Array CGH as a first line diagnostic test in place of karyotyping for postnatal referrals - results from four years’ clinical application for over 8,700 patients

Ahn, Joo Wook; Bint, Susan; Bergbaum, Anne; Mann, Kathy; Hall, R. P.; Ogilvie, Caroline Mackie

doi:10.1186/1755-8166-6-16

Cited by 53 publications

(60 citation statements)

References 12 publications

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“…Furthermore, gene content was also evaluated using databases such as the NCBI Gene Database, GeneCards, and OMIM. CNVs were classified as described by Miller et al (2010) and were classified into 4 groups: I) causatives, when associated with known microdeletion/microduplication syndromes; II) probably causative, when the CNV was not previously associated with known microdeletion/microduplication syndromes, but contained genes known to cause a syndrome of a clear phenotype (Ahn et al, 2013) or because similar CNVs were already described in patients from other studies; III) noncausative (benign); IV) VOUS, variants of unknown clinical significance.…”

Section: Analysis and Cnv Classificationmentioning

confidence: 99%

Array-CGH analysis in patients with intellectual disability and/or congenital malformations in Brazil

et al. 2016

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ABSTRACT. In several patients, intellectual disability and/or congenital malformation may be attributed to chromosomal changes. In this study, we conducted an array-CGH test of 200 patients from the Northeast of Brazil with intellectual disability and/or congenital malformation. Blood samples were collected from the proband and from their parents when possible. DNA was extracted and investigated using the array-CGH test. Findings were evaluated for the pathogenicity in databases of benign and pathogenic changes (ISCA, UCSC, DGV, and DECIPHER). Forty-seven copy number variations (CNVs) were identified in 43/200 (21.5%) patients, including 25/98 (25.5%) in males and 22/102 (21.57%) in females. We considered 33 of these to be clinically significant, reaching a diagnosis rate of 16.5%. The sizes of the CNVs varied from 102 kb to 24 Mb in deletions and from 115 kb to 140 Mb in duplications. In 10/47 (21.3%) patients, the rearrangement involved a sex chromosome. Thirty-nine patients had one chromosomal aberration, while 2 concomitant abnormalities were detected in 4 patients. Ten of 47 CNVs (21.3%) were > 5Mb in size. Fifteen patients had CNVs related to known syndromes. This research highlights the contribution of submicroscopic chromosomal changes to the etiology of intellectual disability and/or congenital malformation, particularly the implication of chromosomal abnormalities detected using an array-CGH test, with a high rate of 16.5%. Thus, our results support the use of array-CGH replacing standard karyotype as the first-tier cytogenetic diagnostic test for patients with multiple congenital anomalies and/or intellectual disability.

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Section: Analysis and Cnv Classificationmentioning

confidence: 99%

Array-CGH analysis in patients with intellectual disability and/or congenital malformations in Brazil

et al. 2016

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“…Taking a practical focus, Ahn et al 72 reported on a study at Guy's and St. Thomas' NHS Foundation Trust in London using oligonucleotide aCGH as a first-line diagnostic test in place of karyotyping for postnatal referrals (ranging from neonatal congenital anomalies to adult neurodisabilities). Two-thirds of the patients tested with aCGH (8794/13,412) had this as their first-line test.…”

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confidence: 99%

“…For cases with completed inheritance studies (about 50% of the patients with imbalances), one-fifth of the imbalances were de novo. With regard to the potential limitations of aCGH, Ahn et al 72 point out that, despite the increase in resolution and the higher diagnostic yield associated with aCGH testing, there may be concern that, without visualisation of chromosomes by traditional cytogenetic techniques, balanced rearrangement will not be detected. These rearrangements may disrupt gene function without causing any loss of coding material and hence may be important diagnostically.…”

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confidence: 99%

A scoping study to explore the cost-effectiveness of next-generation sequencing compared with traditional genetic testing for the diagnosis of learning disabilities in children

