Author's Accepted Manuscript
Article Reviewed: Fraternal Twins with Autism, Severe Cognitive Deficit, and Epilepsy: Diagnostic Role of Chromosomal Microarray Analysis Jaime Imitola, MD, Diana Walleigh, MD, Carol E. Anderson, MD, Reena Jethva, MD, MBA, Karen S. Carvalho, MD, Agustin Legido, MD, PhD, MBA Divya S. Khurana, MD G. Bradley Schaefer MD, FAAP, FACMG www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S1071-9091(14)00050-3 http://dx.doi.org/10.1016/j.spen.2014.05.003 YSPEN497
To appear in: Semin Pediatr Neurol
Cite this article as: G. Bradley Schaefer MD, FAAP, FACMG, Article Reviewed: Fraternal Twins with Autism, Severe Cognitive Deficit, and Epilepsy: Diagnostic Role of Chromosomal Microarray Analysis Jaime Imitola, MD, Diana Walleigh, MD, Carol E. Anderson, MD, Reena Jethva, MD, MBA, Karen S. Carvalho, MD, Agustin Legido, MD, PhD, MBA Divya S. Khurana, MD, Semin Pediatr Neurol , http://dx.doi.org/10.1016/j.spen.2014.05.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Commentary for Seminars in Pediatric Neurology Submitted by: G. Bradley Schaefer, MD, FAAP, FACMG Professor of Genetics and Pediatrics Founding Director, Division of Medical Genetics University of Arkansas for Medical Sciences Committee for the Future Endowed Chair in Medical Genetics Arkansas Children's Hospital Section Chief, Division of Genetics and Metabolism Department of Pediatrics 1 Children's Way Slot 512‐22 Little Rock, AR 72202 Phone: 501/364‐2971 Facsimile: 501/364‐1564 email: [email protected] Article Reviewed:
Fraternal Twins with Autism, Severe Cognitive Deficit, and Epilepsy: Diagnostic Role of Chromosomal Microarray Analysis
Jaime Imitola, MD, * Diana Walleigh, MD, † Carol E. Anderson, MD, ‡ Reena Jethva, MD, MBA†‡, Karen S. Carvalho, MD†, Agustin Legido, MD, PhD, MBA † Divya S. Khurana, MD† This article by Dr. Imitola and colleagues reports a case of monozygotic twins with pathogenic copy number changes that include biallelic deletions of the Neurexin 1 (NRXN1) gene. This case wonderfully highlights several of the salient aspects of the genetic features of autism. First, it is worth emphasizing that autism is indeed a neurogenetic disorder. In fact the reported heritability of autism approaches 0.9 (90%). It is always important to emphasize this
fact to families, and to continue to advocate for timely and appropriate immunizations of all children – not hindered by the unsubstantiated fear of immunization-invoked autism. All patients and families with a diagnosis of autism should be offered a genetic evaluation. The current reported diagnostic yield of clinical genetic evaluation in autism is 3040%. While this is still a somewhat low yield, it is dramatically better than the 6-15% yield from less than a decade ago. Likewise, recent publications suggest that the application of newer testing technologies such as whole exome or whole genome sequencing will significantly increase this yield – potentially doubling it. Once a diagnosis of autism is made, a referral for an etiologic evaluation should be offered. The referring health care professional should be able to describe the details for the family including the process, the diagnostic yield, the cost and the risks / benefits of such evaluations. The patients reported in this paper had copy number changes detectable on chromosomal microarray (CMA). The authors suggest that “Chromosomal microarray analysis should be the clinical standard in all specialties for first tier genetic testing in autism spectrum disorders”. This is a fair and accurate statement. In fact, the American College of Medical Genetics” has published this same conclusion in their Policy and Procedures. CMA should be a first tier test for persons with autism. Using current evidence based data it is the highest yield test in the etiologic evaluation of autism with a positive rate of about 15%. As previously noted this may change as more information is collected and published on the yield of whole genome assessments. The deleted gene in these two patients was the Neurexin-1 gene. The protein product of this gene - as the authors note - is a “cell-adhesion protein forming a synaptic complex with neuroligin”. This gene and over a hundred others have been shown to have a direct etiologic relationship to autism. A quick review of this list highlights yet another important point; autism is
largely a disorder of the synapses. The vast majority of genes associated with autism are known to have a role in synaptic synthesis, function or regulation. Finally, the authors do a nice job of highlighting the genotype:phenotype relationships that can be inferred in this case. With continued advances in genetic testing technology, it is critical that all practitioners ordering genetic tests clearly understand these core concepts. Most importantly it should be emphasized that genotype does not ‘trump’ phenotype. Contrary to what some might surmise, whole genome approaches to testing do not obviate clinical assessment, but rather make it even more critical. Reference: Schaefer, G.B.; Mendelsohn, N.J. and the Professional Practice and Guidelines Committee of the American College of Medical Genetics. Clinical Genetics Evaluation in Identifying the Etiology of Autism Spectrum Disorders – Guidelines Update. Genet. Med. 15(5):399-407, 2013
