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Results from two new studies suggest that genetic testing early in the diagnostic pathway may allow for earlier and more precise diagnoses in early-life epilepsies and a range of other childhood-onset disorders, and potentially limit costs associated with a long diagnostic course.
Both papers, published online July 31 in JAMA Pediatrics, showed the diagnostic yield of genetic testing approaches, including whole-exome sequencing (WES), to be high.
The results also argue for the incorporation of genetic testing into the first diagnostic assessments; not limiting it to severe presentations only; and for broad testing methods to be employed in lieu of narrower ones.
Of these patients, just under half (n = 327) underwent various forms of genetic testing at the discretion of the treating physician, including karyotyping, microarrays, epilepsy gene panels, WES, mitochondrial panels, and other tests. Pathogenic variants were discovered in 132 children, or 40% of those receiving genetic testing (JAMA Pediatr. 2017 July 31. doi: 10.1001/jamapediatrics.2017.1743).
Of all the genetic testing methods employed in the study, diagnostic yields were significantly greater for epilepsy gene panels (29.2%) and WES (27.8%), compared with chromosome microarray (7.9%).
The results, the investigators said, provide “added impetus to move the diagnosis of the specific cause to the point of initial presentation ... it is time to provide greater emphasis on and support for thorough genetic evaluations, particularly sequencing-based evaluations, for children with newly presenting epilepsies in the first few years of life.”
In addition to aiding management decisions, early genetic testing “ends the diagnostic odyssey during which parents and physicians spend untold amounts of time searching for an explanation for a child’s epilepsy and reduces associated costs,” Dr. Berg and her colleagues concluded.
In a separate study led by Tiong Yang Tan, MBBS, PhD, of Victorian Clinical Genetics Services in Melbourne, Australia, and his colleagues, singleton WES was used in 44 children recruited at outpatient clinics of a Melbourne hospital system (JAMA Pediatr. 2017 July 31. doi: 10.1001/jamapediatrics.2017.1755).
Children in the study were aged 2-18 years (with mean age at presentation 28 months) and had a wide variety of suspected genetic disorders, including skeletal, skin, neurometabolic, and intellectual disorders. Some of these had features overlapping several conditions. The children in the cohort had not received prior genetic testing before undergoing WES.
The molecular test resulted in a diagnosis in 52% (n = 23) of the children, including unexpected diagnoses in eight of these. Clinical management was altered as result of sequencing findings in six children.
“Although phenotyping is critical, 35% of children had a diagnosis caused by a gene outside the initially prioritized gene list. This finding not only possibly reflects lack of clinical recognition but also underscores the utility of WES in achieving a diagnosis even when the a priori hypothesis is imprecise,” Dr. Tan and his associates wrote in their analysis.
Dr. Tan and his colleagues conducted a cost analysis that found WES performed at initial tertiary presentation resulted in a cost savings of U.S. $6,838 per additional diagnosis (95% confidence interval, U.S. $3,263-$11,678), compared with the standard diagnostic pathway. The figures reflect costs in an Australian care setting.
The children in the study had a mean diagnostic odyssey of 6 years, including a mean of 19 tests and four clinical genetics and four non–genetics specialist consultations. A quarter of them had undergone at least one diagnostic procedure under general anesthesia.
“The diagnostic odyssey of children suspected of having monogenic disorders is protracted and painful and may not provide a precise diagnosis,” Dr. Tan and his colleagues wrote in their analysis. “This paradigm has markedly shifted with the advent of WES.”
WES is best targeted to children “with genetically heterogeneous disorders or features overlapping several conditions,” the investigators concluded. “Our findings suggest that these children are best served by early recognition by their pediatrician and expedited referral to clinical genetics with WES applied after chromosomal microarray but before an extensive diagnostic process.”
Dr. Tan and his colleagues’ study was funded by the Melbourne Genomics Health Alliance and state and national governments in Australia. None of the authors declared conflicts of interest. Dr. Berg and her colleagues’ study was funded by the Pediatric Epilepsy Research Foundation, and none of its authors disclosed commercial conflicts of interest.
The studies by Tan et al. and Berg et al. demonstrate the dramatic effect of the diagnostic yield of different genetic testing approaches on cost-effectiveness and the potential design of testing strategies in children with suspected monogenic conditions. Both studies emphasize the effect of the results of genetic testing. Whereas Tan et al. showed that, in 26% of cases, the result enabled a specific modification of patient care, Berg et al. also demonstrated that there is no basis for identifying optimal, targeted treatments, when testing is not performed and genetic diagnoses are not made.