Beale

Sanderson²,

Sanniti

et al. 2015

Health Technol Assess

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BackgroundLearning disability (LD) is a serious and lifelong condition characterised by the impairment of cognitive and adaptive skills. Some cases of LD with unidentified causes may be linked to genetic factors. Next-generation sequencing (NGS) techniques are new approaches to genetic testing that are expected to increase diagnostic yield.ObjectivesThis scoping study focused on the diagnosis of LD in children and the objectives were to describe current pathways that involve the use of genetic testing; collect stakeholder views on the changes in service provision that would need to be put in place before NGS could be used in clinical practice; describe the new systems and safeguards that would need to be put in place before NGS could be used in clinical practice; and explore the cost-effectiveness of using NGS compared with conventional genetic testing.MethodsA research advisory group was established. This group provided ongoing support by e-mail and telephone through the lifetime of the study and also contributed face-to-face through a workshop. A detailed review of published studies and reports was undertaken. In addition, information was collected through 33 semistructured interviews with key stakeholders.ResultsNGS techniques consist of targeted gene sequencing, whole-exome sequencing (WES) and whole-genome sequencing (WGS). Targeted gene panels, which are the least complex, are in their infancy in clinical settings. Some interviewees thought that during the next 3–5 years targeted gene panels would be superseded by WES. If NGS technologies were to be fully introduced into clinical practice in the future a number of factors would need to be overcome. The main resource-related issues pertaining to service provision are the need for additional computing capacity, more bioinformaticians, more genetic counsellors and also genetics-related training for the public and a wide range of staff. It is also considered that, as the number of children undergoing genetic testing increases, there will be an increase in demand for information and support for families. The main issues relating to systems and safeguards are giving informed consent, sharing unanticipated findings, developing ethical and other frameworks, equity of access, data protection, data storage and data sharing. There is little published evidence on the cost-effectiveness of NGS technologies. The major barriers to determining cost-effectiveness are the uncertainty around diagnostic yield, the heterogeneity of diagnostic pathways and the lack of information on the impact of a diagnosis on health care, social care, educational support needs and the wider family. Furthermore, as NGS techniques are currently being used only in research, costs and benefits to the NHS are unclear.ConclusionsNGS technologies are at an early stage of development and it is too soon to say whether they can offer value for money to the NHS as part of the LD diagnostic process. Substantial organisational changes, as well as new systems and safeguards, would be required if NGS technologies were to be introduced into NHS clinical practice. Considerable further research is required to establish whether using NGS technologies to diagnose learning disabilities is clinically effective and cost-effective.FundingThe National Institute for Health Research Health Technology Assessment programme.

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“…The resolution will depend on the specific platform used; the 5 oligonucleotide platform used at our centre has an 8x60K format, and a resolution across the 6 genome of approximately 120kb; this results in detection of imbalance in 25% of our patients 7 after exclusion of known benign CNV (Ahn et al 2013). However, approximately 40% of 8 these imbalances are small in size and of unknown clinical significance.…”

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confidence: 99%

A new direction for prenatal chromosome microarray testing: software-targeting for detection of clinically significant chromosome imbalance without equivocal findings

Ahn

Bint²,

Irving

et al. 2014

Preprint

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Purpose. To design and validate a prenatal chromosome microarray testing strategy that moves away from size-based detection thresholds, towards a more clinically relevant analysis, providing higher resolution than G-banded chromosomes but avoiding the detection of imbalances of unclear prognosis that cause parental anxiety.Methods. All prenatal samples fulfilling our criteria for karyotype analysis (n=342) were tested by chromosome microarray and only copy number variants of established deletion/duplication syndrome regions and any other imbalance >3Mb were detected and reported. A retrospective full-resolution analysis of 249 of these samples was carried out to ascertain the performance of this testing strategy.Results. Using our prenatal analysis, 23/342 (6.7%) samples were found to be abnormal. Of the remaining samples, 249 were anonymized and reanalyzed at full-resolution; a further 46 regions of imbalance were detected in 44 of these traces (17.7%). None of these additional imbalances were of clear clinical significance. Conclusion

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Array CGH as a first line diagnostic test in place of karyotyping for postnatal referrals - results from four years’ clinical application for over 8,700 patients

Cited by 53 publications

References 12 publications

Array-CGH analysis in patients with intellectual disability and/or congenital malformations in Brazil

Array-CGH analysis in patients with intellectual disability and/or congenital malformations in Brazil

A scoping study to explore the cost-effectiveness of next-generation sequencing compared with traditional genetic testing for the diagnosis of learning disabilities in children

A new direction for prenatal chromosome microarray testing: software-targeting for detection of clinically significant chromosome imbalance without equivocal findings

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