people, the Benson family had never even heard of this disease and yet, after their daughter’s diagnosis, both father and mother discovered that they were carriers for a mutation in one of the genes that cause the disease.

Two years ago, Mr.Benson and others formed the Beyond Batten Disease Foundation (BBDF) and found themselves confronting the question of how a carrier screening concept, inspired by the example of Tay-Sachs, could be applied broadly to all recessive genetic diseases.

The January publication by Callum J. Bell, Ph.D., and colleagues, is the outcome of a collaboration between BBDF and the National Center for Genome Resources (NCGR) in Santa Fe, N.M. (Sci. Transl. Med. 2011;3:65ra4).

The concept appears relatively straightforward. With the cost of DNA sequencing now inexpensive enough to consider offering trait carrier screening to prospective parents for the many rare conditions that in aggregate drive significant childhood morbidity and mortality, and since screening could potentially lead to fewer couples having children with devastating autosomal recessive conditions, then perhaps it is time to make this testing widely available to any adult considering future childbearing. The data in Dr. Bell’s paper suggest that DNA-sequence–based testing on approximately 450 genes linked to genetic conditions can be performed accurately and in a cost-effective manner. According to a statement issued by BBDF and NCGR, “The carrier-screening test is expected to become commercially available in the third quarter of 2011.”

If this preconceptual screening strategy overcomes hurdles and becomes clinically available this year, this screening will be the first of its kind.

Although the authors cite Tay-Sachs screening and many practitioners are familiar with other preconceptual genetic screening such as for cystic fibrosis, this is different. Two new features of this proposed screening are that its use would not be limited to a defined at-risk group (i.e., an ethnic or racial group with a “high” carrier rate) nor would it use a “common mutation” approach. This approach will seek to find any and all mutations in the genes of interest and will seek to offer it to an unselected population.

The analysis from Dr. Bell and his colleagues suggests that everyone who undergoes the testing will have “positive results” that require review. Such positive results that will require counseling fall into two categories: well-defined “mutations” and variants of unknown significance (VUS). Among the 104 volunteers studied, each individual silently harbored between zero and seven mutations conferring recessive traits (average 2.4) and approximately 11 VUS.

If an individual with a mutation mates with another individual with a mutation conferring one of the same recessive traits, then that couple has a 25% chance with each pregnancy of having a child with the recessive condition in question. Any provider who has ever ordered a single genetic screening test and then dealt with the counseling and other needs of the patient when there is a positive result, can appreciate the mountain of patient care that this kind of testing will generate, with the more than 10 results per patient available to review.

If such testing becomes clinically available later this year, there will still be many unanswered questions related to its use. Among them: What is the rate of false positives and false negatives? Who will provide the counseling for each patient who undergoes the testing? Who will pay for the time spent by the provider discussing the complicated results? What kind of changes in reproductive choices will this testing result in? Will this testing generate significant “downstream” costs related to diagnostic evaluations in healthy adults? Will there be a net cost savings for the health care system when the up-front and downstream costs are balanced against whatever savings are realized with less overall childhood morbidity and mortality?

While the prediction that such tests will be available by the third quarter of 2011 might be overly optimistic, it seems certain that it is coming soon to a medical practice near you, perhaps yours. 

A recently published paper on universal preconception screening should be on internists’ radar as it heralds a potential broad new application for genetics in adult care.

The back story behind the publication of “Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing,” has been told in the lay press and it is both tragic and compelling.

Craig Benson got interested in carrier screening for recessive genetic conditions after he and his wife found out that their young daughter had Batten disease, a rare neurodegenerative disease affecting about 1 in 100,000 people. Like most people, the Benson family had never even heard of this disease and yet, after their daughter’s diagnosis, both father and mother discovered that they were carriers for a mutation in one of the genes that cause the disease.

Two years ago, Mr.Benson and others formed the Beyond Batten Disease Foundation (BBDF) and found themselves confronting the question of how a carrier screening concept, inspired by the example of Tay-Sachs, could be applied broadly to all recessive genetic diseases.

The January publication by Callum J. Bell, Ph.D., and colleagues, is the outcome of a collaboration between BBDF and the National Center for Genome Resources (NCGR) in Santa Fe, N.M. (Sci. Transl. Med. 2011;3:65ra4).

The concept appears relatively straightforward. With the cost of DNA sequencing now inexpensive enough to consider offering trait carrier screening to prospective parents for the many rare conditions that in aggregate drive significant childhood morbidity and mortality, and since screening could potentially lead to fewer couples having children with devastating autosomal recessive conditions, then perhaps it is time to make this testing widely available to any adult considering future childbearing. The data in Dr. Bell’s paper suggest that DNA-sequence–based testing on approximately 450 genes linked to genetic conditions can be performed accurately and in a cost-effective manner. According to a statement issued by BBDF and NCGR, “The carrier-screening test is expected to become commercially available in the third quarter of 2011.”