However, in the absence of targeted treatments, a genetic diagnosis is of high value for the patients, their families, and treating physicians. A clear diagnosis may not only be of prognostic value but also put an end to a possibly stressful and demanding diagnostic odyssey. It may enable patient care that is explicitly focused on the individual needs of the patient. A clear diagnosis usually also allows a better assessment of the risks of recurrence in the family and possibly enables prenatal testing in relatives. Finally, it enables research and a better scientific understanding of the underlying pathophysiology, which may ideally lead to the identification of novel therapeutic prospects. Seven years ago, an international consensus statement endorsed the replacement of classic cytogenetic karyotype analysis by chromosomal microarrays as a first-tier diagnostic test in individuals with developmental disabilities or congenital anomalies. The studies add to the growing evidence that this consensus may already be outdated, as high-throughput sequencing techniques may achieve even higher diagnostic yields and, thus, are capable to become the new first-tier diagnostic test in congenital and early-onset disorders.
Johannes R. Lemke, MD, is with the Institute of Human Genetics at the University of Leipzig (Germany) Hospitals and Clinics. He reports no conflicts of interest associated with his editorial, which accompanied the JAMA Pediatrics reports (JAMA Pediatr. 2017 July 31. doi: 10.1001/jamapediatrics.2017.1743).
The studies by Tan et al. and Berg et al. demonstrate the dramatic effect of the diagnostic yield of different genetic testing approaches on cost-effectiveness and the potential design of testing strategies in children with suspected monogenic conditions. Both studies emphasize the effect of the results of genetic testing. Whereas Tan et al. showed that, in 26% of cases, the result enabled a specific modification of patient care, Berg et al. also demonstrated that there is no basis for identifying optimal, targeted treatments, when testing is not performed and genetic diagnoses are not made.
However, in the absence of targeted treatments, a genetic diagnosis is of high value for the patients, their families, and treating physicians. A clear diagnosis may not only be of prognostic value but also put an end to a possibly stressful and demanding diagnostic odyssey. It may enable patient care that is explicitly focused on the individual needs of the patient. A clear diagnosis usually also allows a better assessment of the risks of recurrence in the family and possibly enables prenatal testing in relatives. Finally, it enables research and a better scientific understanding of the underlying pathophysiology, which may ideally lead to the identification of novel therapeutic prospects. Seven years ago, an international consensus statement endorsed the replacement of classic cytogenetic karyotype analysis by chromosomal microarrays as a first-tier diagnostic test in individuals with developmental disabilities or congenital anomalies. The studies add to the growing evidence that this consensus may already be outdated, as high-throughput sequencing techniques may achieve even higher diagnostic yields and, thus, are capable to become the new first-tier diagnostic test in congenital and early-onset disorders.
Johannes R. Lemke, MD, is with the Institute of Human Genetics at the University of Leipzig (Germany) Hospitals and Clinics. He reports no conflicts of interest associated with his editorial, which accompanied the JAMA Pediatrics reports (JAMA Pediatr. 2017 July 31. doi: 10.1001/jamapediatrics.2017.1743).
The studies by Tan et al. and Berg et al. demonstrate the dramatic effect of the diagnostic yield of different genetic testing approaches on cost-effectiveness and the potential design of testing strategies in children with suspected monogenic conditions. Both studies emphasize the effect of the results of genetic testing. Whereas Tan et al. showed that, in 26% of cases, the result enabled a specific modification of patient care, Berg et al. also demonstrated that there is no basis for identifying optimal, targeted treatments, when testing is not performed and genetic diagnoses are not made.
However, in the absence of targeted treatments, a genetic diagnosis is of high value for the patients, their families, and treating physicians. A clear diagnosis may not only be of prognostic value but also put an end to a possibly stressful and demanding diagnostic odyssey. It may enable patient care that is explicitly focused on the individual needs of the patient. A clear diagnosis usually also allows a better assessment of the risks of recurrence in the family and possibly enables prenatal testing in relatives. Finally, it enables research and a better scientific understanding of the underlying pathophysiology, which may ideally lead to the identification of novel therapeutic prospects. Seven years ago, an international consensus statement endorsed the replacement of classic cytogenetic karyotype analysis by chromosomal microarrays as a first-tier diagnostic test in individuals with developmental disabilities or congenital anomalies. The studies add to the growing evidence that this consensus may already be outdated, as high-throughput sequencing techniques may achieve even higher diagnostic yields and, thus, are capable to become the new first-tier diagnostic test in congenital and early-onset disorders.