Article Reviewed: Fraternal Twins with Autism, Severe Cognitive Deficit, and Epilepsy: Diagnostic Role of Chromosomal Microarray Analysis Jaime Imitola, MD, Diana Walleigh, MD, Carol E. Anderson, MD, Reena Jethva, MD, MBA, Karen S. Carvalho, MD, Agustin Legido, MD, PhD, MBA Divya S. Khurana, MD G. Bradley Schaefer MD, FAAP, FACMG www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S1071-9091(14)00050-3 http://dx.doi.org/10.1016/j.spen.2014.05.003 YSPEN497
To appear in: Semin Pediatr Neurol
Cite this article as: G. Bradley Schaefer MD, FAAP, FACMG, Article Reviewed: Fraternal Twins with Autism, Severe Cognitive Deficit, and Epilepsy: Diagnostic Role of Chromosomal Microarray Analysis Jaime Imitola, MD, Diana Walleigh, MD, Carol E. Anderson, MD, Reena Jethva, MD, MBA, Karen S. Carvalho, MD, Agustin Legido, MD, PhD, MBA Divya S. Khurana, MD, Semin Pediatr Neurol , http://dx.doi.org/10.1016/j.spen.2014.05.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Commentary for Seminars in Pediatric Neurology Submitted by: G. Bradley Schaefer, MD, FAAP, FACMG Professor of Genetics and Pediatrics Founding Director, Division of Medical Genetics University of Arkansas for Medical Sciences Committee for the Future Endowed Chair in Medical Genetics Arkansas Children's Hospital Section Chief, Division of Genetics and Metabolism Department of Pediatrics 1 Children's Way Slot 512‐22 Little Rock, AR 72202 Phone: 501/364‐2971 Facsimile: 501/364‐1564 email: [email protected] Article Reviewed:
Fraternal Twins with Autism, Severe Cognitive Deficit, and Epilepsy: Diagnostic Role of Chromosomal Microarray Analysis
Jaime Imitola, MD, * Diana Walleigh, MD, † Carol E. Anderson, MD, ‡ Reena Jethva, MD, MBA†‡, Karen S. Carvalho, MD†, Agustin Legido, MD, PhD, MBA † Divya S. Khurana, MD† This article by Dr. Imitola and colleagues reports a case of monozygotic twins with pathogenic copy number changes that include biallelic deletions of the Neurexin 1 (NRXN1) gene. This case wonderfully highlights several of the salient aspects of the genetic features of autism. First, it is worth emphasizing that autism is indeed a neurogenetic disorder. In fact the reported heritability of autism approaches 0.9 (90%). It is always important to emphasize this
fact to families, and to continue to advocate for timely and appropriate immunizations of all children – not hindered by the unsubstantiated fear of immunization-invoked autism. All patients and families with a diagnosis of autism should be offered a genetic evaluation. The current reported diagnostic yield of clinical genetic evaluation in autism is 3040%. While this is still a somewhat low yield, it is dramatically better than the 6-15% yield from less than a decade ago. Likewise, recent publications suggest that the application of newer testing technologies such as whole exome or whole genome sequencing will significantly increase this yield – potentially doubling it. Once a diagnosis of autism is made, a referral for an etiologic evaluation should be offered. The referring health care professional should be able to describe the details for the family including the process, the diagnostic yield, the cost and the risks / benefits of such evaluations. The patients reported in this paper had copy number changes detectable on chromosomal microarray (CMA). The authors suggest that “Chromosomal microarray analysis should be the clinical standard in all specialties for first tier genetic testing in autism spectrum disorders”. This is a fair and accurate statement. In fact, the American College of Medical Genetics” has published this same conclusion in their Policy and Procedures. CMA should be a first tier test for persons with autism. Using current evidence based data it is the highest yield test in the etiologic evaluation of autism with a positive rate of about 15%. As previously noted this may change as more information is collected and published on the yield of whole genome assessments. The deleted gene in these two patients was the Neurexin-1 gene. The protein product of this gene - as the authors note - is a “cell-adhesion protein forming a synaptic complex with neuroligin”. This gene and over a hundred others have been shown to have a direct etiologic relationship to autism. A quick review of this list highlights yet another important point; autism is
largely a disorder of the synapses. The vast majority of genes associated with autism are known to have a role in synaptic synthesis, function or regulation. Finally, the authors do a nice job of highlighting the genotype:phenotype relationships that can be inferred in this case. With continued advances in genetic testing technology, it is critical that all practitioners ordering genetic tests clearly understand these core concepts. Most importantly it should be emphasized that genotype does not ‘trump’ phenotype. Contrary to what some might surmise, whole genome approaches to testing do not obviate clinical assessment, but rather make it even more critical. Reference: Schaefer, G.B.; Mendelsohn, N.J. and the Professional Practice and Guidelines Committee of the American College of Medical Genetics. Clinical Genetics Evaluation in Identifying the Etiology of Autism Spectrum Disorders – Guidelines Update. Genet. Med. 15(5):399-407, 2013
