Clinical relevance of small copy-number variants in chromosomal microarray clinical testing

Hollenbeck, Dana; Williams, Crescenda L.; Drazba, Kathryn T.; Descartes, Maria; Korf, Bruce R.; Rutledge, S. Lane; Lose, Edward J.; Robin, Nathaniel H.; Carroll, Andrew J.; Mikhail, Fady M.

doi:10.1038/gim.2016.132

Cited by 25 publications

(24 citation statements)

References 40 publications

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“…The VOUS reporting rate (4.6%) in this study is consistent with that of other cohorts (4.2% and 4.8%) but higher than others (2.2% and 1.6%) . These differences may be due to platform designs, diverse reporting criteria such as size cutoff settings, choice and interpretation of targeted regions, as well as interpretation and reporting deviations between laboratories, especially in the category of uncertain results …”

Section: Discussioncontrasting

confidence: 49%

“…Further, using a high‐resolution platform with different size filter cutoffs yields extensive variations in detection (combination D and G, Table ). In addition, applying a platform of lower resolution but with smaller size filter cutoffs as used in the paper published by Hollenbeck et al, the detection did not critically decrease (Table ).…”

Section: Discussionmentioning

confidence: 93%

“…Underutilization of this setting may potentially contribute to a failure to detect clinically relevant CNVs. It is notable that a recent study demonstrated that 24 (44%) of 54 clinically relevant genes were located in the nontargeted genomic regions . In comparison, in our study, the majority of the identified microdeletions and microduplications were located in the targeted regions, except three microdeletions: 6.6‐kb homozygous microdeletion of the HSD17B4 gene (OMIM 601860); 80‐kb deletion involving the hemoglobin beta and delta genes, HBB (141900) and HBD (142000), and the 225‐kb deletion of the FANCB gene (300515).…”

Section: Discussionmentioning

confidence: 99%

“…A recent study demonstrated that clinically relevant CNVs of less than 500 kb could be potentially missed with these approaches in postnatal CMA analyses. In that study, 24 (44%) of 54 genes associated with single‐gene deletions were located in the nontargeted genomic regions; these included 24 with well‐characterized haploinsufficiency, 16 genes with evidence of dosage sensitivity, 1 gene with intragenic dominant‐negative deletion, 1 recessive gene, and 12 chromosome X‐linked Online Mendelian Inheritance in Man (OMIM) morbid genes . Thus, the platform design of targeted and nontargeted regions, as well as the size filter cutoff settings used for data analysis, can affect the detection of CNVs for prenatal CMA.…”

Section: Introductionmentioning

confidence: 99%

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Effects of platforms, size filter cutoffs, and targeted regions of cytogenomic microarray on detection of copy number variants and uniparental disomy in prenatal diagnosis: Results from 5026 pregnancies

et al. 2019

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Objective We evaluated the effects of platforms, size filter cutoffs, and targeted regions of cytogenomic microarray (CMA) on the detection of copy number variants (CNVs) and uniparental disomy (UPD) in prenatal diagnosis. Methods Five thousand twenty‐six consecutive prenatal specimens (>98% high‐risk pregnancy) were studied by high‐resolution CMA, with cutoffs of 50 kb for losses and 200 kb for gains in nontargeted regions and 20 kb for losses and 100 kb for gains in targeted regions. We assessed actual detection rates using the current assay as well as hypothetical detection rates using platforms with the same or lower resolution and smaller or larger cutoffs. Results The detection rate of our current assay was 11.2% (562 of 5026), including abnormal findings in 543 cases and likely pathogenic variants in 19. The hypothetical decrease in the overall detection of variants (excluding likely benign) and UPD ranged from 3.8% to 23.0%. For the subgroup of pathogenic and likely pathogenic CNVs < 1 Mb, the decrease of detection ranged from 2.7% to 24.3%. Conclusions These findings underscore the significant effects of chosen CMA platform, as well as size filter cutoffs and targeted regions used in data analysis, on detection of CNVs and UPDs in a cohort of prenatal cases.