Johannes R. Lemke, MD, is with the Institute of Human Genetics at the University of Leipzig (Germany) Hospitals and Clinics. He reports no conflicts of interest associated with his editorial, which accompanied the JAMA Pediatrics reports (JAMA Pediatr. 2017 July 31. doi: 10.1001/jamapediatrics.2017.1743).
Results from two new studies suggest that genetic testing early in the diagnostic pathway may allow for earlier and more precise diagnoses in early-life epilepsies and a range of other childhood-onset disorders, and potentially limit costs associated with a long diagnostic course.
Both papers, published online July 31 in JAMA Pediatrics, showed the diagnostic yield of genetic testing approaches, including whole-exome sequencing (WES), to be high.
The results also argue for the incorporation of genetic testing into the first diagnostic assessments; not limiting it to severe presentations only; and for broad testing methods to be employed in lieu of narrower ones.
Of these patients, just under half (n = 327) underwent various forms of genetic testing at the discretion of the treating physician, including karyotyping, microarrays, epilepsy gene panels, WES, mitochondrial panels, and other tests. Pathogenic variants were discovered in 132 children, or 40% of those receiving genetic testing (JAMA Pediatr. 2017 July 31. doi: 10.1001/jamapediatrics.2017.1743).
Of all the genetic testing methods employed in the study, diagnostic yields were significantly greater for epilepsy gene panels (29.2%) and WES (27.8%), compared with chromosome microarray (7.9%).
The results, the investigators said, provide “added impetus to move the diagnosis of the specific cause to the point of initial presentation ... it is time to provide greater emphasis on and support for thorough genetic evaluations, particularly sequencing-based evaluations, for children with newly presenting epilepsies in the first few years of life.”
In addition to aiding management decisions, early genetic testing “ends the diagnostic odyssey during which parents and physicians spend untold amounts of time searching for an explanation for a child’s epilepsy and reduces associated costs,” Dr. Berg and her colleagues concluded.
In a separate study led by Tiong Yang Tan, MBBS, PhD, of Victorian Clinical Genetics Services in Melbourne, Australia, and his colleagues, singleton WES was used in 44 children recruited at outpatient clinics of a Melbourne hospital system (JAMA Pediatr. 2017 July 31. doi: 10.1001/jamapediatrics.2017.1755).
Children in the study were aged 2-18 years (with mean age at presentation 28 months) and had a wide variety of suspected genetic disorders, including skeletal, skin, neurometabolic, and intellectual disorders. Some of these had features overlapping several conditions. The children in the cohort had not received prior genetic testing before undergoing WES.
The molecular test resulted in a diagnosis in 52% (n = 23) of the children, including unexpected diagnoses in eight of these. Clinical management was altered as result of sequencing findings in six children.
“Although phenotyping is critical, 35% of children had a diagnosis caused by a gene outside the initially prioritized gene list. This finding not only possibly reflects lack of clinical recognition but also underscores the utility of WES in achieving a diagnosis even when the a priori hypothesis is imprecise,” Dr. Tan and his associates wrote in their analysis.
Dr. Tan and his colleagues conducted a cost analysis that found WES performed at initial tertiary presentation resulted in a cost savings of U.S. $6,838 per additional diagnosis (95% confidence interval, U.S. $3,263-$11,678), compared with the standard diagnostic pathway. The figures reflect costs in an Australian care setting.
The children in the study had a mean diagnostic odyssey of 6 years, including a mean of 19 tests and four clinical genetics and four non–genetics specialist consultations. A quarter of them had undergone at least one diagnostic procedure under general anesthesia.
“The diagnostic odyssey of children suspected of having monogenic disorders is protracted and painful and may not provide a precise diagnosis,” Dr. Tan and his colleagues wrote in their analysis. “This paradigm has markedly shifted with the advent of WES.”
WES is best targeted to children “with genetically heterogeneous disorders or features overlapping several conditions,” the investigators concluded. “Our findings suggest that these children are best served by early recognition by their pediatrician and expedited referral to clinical genetics with WES applied after chromosomal microarray but before an extensive diagnostic process.”
