EGA00190GenomicsArray Comparative Genomic HybridizationdbGaPEGA study phs000205.v4.p2http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000205.v4.p2EGArestrictedhttps://ega-archive.org/studies/phs000205.v4.p2<h4>Purpose</h4>Array comparative genomic hybridization is rapidly becoming an integral part of cytogenetic diagnostics. We report the design, validation, and clinical utility of an oligonucleotide array which combines genome-wide coverage with targeted enhancement at known clinically relevant regions.<h4>Methods</h4>Probes were placed every 75 kb across the entire euchromatic genome to establish a chromosomal "backbone" with a resolution of approximately 500 kb, which is increased to approximately 50 kb in targeted regions.<h4>Results</h4>For validation, 30 samples showed 100% concordance with previous G-banding and/or fluorescence in situ hybridization results. Prospective array analysis of 211 clinical samples identified 33 (15.6%) cases with clinically significant abnormalities. Of these, 23 (10.9%) were detected by the "targeted" coverage and 10 (4.7%) by the genome-wide coverage (average size of 3.7 Mb). All abnormalities were verified by fluorescence in situ hybridization, using commercially available or homebrew probes using the 32K bacterial artificial chromosome set. Four (1.9%) cases had previously reported imbalances of uncertain clinical significance. Five (2.4%) cases required parental studies for interpretation and all were benign familial variants.<h4>Conclusions</h4>Our results highlight the enhanced diagnostic utility of a genome-wide plus targeted array design, as the use of only a targeted array would have failed to detect 4.7% of the clinically relevant imbalances.Copy number variants (CNVs) have a major role in the etiology of autism spectrum disorders (ASD), and several of these have reached statistical significance in case-control analyses. Nevertheless, current ASD cohorts are not large enough to detect very rare CNVs that may be causative or contributory (that is, risk alleles). Here, we use a tiered approach, in which clinically significant CNVs are first identified in large clinical cohorts of neurodevelopmental disorders (including but not specific to ASD), after which these CNVs are then systematically identified within well-characterized ASD cohorts. We focused our initial analysis on 48 recurrent CNVs (segmental duplication-mediated 'hotspots') from 24 loci in 31 516 published clinical cases with neurodevelopmental disorders and 13 696 published controls, which yielded a total of 19 deletion CNVs and 11 duplication CNVs that reached statistical significance. We then investigated the overlap of these 30 CNVs in a combined sample of 3955 well-characterized ASD cases from three published studies. We identified 73 deleterious recurrent CNVs, including 36 deletions from 11 loci and 37 duplications from seven loci, for a frequency of 1 in 54; had we considered the ASD cohorts alone, only 58 CNVs from eight loci (24 deletions from three loci and 34 duplications from five loci) would have reached statistical significance. In conclusion, until there are sufficiently large ASD research cohorts with enough power to detect very rare causative or contributory CNVs, data from larger clinical cohorts can be used to infer the likely clinical significance of CNVs in ASD.Whole-genome analysis, now including whole-genome sequencing, is moving rapidly into the clinical setting, leading to detection of human variation on a broader scale than ever before. Interpreting this information will depend on the availability of thorough and accurate phenotype information, and the ability to curate, store, and access data on genotype-phenotype relationships. This idea has already been demonstrated within the context of chromosomal microarray (CMA) testing. The International Standards for Cytogenomic Arrays (ISCA) Consortium promotes standardization of variant interpretation for this technology through its initiatives, including the formation of a publicly available database housing clinical CMA data. Recognizing that phenotypic data are essential for the interpretation of genomic variants, the ISCA Consortium has developed tools to facilitate the collection of these data and its deposition in a standardized structured format within the ISCA Consortium database. This rich source of phenotypic data can also be used within broader applications such as developing phenotypic profiles of emerging genomic disorders, identification of candidate regions for particular phenotypes, or creation of tools for use in clinical practice. We summarize the ISCA experience as a model for ongoing efforts incorporating phenotype data with genotype data to improve the