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Section: Discussioncontrasting

confidence: 49%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of platforms, size filter cutoffs, and targeted regions of cytogenomic microarray on detection of copy number variants and uniparental disomy in prenatal diagnosis: Results from 5026 pregnancies

et al. 2019

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“…A total of 174 population‐based controls without cardiac lesions were drawn from the local database. Additional controls included the Wellcome Trust Case Control Consortium study (http://www.wtccc.org.uk/), DECIPHER (http://decipher.sanger.ac.uk/), the Database of Genomic Variants (DGV) (http://dgv.tcag.ca/dgv/app/home), the 1000 Genomes Project (http://www.1000genomes.org/), the DDD Controls Project (http://www.ddduk.org/), and previously published studies that used high‐density microarray platforms comparable with the ones used in this study …”

Section: Methodsmentioning

confidence: 99%

Clinical application of chromosomal microarray analysis for the prenatal diagnosis of chromosomal abnormalities and copy number variations in fetuses with congenital heart disease

et al. 2018

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Loss‐of‐function variants in NFIA provide further support that NFIA is a critical gene in 1p32‐p31 deletion syndrome: A four patient series

Revah‐Politi

Ganapathi

Bier

et al. 2017

American J of Med Genetics Pt A

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The association between 1p32-p31 contiguous gene deletions and a distinct phenotype that includes anomalies of the corpus callosum, ventriculomegaly, developmental delay, seizures, and dysmorphic features has been long recognized and described. Recently, the observation of overlapping phenotypes in patients with chromosome translocations that disrupt NFIA (Nuclear factor I/A), a gene within this deleted region, and NFIA intragenic deletions has led to the hypothesis that NFIA is a critical gene within this region. The wide application and increasing accessibility of whole exome sequencing (WES) has helped identify new cases to support this hypothesis. Here, we describe four patients with loss-of-function variants in the NFIA gene identified through WES. The clinical presentation of these patients significantly overlaps with the phenotype described in previously reported cases of 1p32-p31 deletion syndrome, NFIA gene disruptions and intragenic NFIA deletions. Our cohort includes a mother and daughter as well as an unrelated individual who share the same nonsense variant (c.205C>T, p.Arg69Ter; NM_001145512.1). We also report a patient with a frameshift NFIA variant (c.159_160dupCC, p.Gln54ProfsTer49). We have compared published cases of 1p32-p31 microdeletion syndrome, translocations resulting in NFIA gene disruption, intragenic deletions, and loss-of-function mutations (including our four patients) to reveal that abnormalities of the corpus callosum, ventriculomegaly/hydrocephalus, macrocephaly, Chiari I malformation, dysmorphic features, developmental delay, hypotonia, and urinary tract defects are common findings. The consistent overlap in clinical presentation provides further evidence of the critical role of NFIA haploinsufficiency in the development of the 1p32-p31 microdeletion syndrome phenotype.

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Clinical relevance of small copy-number variants in chromosomal microarray clinical testing

Abstract: Our study demonstrates the diagnostic clinical relevance of small, nonrecurrent CNVs <500 kb during CMA clinical testing and underscores the need for careful clinical interpretation of these CNVs.Genet Med 19 4, 377-385.

Cited by 25 publications

References 40 publications

Effects of platforms, size filter cutoffs, and targeted regions of cytogenomic microarray on detection of copy number variants and uniparental disomy in prenatal diagnosis: Results from 5026 pregnancies

Effects of platforms, size filter cutoffs, and targeted regions of cytogenomic microarray on detection of copy number variants and uniparental disomy in prenatal diagnosis: Results from 5026 pregnancies

Clinical application of chromosomal microarray analysis for the prenatal diagnosis of chromosomal abnormalities and copy number variations in fetuses with congenital heart disease

Loss‐of‐function variants in NFIA provide further support that NFIA is a critical gene in 1p32‐p31 deletion syndrome: A four patient series

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