Dr. Tan and his colleagues’ study was funded by the Melbourne Genomics Health Alliance and state and national governments in Australia. None of the authors declared conflicts of interest. Dr. Berg and her colleagues’ study was funded by the Pediatric Epilepsy Research Foundation, and none of its authors disclosed commercial conflicts of interest.
Results from two new studies suggest that genetic testing early in the diagnostic pathway may allow for earlier and more precise diagnoses in early-life epilepsies and a range of other childhood-onset disorders, and potentially limit costs associated with a long diagnostic course.
Both papers, published online July 31 in JAMA Pediatrics, showed the diagnostic yield of genetic testing approaches, including whole-exome sequencing (WES), to be high.
The results also argue for the incorporation of genetic testing into the first diagnostic assessments; not limiting it to severe presentations only; and for broad testing methods to be employed in lieu of narrower ones.
Of these patients, just under half (n = 327) underwent various forms of genetic testing at the discretion of the treating physician, including karyotyping, microarrays, epilepsy gene panels, WES, mitochondrial panels, and other tests. Pathogenic variants were discovered in 132 children, or 40% of those receiving genetic testing (JAMA Pediatr. 2017 July 31. doi: 10.1001/jamapediatrics.2017.1743).
Of all the genetic testing methods employed in the study, diagnostic yields were significantly greater for epilepsy gene panels (29.2%) and WES (27.8%), compared with chromosome microarray (7.9%).
The results, the investigators said, provide “added impetus to move the diagnosis of the specific cause to the point of initial presentation ... it is time to provide greater emphasis on and support for thorough genetic evaluations, particularly sequencing-based evaluations, for children with newly presenting epilepsies in the first few years of life.”
In addition to aiding management decisions, early genetic testing “ends the diagnostic odyssey during which parents and physicians spend untold amounts of time searching for an explanation for a child’s epilepsy and reduces associated costs,” Dr. Berg and her colleagues concluded.
In a separate study led by Tiong Yang Tan, MBBS, PhD, of Victorian Clinical Genetics Services in Melbourne, Australia, and his colleagues, singleton WES was used in 44 children recruited at outpatient clinics of a Melbourne hospital system (JAMA Pediatr. 2017 July 31. doi: 10.1001/jamapediatrics.2017.1755).
Children in the study were aged 2-18 years (with mean age at presentation 28 months) and had a wide variety of suspected genetic disorders, including skeletal, skin, neurometabolic, and intellectual disorders. Some of these had features overlapping several conditions. The children in the cohort had not received prior genetic testing before undergoing WES.
The molecular test resulted in a diagnosis in 52% (n = 23) of the children, including unexpected diagnoses in eight of these. Clinical management was altered as result of sequencing findings in six children.
“Although phenotyping is critical, 35% of children had a diagnosis caused by a gene outside the initially prioritized gene list. This finding not only possibly reflects lack of clinical recognition but also underscores the utility of WES in achieving a diagnosis even when the a priori hypothesis is imprecise,” Dr. Tan and his associates wrote in their analysis.
Dr. Tan and his colleagues conducted a cost analysis that found WES performed at initial tertiary presentation resulted in a cost savings of U.S. $6,838 per additional diagnosis (95% confidence interval, U.S. $3,263-$11,678), compared with the standard diagnostic pathway. The figures reflect costs in an Australian care setting.
The children in the study had a mean diagnostic odyssey of 6 years, including a mean of 19 tests and four clinical genetics and four non–genetics specialist consultations. A quarter of them had undergone at least one diagnostic procedure under general anesthesia.
“The diagnostic odyssey of children suspected of having monogenic disorders is protracted and painful and may not provide a precise diagnosis,” Dr. Tan and his colleagues wrote in their analysis. “This paradigm has markedly shifted with the advent of WES.”
WES is best targeted to children “with genetically heterogeneous disorders or features overlapping several conditions,” the investigators concluded. “Our findings suggest that these children are best served by early recognition by their pediatrician and expedited referral to clinical genetics with WES applied after chromosomal microarray but before an extensive diagnostic process.”
Dr. Tan and his colleagues’ study was funded by the Melbourne Genomics Health Alliance and state and national governments in Australia. None of the authors declared conflicts of interest. Dr. Berg and her colleagues’ study was funded by the Pediatric Epilepsy Research Foundation, and none of its authors disclosed commercial conflicts of interest.
FROM JAMA PEDIATRICS