quality of research and clinical care in human genetics.The evidence-based review (EBR) process has been widely used to develop standards for medical decision-making and to explore complex clinical questions. This approach can be applied to genetic tests, such as chromosomal microarrays, in order to assist in the clinical interpretation of certain copy number variants (CNVs), particularly those that are rare, and guide array design for optimal clinical utility. To address these issues, the International Standards for Cytogenomic Arrays Consortium has established an EBR Work Group charged with building a framework to systematically assess the potential clinical relevance of CNVs throughout the genome. This group has developed a rating system enumerating the evidence supporting or refuting dosage sensitivity for individual genes and regions that considers the following criteria: number of causative mutations reported; patterns of inheritance; consistency of phenotype; evidence from large-scale case-control studies; mutational mechanisms; data from public genome variation databases; and expert consensus opinion. The system is designed to be dynamic in nature, with regions being reevaluated periodically to incorporate emerging evidence. The evidence collected will be displayed within a publically available database, and can be used in part to inform clinical laboratory CNV interpretations as well as to guide array design.Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype ( approximately 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.The International Standards for Cytogenomic Arrays (ISCA) Consortium is a worldwide collaborative effort dedicated to optimizing patient care by improving the quality of chromosomal microarray testing. The primary effort of the ISCA Consortium has been the development of a database of copy number variants (CNVs) identified during the course of clinical microarray testing. This database is a powerful resource for clinicians, laboratories, and researchers, and can be utilized for a variety of applications, such as facilitating standardized interpretations of certain CNVs across laboratories or providing phenotypic information for counseling purposes when published data is sparse. A recognized limitation to the clinical utility of this database, however, is the quality of clinical information available for each patient. Clinical genetic counselors are uniquely suited to facilitate the communication of this information to the laboratory by virtue of their existing clinical responsibilities, case management skills, and appreciation of the evolving nature of scientific knowledge. We intend to highlight the critical role that genetic counselors play in ensuring optimal patient care through contributing to the clinical utility of the ISCA Consortium's database, as well as the quality of individual patient microarray reports provided by contributing laboratories. Current tools, paper and electronic forms, created to maximize this collaboration are shared. In addition to making a professional commitment to providing complete clinical information, genetic counselors are invited to become ISCA members and to become involved in the discussions and initiatives within the Consortium.Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.<h4>Purpose</h4>Copy number variants have emerged as a major cause of human disease such as autism and intellectual disabilities. Because copy number variants are common in normal individuals, determining the functional and clinical significance of rare copy number variants in patients remains challenging. The adoption of whole-genome chromosomal microarray analysis as a first-tier diagnostic test for individuals with unexplained developmental disabilities provides a unique opportunity to obtain large copy number variant datasets generated through routine patient care.<h4>Methods</h4>A consortium of diagnostic laboratories was established (the International Standards for Cytogenomic Arrays consortium) to share copy number variant and phenotypic data in a central, public database. We present the largest copy number variant case-control study to date comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing our initial analysis on recurrent deletions and duplications involving 14 copy number variant regions.<h4>Results</h4>Compared with controls, 14 deletions and seven duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic.<h4>Conclusion</h4>Given the rapid expansion of clinical chromosomal microarray analysis testing, very large datasets will be available to determine the functional significance of increasingly rare copy number variants. This data will provide an evidence-based guide to clinicians across many disciplines involved in the diagnosis, management, and care of these patients and their families.Phenotypic information in genomic variant databases enhances clinical care and research: the International Standards for Cytogenomic Arrays Consortium experience.Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts.An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities.Enhanced detection of clinically relevant genomic imbalances using a targeted plus whole genome oligonucleotide microarray.Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies.Towards an evidence-based process for the clinical interpretation of copy number variation.Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.The laboratory-clinician team: a professional call to action to improve communication and collaboration for optimal patient care in chromosomal microarray testing.Miller David T DT, Adam Margaret P MP, Aradhya Swaroop S, Biesecker Leslie G LG, Brothman Arthur R AR, Carter Nigel P NP, Church Deanna M DM, Crolla John A JA, Eichler Evan E EE, Epstein Charles J CJ, Faucett W Andrew WA, Feuk Lars L, Friedman Jan M JM, Hamosh Ada A, Jackson Laird L, Kaminsky Erin B EB, Kok Klaas K, Krantz Ian D ID, Kuhn Robert M RM, Lee Charles C, Ostell James M JM, Rosenberg Carla C, Scherer Stephen W SW, Spinner Nancy B NB, Stavropoulos Dimitri J DJ, Tepperberg James H JH, Thorland Erik C EC, Vermeesch Joris R JR, Waggoner Darrel J DJ, Watson Michael S MS, Martin Christa Lese CL, Ledbetter David H DHMoreno-De-Luca D D, Sanders S J SJ, Willsey A J AJ, Mulle J G JG, Lowe J K JK, Geschwind D H DH, State M W MW, Martin C L CL, Ledbetter D H DHRiggs E R ER, Church D M DM, Hanson K K, Horner V L VL, Kaminsky E B EB, Kuhn R M RM, Wain K E KE, Williams E S ES, Aradhya S S, Kearney H M HM, Ledbetter D H DH, South S T ST, Thorland E C EC, Martin C L CLWain Karen E KE, Riggs Erin E, Hanson Karen K, Savage Melissa M, Riethmaier Darlene D, Muirhead Andrea A, Mitchell Elyse E, Packard Bethanny Smith BS, Faucett W Andrew WAKaminsky Erin B EB, Kaul Vineith V, Paschall Justin J, Church Deanna M DM, Bunke Brian B, Kunig Dawn D, Moreno-De-Luca Daniel D, Moreno-De-Luca Andres A, Mulle Jennifer G JG, Warren Stephen T ST, Richard Gabriele G, Compton John G JG, Fuller Amy E AE, Gliem Troy J TJ, Huang Shuwen S, Collinson Morag N MN, Beal Sarah J SJ, Ackley Todd T, Pickering Diane L DL, Golden Denae M DM, Aston Emily E, Whitby Heidi H, Shetty Shashirekha S, Rossi Michael R MR, Rudd M Katharine MK, South Sarah T ST, Brothman Arthur R AR, Sanger Warren G WG, Iyer Ramaswamy K RK, Crolla John A JA, Thorland Erik C EC, Aradhya Swaroop S, Ledbetter David H DH, Martin Christa L CLBaldwin Erin L EL, Lee Ji-Yun JY, Blake Douglas M DM, Bunke Brian P BP, Alexander Chad R CR, Kogan Amy L AL, Ledbetter David H DH, Martin Christa L CLRiggs Erin Rooney ER, Jackson Laird L, Miller David T DT, Van Vooren Steven SMoreno-De-Luca Daniel D, Mulle Jennifer G JG, Kaminsky Erin B EB, Sanders Stephan J SJ, Myers Scott M SM, Adam Margaret P MP, Pakula Amy T AT, Eisenhauer Nancy J NJ, Uhas Kim K, Weik LuAnn L, Guy Lisa L, Care Melanie E ME, Morel Chantal F CF, Boni Charlotte C, Salbert Bonnie Anne BA, Chandrareddy Ashadeep A, Demmer Laurie A LA, Chow Eva W C EW, Surti Urvashi U, Aradhya Swaroop S, Pickering Diane L DL, Golden Denae M DM, Sanger Warren G WG, Aston Emily E, Brothman Arthur R AR, Gliem Troy J TJ, Thorland Erik C EC, Ackley Todd T, Iyer Ram R, Huang Shuwen S, Barber John C JC, Crolla John A JA, Warren Stephen T ST, Martin Christa L CL, Ledbetter David H DHMental and motor retardation, projections, malignant Growth, Comparative Genome, Disorders, Activity, Laboratory, autism (disease), Kanner's Syndrome, Intellectual Disabilities, Addresses, Poor school performance, Mental-retardation, composed of, cares, childhood autism, Genetic Predictive Testing, Motor and developmental delay, Child Development Deviations, Research Activity, infantile autism, Laboratory Research, 2310040B03Rik, Autisms, Priorities, Developmental Disabilities, Multicase, Retarded development, Retardation, Predictive Genetic, Genetic Predisposition, Disabilities, Child Development Disorders, global, Genomes, Chip, ChIP, Early Infantile Autism, Comparative Genomics, neoplasm (disease), Delayed milestones, Dull intelligence, CHIP, Developmental delay in early childhood, composition, Intellectual, number of, benign, Child Development, free, CA, Delayed intellectual development, Retarded psychomotor development, genetic, chip, Developmental retardation, Genome Hybridization, malignant neoplasm, papilla, comparative genomic hybridization, Comparative Genomic Hybridizations, AW046544, Autism, For Children, Retardations, Research Priority, Motormental