If this preconceptual screening strategy overcomes hurdles and becomes clinically available this year, this screening will be the first of its kind.

Although the authors cite Tay-Sachs screening and many practitioners are familiar with other preconceptual genetic screening such as for cystic fibrosis, this is different. Two new features of this proposed screening are that its use would not be limited to a defined at-risk group (i.e., an ethnic or racial group with a “high” carrier rate) nor would it use a “common mutation” approach. This approach will seek to find any and all mutations in the genes of interest and will seek to offer it to an unselected population.

The analysis from Dr. Bell and his colleagues suggests that everyone who undergoes the testing will have “positive results” that require review. Such positive results that will require counseling fall into two categories: well-defined “mutations” and variants of unknown significance (VUS). Among the 104 volunteers studied, each individual silently harbored between zero and seven mutations conferring recessive traits (average 2.4) and approximately 11 VUS.

If an individual with a mutation mates with another individual with a mutation conferring one of the same recessive traits, then that couple has a 25% chance with each pregnancy of having a child with the recessive condition in question. Any provider who has ever ordered a single genetic screening test and then dealt with the counseling and other needs of the patient when there is a positive result, can appreciate the mountain of patient care that this kind of testing will generate, with the more than 10 results per patient available to review.

If such testing becomes clinically available later this year, there will still be many unanswered questions related to its use. Among them: What is the rate of false positives and false negatives? Who will provide the counseling for each patient who undergoes the testing? Who will pay for the time spent by the provider discussing the complicated results? What kind of changes in reproductive choices will this testing result in? Will this testing generate significant “downstream” costs related to diagnostic evaluations in healthy adults? Will there be a net cost savings for the health care system when the up-front and downstream costs are balanced against whatever savings are realized with less overall childhood morbidity and mortality?

While the prediction that such tests will be available by the third quarter of 2011 might be overly optimistic, it seems certain that it is coming soon to a medical practice near you, perhaps yours. 

A recently published paper on universal preconception screening should be on internists’ radar as it heralds a potential broad new application for genetics in adult care.

The back story behind the publication of "Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing," has been told in the lay press and it is both tragic and compelling.

Craig Benson got interested in carrier screening for recessive genetic conditions after he and his wife found out that their young daughter had Batten disease, a rare neurodegenerative disease affecting about 1 in 100,000 people. Like most people, the Benson family had never even heard of this disease and yet, after their daughter’s diagnosis, both father and mother discovered that they were carriers for a mutation in one of the genes that cause the disease.

Two years ago, Mr.Benson and others formed the Beyond Batten Disease Foundation (BBDF) and found themselves confronting the question of how a carrier screening concept, inspired by the example of Tay-Sachs, could be applied broadly to all recessive genetic diseases.

The January publication by Callum J. Bell, Ph.D., and colleagues, is the outcome of a collaboration between BBDF and the National Center for Genome Resources (NCGR) in Santa Fe, N.M. (Sci. Transl. Med. 2011;3:65ra4).

The concept appears relatively straightforward. With the cost of DNA sequencing now inexpensive enough to consider offering trait carrier screening to prospective parents for the many rare conditions that in aggregate drive significant childhood morbidity and mortality, and since screening could potentially lead to fewer couples having children with devastating autosomal recessive conditions, then perhaps it is time to make this testing widely available to any adult considering future childbearing. The data in Dr. Bell’s paper suggest that DNA-sequence–based testing on approximately 450 genes linked to genetic conditions can be performed accurately and in a cost-effective manner. According to a statement issued by BBDF and NCGR, "The carrier-screening test is expected to become commercially available in the third quarter of 2011."

If this preconceptual screening strategy overcomes hurdles and becomes clinically available this year, this screening will be the first of its kind.

Although the authors cite Tay-Sachs screening and many practitioners are familiar with other preconceptual genetic screening such as for cystic fibrosis, this is different. Two new features of this proposed screening are that its use would not be limited to a defined at-risk group (i.e., an ethnic or racial group with a "high" carrier rate) nor would it use a "common mutation" approach. This approach will seek to find any and all mutations in the genes of interest and will seek to offer it to an unselected population.

The analysis from Dr. Bell and his colleagues suggests that everyone who undergoes the testing will have "positive results" that require review. Such positive results that will require counseling fall into two categories: well-defined "mutations" and variants of unknown significance (VUS). Among the 104 volunteers studied, each individual silently harbored between zero and seven mutations conferring recessive traits (average 2.4) and approximately 11 VUS.