retardation, CHILD DEVELOPMENT DIS, Development Deviations, Genetic Predictive, Genetic Testing, Intellectual Development Disorder, malignancy, Genomics, Array-Based Comparative Genomic Hybridization, l(2)k04405, Developmental Delay Disorders, anatomical protrusion, Hybridization, PubMed, Developmental delay, Comparative, Arts, familial, lamina, flanges, Research Priorities, Infantile, extra or missing physical or functional parts, Functional Genomics, Hybridizations, nonspecific, Development Disorders, Genetic Screenings, results, Psychosocial Mental Retardations, DEVELOPMENT DIS CHILD, Autistic Disorder, Screenings, Delayed developmental milestones, Delayed development, organ system cancer, shelf, laboratory, Kids' Page, Early, Deviation, SDCCAG7, Intellectual Development Disorders, Developmental, Research and Development, Industrial, dLdb, Industrial Arts, Review, Predisposition Testing, Mental retardation, content, shelves, Array Based Comparative Genomic Hybridization, Disability, Nonprogressive intellectual disability, Child Development Deviation, common, Informal., projection, ridge, Activities, Psychomotor developmental delay, Comparative Genomic, Patient, spine, Genome Hybridizations, Autistic disorder of childhood onset (disorder), Development Disorder, microarray, inherited genetic, Mental deficiency, Review of Reported Cases, Mental Retardations, Intellectual Development, cancer, Gruppe, HSPABP2, Mental, criteria, Development Deviation, lamellae, cell type cancer, 2210017D18Rik, dCHIP, Deficiencies, number, Intellectual disability, SCAR16, guidelines, presence, process of organ, Child, protrusion, lamella, Developmental Disability, DmelCG5203, Structural, Infantile autism (disorder), Array Comparative Genomic Hybridization, heredity, Care, Infantile Autism, Functional, Screening, Early Infantile, Psychomotor development failure, susceptiblity to, neoplasm, malignant tumour, care, Kanner Syndrome, Informal care, NY-CO-7, Mental Retardation, Genetic, Academic, Research, Low intelligence, ridges, chromosomal comparative genomic hybridization, Psychomotor delay, Kanner's, grupos, Retarded mental development, Disorder, DmelCG3924, Syndrome, has or lacks parts of type, Development and Research, UBOX1, Predictive, 0610033N24Rik, constitutitional genetic, laminae, Lack of psychomotor development, data, grupo, bead, Genomic Hybridizations, malignant, Mental Deficiencies, anatomical process, CG5203, Predictive Testing, Idiocy, Comparative Genome Hybridization, compositionality, l(2)04405, Genetic Screening, autism spectrum disorder, group, Testing, Psychosocial Mental, mereological quality, count in organism, Priority, Psychosocial Mental Retardation, MT, Review Literature, Cognitive delay, malignant neoplasm (disease), Research Activities, Kanners Syndrome, sequence, Infantile psychosis (disorder), genotype profiling, Comparative Genome Hybridizations, flange, organ process, Data Base, Predictive Genetic Testing, Delayed cognitive development, developmental disability, primary cancer, autistic disorder, Cytogenetic, Child Development Disorder, Ldb, LDB, Kanner's syndrome, Autistic, Rest, DEVELOPMENTAL DELAY DIS, Nonprogressive mental retardation, Informal cares, CG3924, Developmental Delay Disorder, CHILD DEVELOPMENT DIS SPECIFIC, malignant tumor, primary structure of sequence macromolecule, Genetic Predisposition Testing, Psychosocial, processes, process, Deficiency, dLDB/Chip, Mental Deficiency, autistic disorder of childhood onset, malignant neoplastic disease, Genomic Hybridization, Specific, Psychomotor development deficiency, autism, structure, cardinality, Delayed psychomotor development, processus, Structural Genomics, quantitative, Informal, hereditary, groupe, presence or absence in organism, SNP analysisResearch and Development, Activities, Priorities, Priority, criteria, Activity, Research, Laboratory, Research Activities, Research Priorities, Development and Research, Research Priority, Research Activity, variable, Laboratory Research, guidelines.criteria, guidelines.postcranial axial skeleton, Backbone, Comparative Genome, IPP2A2, Procedures, spinal column, determination, axial skeleton, columna vertebralis, broad, congenital defects, supernumerary, aplasia, PHAPII, 5730420M11Rik, Techniques, vertebral region, template-activating factor I, Array Comparative Genomic Hybridization, Method, Studies, In Situ, defects, Technique, vertebral column skeleton, Aggravating interaction, in situ hybridization, Normalities, average, increased, SET, Genomes, Spinal column, TAF-I, phosphatase 2A inhibitor I2PP2A, ipp2a2, hypoplasia, 2pp2a, Hybridization in Situ, procedures, chromosomal comparative genomic hybridization, benign, backbone, CG10574, ISH, DmelCG4299, genetic, Study, set, IGAAD, Genome Hybridization, 2PP2A, Methodological Studies, DmelCG10574, taf-ibeta, comparative genomic hybridization, Comparative Genomic Hybridizations, dSET, dSet, In Situ Hybridizations, constitutitional genetic, phapii, Spine, Array-Based Comparative Genomic Hybridization, wide/broad, Genomic Hybridizations, Hybridization, Comparative, igaad, familial, StF-IT-1, Comparative Genome Hybridization, Normalcy, Procedure, Oligonucleotide, Hybridizations, results, deformities, microarray., I-2PP2A, <new synonym>, agenesis, dorsal spine, chemical analysis, Dm I-2, I2PP2A, techniques, Comparative Genome Hybridizations, Artificial, atresia, Cytogenetic, HLA-DR-associated protein II, DI-2, Normality, increased number, I-2Dm, Array Based Comparative Genomic Hybridization, malformations, Artificial Chromosomes, Methodological, CG4299, inhibitor of granzyme A-activated DNase, Methodological Study, I-2PP1, present in greater numbers in organism, dSET/TAF-Ibeta, wide, Health, 2610030F17Rik, Comparative Genomic, TAF-IBETA, Chromosome, spine, Genomic Hybridization, birth defects, anomalies, Genome Hybridizations, microarray, TAF-Ibeta, inherited genetic, assay, AA407739, i2pp2a, hereditary, Artificial Chromosome, vertebral column, accessory, methodology19falseInternational Standards for Cytogenomic Arrays<p>The International Standards for Cytogenomic Arrays (ISCA) Consortium is a rapidly growing group of clinical cytogenetics and molecular genetics laboratories committed to improving quality of patient care related to clinical genetic testing using new molecular cytogenetic technologies including array comparative genomic hybridization (aCGH) and quantitative SNP analysis by microarrays or bead chip technology.</p> <p>Efforts of the Consortium include:</p> <p><b>Clinical Utility:</b> The ISCA Consortium has made recommendations regarding the appropriate clinical indications for cytogenetic array testing (Miller et al. AJHG 2010, PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/20466091" target="_blank">20466091</a>). Currently, discussions are focused on pediatric applications for children with unexplained developmental delay, intellectual disability, autism and other developmental disabilities. A separate committee has been developed to address appropriate cancer genetic applications (<a href="http://www.urmc.rochester.edu/ccmc/" target="_blank">http://www.urmc.rochester.edu/ccmc/</a>).</p> <p><b>Evidence-based standards for cytogenomic array design:</b> The Consortium will develop recommendations for standards for the design, resolution and content of cytogenomic arrays using an evidence-based process and an international panel of experts in clinical genetics, clinical laboratory genetics (cytogenetics and molecular genetics), genomics and bioinformatics. This design is intended to be platform and vendor-neutral (common denominator is genome sequence coordinates), and is a dynamic process with input from the broader genetics community and evidence-based review by the expert panel (a Steering Committee with international representation).</p> <p><b>Public Database for clinical and research community:</b> It is essential that a publicly available database be created and maintained for cytogenetic array data generated in clinical testing laboratories. This will be integrated into the current dbGaP database at NCBI/NIH and released through dbVar, and curated by a committee of clinical genetics laboratory experts. The very high quality of copy number data (i.e., deletions and duplications) coming from clinical laboratories combined with expert curation will produce an invaluable resource to the clinical and research communities.</p> <p><b>Standards for interpretation of cytogenetic array results:</b> Using the ISCA Database, along with other genomic and genetics databases, the Consortium will develop recommendations for the interpretation and reporting of pathogenic vs. benign copy number changes as well as imbalances of uncertain clinical significance.</p> <p><b>Membership</b> in the ISCA Consortium is open to all individuals and laboratories involved in cytogenetic array testing who are committed to free data sharing and to participation in a process to develop evidence-based standards and guidelines to improve patient care.</p> <p><b>ISCA is available through dbVar:</b><br/> <a href="http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd37" target="_blank">http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd37/</a><br/> <a href="http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd45" target="_blank">http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd45/</a> </p>
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