If an individual with a mutation mates with another individual with a mutation conferring one of the same recessive traits, then that couple has a 25% chance with each pregnancy of having a child with the recessive condition in question. Any provider who has ever ordered a single genetic screening test and then dealt with the counseling and other needs of the patient when there is a positive result, can appreciate the mountain of patient care that this kind of testing will generate, with the more than 10 results per patient available to review.

If such testing becomes clinically available later this year, there will still be many unanswered questions related to its use. Among them: What is the rate of false positives and false negatives? Who will provide the counseling for each patient who undergoes the testing? Who will pay for the time spent by the provider discussing the complicated results? What kind of changes in reproductive choices will this testing result in? Will this testing generate significant "downstream" costs related to diagnostic evaluations in healthy adults? Will there be a net cost savings for the health care system when the up-front and downstream costs are balanced against whatever savings are realized with less overall childhood morbidity and mortality?

While the prediction that such tests will be available by the third quarter of 2011 might be overly optimistic, it seems certain that it is coming soon to a medical practice near you, perhaps yours.

This column, "Genetics in Your Practice," regularly appears on the Internal Medicine News Digital Network and in Internal Medicine News, an Elsevier publication. Dr. Murray is the clinical chief of genetics at Brigham and Women’s Hospital and an instructor at Harvard Medical School, Boston. To respond to this column, e-mail him.

A recently published paper on universal preconception screening should be on internists’ radar as it heralds a potential broad new application for genetics in adult care.

The back story behind the publication of "Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing," has been told in the lay press and it is both tragic and compelling.

Craig Benson got interested in carrier screening for recessive genetic conditions after he and his wife found out that their young daughter had Batten disease, a rare neurodegenerative disease affecting about 1 in 100,000 people. Like most people, the Benson family had never even heard of this disease and yet, after their daughter’s diagnosis, both father and mother discovered that they were carriers for a mutation in one of the genes that cause the disease.

Two years ago, Mr.Benson and others formed the Beyond Batten Disease Foundation (BBDF) and found themselves confronting the question of how a carrier screening concept, inspired by the example of Tay-Sachs, could be applied broadly to all recessive genetic diseases.

The January publication by Callum J. Bell, Ph.D., and colleagues, is the outcome of a collaboration between BBDF and the National Center for Genome Resources (NCGR) in Santa Fe, N.M. (Sci. Transl. Med. 2011;3:65ra4).

The concept appears relatively straightforward. With the cost of DNA sequencing now inexpensive enough to consider offering trait carrier screening to prospective parents for the many rare conditions that in aggregate drive significant childhood morbidity and mortality, and since screening could potentially lead to fewer couples having children with devastating autosomal recessive conditions, then perhaps it is time to make this testing widely available to any adult considering future childbearing. The data in Dr. Bell’s paper suggest that DNA-sequence–based testing on approximately 450 genes linked to genetic conditions can be performed accurately and in a cost-effective manner. According to a statement issued by BBDF and NCGR, "The carrier-screening test is expected to become commercially available in the third quarter of 2011."

If this preconceptual screening strategy overcomes hurdles and becomes clinically available this year, this screening will be the first of its kind.

Although the authors cite Tay-Sachs screening and many practitioners are familiar with other preconceptual genetic screening such as for cystic fibrosis, this is different. Two new features of this proposed screening are that its use would not be limited to a defined at-risk group (i.e., an ethnic or racial group with a "high" carrier rate) nor would it use a "common mutation" approach. This approach will seek to find any and all mutations in the genes of interest and will seek to offer it to an unselected population.

The analysis from Dr. Bell and his colleagues suggests that everyone who undergoes the testing will have "positive results" that require review. Such positive results that will require counseling fall into two categories: well-defined "mutations" and variants of unknown significance (VUS). Among the 104 volunteers studied, each individual silently harbored between zero and seven mutations conferring recessive traits (average 2.4) and approximately 11 VUS.

If an individual with a mutation mates with another individual with a mutation conferring one of the same recessive traits, then that couple has a 25% chance with each pregnancy of having a child with the recessive condition in question. Any provider who has ever ordered a single genetic screening test and then dealt with the counseling and other needs of the patient when there is a positive result, can appreciate the mountain of patient care that this kind of testing will generate, with the more than 10 results per patient available to review.

If such testing becomes clinically available later this year, there will still be many unanswered questions related to its use. Among them: What is the rate of false positives and false negatives? Who will provide the counseling for each patient who undergoes the testing? Who will pay for the time spent by the provider discussing the complicated results? What kind of changes in reproductive choices will this testing result in? Will this testing generate significant "downstream" costs related to diagnostic evaluations in healthy adults? Will there be a net cost savings for the health care system when the up-front and downstream costs are balanced against whatever savings are realized with less overall childhood morbidity and mortality?

While the prediction that such tests will be available by the third quarter of 2011 might be overly optimistic, it seems certain that it is coming soon to a medical practice near you, perhaps yours.

This column, "Genetics in Your Practice," regularly appears on the Internal Medicine News Digital Network and in Internal Medicine News, an Elsevier publication. Dr. Murray is the clinical chief of genetics at Brigham and Women’s Hospital and an instructor at Harvard Medical School, Boston. To respond to this column, e-mail him.

A recently published paper on universal preconception screening should be on internists’ radar as it heralds a potential broad new application for genetics in adult care.

The back story behind the publication of "Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing," has been told in the lay press and it is both tragic and compelling.

Craig Benson got interested in carrier screening for recessive genetic conditions after he and his wife found out that their young daughter had Batten disease, a rare neurodegenerative disease affecting about 1 in 100,000 people. Like most people, the Benson family had never even heard of this disease and yet, after their daughter’s diagnosis, both father and mother discovered that they were carriers for a mutation in one of the genes that cause the disease.

Two years ago, Mr.Benson and others formed the Beyond Batten Disease Foundation (BBDF) and found themselves confronting the question of how a carrier screening concept, inspired by the example of Tay-Sachs, could be applied broadly to all recessive genetic diseases.

The January publication by Callum J. Bell, Ph.D., and colleagues, is the outcome of a collaboration between BBDF and the National Center for Genome Resources (NCGR) in Santa Fe, N.M. (Sci. Transl. Med. 2011;3:65ra4).

The concept appears relatively straightforward. With the cost of DNA sequencing now inexpensive enough to consider offering trait carrier screening to prospective parents for the many rare conditions that in aggregate drive significant childhood morbidity and mortality, and since screening could potentially lead to fewer couples having children with devastating autosomal recessive conditions, then perhaps it is time to make this testing widely available to any adult considering future childbearing. The data in Dr. Bell’s paper suggest that DNA-sequence–based testing on approximately 450 genes linked to genetic conditions can be performed accurately and in a cost-effective manner. According to a statement issued by BBDF and NCGR, "The carrier-screening test is expected to become commercially available in the third quarter of 2011."

If this preconceptual screening strategy overcomes hurdles and becomes clinically available this year, this screening will be the first of its kind.

Although the authors cite Tay-Sachs screening and many practitioners are familiar with other preconceptual genetic screening such as for cystic fibrosis, this is different. Two new features of this proposed screening are that its use would not be limited to a defined at-risk group (i.e., an ethnic or racial group with a "high" carrier rate) nor would it use a "common mutation" approach. This approach will seek to find any and all mutations in the genes of interest and will seek to offer it to an unselected population.

The analysis from Dr. Bell and his colleagues suggests that everyone who undergoes the testing will have "positive results" that require review. Such positive results that will require counseling fall into two categories: well-defined "mutations" and variants of unknown significance (VUS). Among the 104 volunteers studied, each individual silently harbored between zero and seven mutations conferring recessive traits (average 2.4) and approximately 11 VUS.

If an individual with a mutation mates with another individual with a mutation conferring one of the same recessive traits, then that couple has a 25% chance with each pregnancy of having a child with the recessive condition in question. Any provider who has ever ordered a single genetic screening test and then dealt with the counseling and other needs of the patient when there is a positive result, can appreciate the mountain of patient care that this kind of testing will generate, with the more than 10 results per patient available to review.

If such testing becomes clinically available later this year, there will still be many unanswered questions related to its use. Among them: What is the rate of false positives and false negatives? Who will provide the counseling for each patient who undergoes the testing? Who will pay for the time spent by the provider discussing the complicated results? What kind of changes in reproductive choices will this testing result in? Will this testing generate significant "downstream" costs related to diagnostic evaluations in healthy adults? Will there be a net cost savings for the health care system when the up-front and downstream costs are balanced against whatever savings are realized with less overall childhood morbidity and mortality?

While the prediction that such tests will be available by the third quarter of 2011 might be overly optimistic, it seems certain that it is coming soon to a medical practice near you, perhaps yours.

This column, "Genetics in Your Practice," regularly appears on the Internal Medicine News Digital Network and in Internal Medicine News, an Elsevier publication. Dr. Murray is the clinical chief of genetics at Brigham and Women’s Hospital and an instructor at Harvard Medical School, Boston. To respond to this column, e-mail him.